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Consulter

ENDOBULINE®
GAMMAGARD®
KIOVIG®
OCTAGAM®
SANDOGLOBULINE®
SANDOGLOBULINE 120 mg/ml®
TEGELINE®
1
DENOMINATION COMMUNE INTERNATIONALE :
IMMUNOGLOBULINES IV
NOM COMMERCIAL :
ENDOBULINE®, GAMMAGARD®, KIOVIG®, OCTAGAM®, SANDOGLOBULINE®,
SANDOGLOBULINE 120MG/ML®, TEGELINE®
LABORATOIRES EXPLOITANTS OU TITULAIRES DE L’AMM :
BAXTER, OCTAPHARMA, CLB BEHRING, LFB BIOMÉDICAMENTS
Version : 1
Date : Janvier 2009
Date de révision :
Historique des modifications :
I.
Condition de prescription :
PH
Autorisation de Mise sur le Marché (AMM)
Cf Résumé des Caractéristiques du Produit (RCP)
II.
Situations temporairement acceptables
Protocoles thérapeutiques temporaires
• Myasthénie aiguë dans les phases de poussées
• Syndrome de Lambert-Eaton : formes auto-immunes non paranéoplasiques, sous réserve de l’avis d’un
centre de référence ou de compétence des maladies neuromusculaires.
• Myosites à inclusion avec dysphagie grave
• Polymyosite cortico-résistante en 2ème intention en cas d’échec, de dépendance, d’intolérance et de
contre-indication aux corticoïdes
• Syndrome de Miller-Fisher
• Syndrome de l’homme raide réfractaire aux anti-convulsivants ou insuffisamment contrôlés par les antiépileptiques
• Vascularites systémiques ANCA positives en cas de rechute ou de résistance à l'
association corticoïdes
et immunosuppresseurs
• Maladie de Willebrand acquise, notamment asscociée à une gammapathie monoclonale IgG (MGUS
IgG), en cas d’échec ou d’intolérance à la desmopressine et/ou aux concentrés de vWF
• Syndrome catastrophique des antiphospholipides en cas d’échec du traitement anticoagulant IV associé
à des corticostéroïdes en complément ou en alternative à la plasmaphérèse
• Dermatomyosite corticorésistante
• En 3ème intention dans le pemphigus après un traitement bien conduit en 1ère intention par des
corticoïdes et des immunosuppresseurs et en seconde intention par du rituximab
• Pemphigoïde cicatricielle avec atteinte muqueuse étendue ou atteinte ou atteinte oculaire ne répondant
à l’association bien conduite ou corticoïdes et immunosuppresseurs (3 à 6 mois
d’immunosuppresseurs) ou en cas d’intolérance à ces traitements
2
III.
Situations non acceptables
•
Neutropénie auto-immune
•
Echecs récidivants de FIV avec ou sans anticorps anti-phospholipides
•
Syndrome d’activation macrophagique (SAM) secondaire à une infection à EBV, SAM
dans le cadre d’un lupus en poussées (hors-infection), SAM associé à un cancer
notamment un lymphome
•
Prévention des infections chez le grand prématuré
L’utilisation aussi bien en préventif qu’en curatif des immunoglobulines polyspécifiques en substitution
aux immunoglobulines spécifiques anti-varicelle-zona ne relève pas d’un PTT. Il existe une
immunoglobuline spécifique anti-varicelle zona (Varitec®), qui dispose d’une autorisation temporaire
d’utilisation. Un PTT ne peut être envisagé pour pallier une éventuelle rupture d’approvisionnement.
3
Situation temporairement acceptable
Myasthénie aiguë dans les phases de poussées
1.
PROTOCOLE THERAPEUTIQUE TEMPORAIRE
Le protocole temporaire de traitement nécessite de se référer au Résumé des Caractéristiques du
Produit (RCP) de l’AMM. Il est nécessaire d’informer le patient que la prescription est faite hors-AMM
sous la responsabilité du médecin prescripteur.
Schéma d’administration
1 à 2 g/kg/cure
La dose est délivrée en 2 jours si la fonction rénale est normale et sur 5 jours pour les sujets à risque.
Les sujets à risque étant les insuffisants rénaux, les sujets âgés avec une hypovolémie et une
hyperviscosité, les sujets obèses et les patients sous médicaments néphrotoxiques.
Contre-indications
Ce médicament est contre-indiqué dans les situations suivantes :
· chez les patients présentant un déficit en IgA et avec des anticorps circulants anti-IgA (à l’exception
de Gammagard®);
· hypersensibilité connue à l'
un des constituants de la préparation
Sandoglobuline 120 mg/ml® contient de la L-isoleucine et de la L-proline en tant qu'
excipients et est
contre-indiqué chez les patients atteints de maladie des urines à odeur de sirop d'
érable et
d'
hyperprolinémie.
Sécurité d’emploi et mises en garde (cf RCP)
Certains effets indésirables peuvent être associés au débit d'
administration. Le débit recommandé doit
être scrupuleusement observé et les patients doivent rester sous surveillance pendant toute la durée
de la perfusion afin de détecter d'
éventuels signes d'
intolérance.
Le risque de réactions anaphylactiques, voire d'
état de choc, est plus fréquent :
· en cas de perfusion intraveineuse rapide,
· chez les patients hypo- ou agammaglobulinémiques, avec ou sans déficit en IgA,
· plus particulièrement lors de la première perfusion d'
IgIV, ou lorsque le dernier traitement par les IgIV
remonte à plus de 8 semaines.
Les vraies réponses allergiques à ce médicament sont rares. Une intolérance aux IgIV peut se
développer dans les très rares cas de déficit en IgA où le patient possède des anticorps anti-IgA.
Très rarement, les IgIV peuvent entraîner une chute brutale de la pression artérielle associée à une
réaction anaphylactique même chez des patients qui ont présenté une bonne tolérance à une
administration précédente d'
IgIV.
Les complications potentielles peuvent être souvent évitées ; il est souhaitable :
- de surveiller attentivement le débit des perfusions;
- de s'
assurer initialement de la tolérance de l'
administration des IgIV par une perfusion lente (0,5
ml/kg/h ( 0.5 ml/kg/h pour Sandoglobuline 120 mg/ml® et 1ml/kg/h maximum pour la Tégéline®)) ;
chez les patients ayant déjà reçu des IgIV, le débit sera adapté en fonction de la tolérance clinique,
sans dépasser 1 ml/kg/h (0.5ml/kg/h pour Sandoglobuline 120 mg/ml® et Kiovig®) pendant les 30
premières minutes en augmentant progressivement jusqu’à un maximum de 4 ml/kg/h (2ml/kg/h pour
Sandoglobuline 120 mg/ml® et 6ml/kg/h pour Kiovig® voire 8ml/kg/h chez les adultes atteints de
déficits immunitaires primitifs);
4
- de tenir compte de la teneur en glucose (1 g/g d’IgG Endobuline®, 0,43 g /g d'
IgG Gammagard®) et
en saccharose (1,67 g/g d’IgG Sandoglobuline® et 2g/g d’IgG Tégéline®), en cas de diabète latent où
une glycosurie passagère peut survenir, de diabète ou de régime hypoglucidique;
- de tenir compte de la présence de maltose (Octagam® contient du maltose) afin d’éviter tout rique
d’interférence et de surestimation de la glycémie pouvant conduire à un risque d’hypoglycémie grave
par perturbation de certains tests glycémiques, principalement ceux utilisant des réactifs contenant de
la GDH-PQQ (glucose déshydrogénase pyrroloquinoléine quinone);
- en cas de restriction hydrosodée, de tenir compte de la teneur en sodium, notamment Gammagard®
(3,4 mg/ml) et Tégéline® (0.8 mg/ml);
- de garder les patients sous observation pendant au moins 20 minutes après la fin de la perfusion afin
de détecter d'
intolérance. En cas de première perfusion d’IgIV, le patient doit être
maintenu sous observation pendant au moins 1 heure après la fin de la perfusion.
En cas de réactions de type allergique ou anaphylactique, il convient d’interrompre immédiatement la
perfusion. En cas de choc, le traitement symptomatique relatif à l’état de choc devra être instauré.
Le risque d'
accidents thrombotiques artériels et veineux est plus fréquent en cas de perfusion
intraveineuse rapide, plus particulièrement chez le sujet à risque vasculaire.
Des cas d'
insuffisance rénale aiguë ont été rapportés chez des patients recevant des IgIV. Dans la
plupart des cas, des facteurs de risque ont été identifiés, tels une insuffisance rénale pré-existante, un
diabète, un âge supérieur à 65 ans, une hypovolémie ou une obésité.
Chez ces patients, l'
administration d'
IgIV impose :
· une hydratation correcte avant l’administration d’IgIV,
· une surveillance de la diurèse,
· le dosage de la créatininémie,
· d’éviter d’associer des diurétiques de l’anse.
Bien que ces cas d'
insuffisance rénale aient été associés à l'
utilisation de nombreuses spécialités
d'
IgIV, celles contenant du saccharose comme stabilisant représentent la plus large part.
Aussi, chez les patients à risque, l'
utilisation de préparations d'
IgIV ne contenant pas de saccharose
doit être envisagée. Gammagard®, Octagam®, Kiovig® ne contiennent pas de saccharose.
En cas d’obésité définie par un IMC > ou = 30, la dose thérapeutique d’IgIV administrée en cas
d’immunomodulation doit être réduite pour éviter les complications aiguës soit en l’adaptant au poids
maigre calculé soit en la réduisant de 20%.
Traitement associé
Vaccins constitués de virus vivants atténués
L'
administration d’IgIV peut entraver l'
efficacité des vaccins constitués de virus vivants atténués tels
que les vaccins contre la rougeole, la rubéole, les oreillons et la varicelle. Après perfusion de ce
médicament, attendre au minimum 6 semaines (de préférence 3 mois) avant d'
administrer ce type de
vaccins.
Si le patient a reçu ce type de vaccins au cours des 2 semaines précédant la perfusion, un contrôle
des anticorps protecteurs post-vaccinaux peut être nécessaire en vue d'
un éventuel rappel.
Interférence avec des tests sérologiques
Après administration d'
IgIV, l'
augmentation transitoire de la concentration de divers anticorps
transférés peut être responsable de sérologies positives temporaires.
Ce médicament contenant des anticorps anti-érythrocytaires, son administration peut être suivie de
façon transitoire d'
un test de Coombs positif.
Grossesse et allaitement
Grossesse : Aucune étude de reproduction chez l'
animal n'
a été conduite avec les immunoglobulines
IV, et l'
expérience chez la femme enceinte est limitée. Bien qu'
aucune réaction indésirable sur le
fœtus et le nouveau-né n'
ait été observée, les IgIV ne doivent être administrées chez la femme
enceinte qu'
en cas de nécessité bien établie.
Allaitement : Les protéines contenues dans l’IgIV étant des constituants normaux du plasma humain,
leur passage dans le lait maternel ne doit pas provoquer d'
effets indésirables chez le nouveau-né.
5
Nous vous rappelons que tout effet indésirable grave ou inattendu doit être déclaré au Centre
Régional de Pharmacovigilance dont vous dépendez (coordonnées disponibles sur le site internet
www.afssaps.sante.fr ou sur les premières pages du Vidal).
• Ce protocole temporaire de traitement est limité à une durée de 4 ans.
6
2.
ARGUMENTAIRE
La myasthénie est une maladie auto-immune chronique liée à un défaut de transmission de l'
influx
nerveux entre le nerf moteur et le muscle strié. Elle se manifeste par une faiblesse musculaire qui
s'
aggrave à l'
effort et s'
améliore au repos. Sa gravité tient au risque de complications respiratoires qui
peuvent mettre en jeu le pronostic vital. Il s’agit d’une maladie relativement rare (environ 5 cas pour
100 000 habitants). Elle atteint les deux sexes et peut débuter à n'
importe quel âge, avec 2 pics de
fréquence : l'
un avant 35 ans avec une nette prédominance féminine, l'
autre après 50 ans.
Dans cette situation, un essai (Gajdos 2005 n = 173) n’a pas mis en évidence de différence entre une
posologie de 2 g/kg et une posologie de 1 g/kg d’IgIV. Zinman (2007) a réalisé un essai randomisé en
double insu contre placebo chez 52 patients. Cette étude rapporte des résultats statistiquement
significatifs en faveur des IgIV.
D’autres essais n’ont pas retrouvé de différence par rapport aux échanges plasmatiques, sans
qu’aucun de ces essais n’ait formellement non plus démontré de non infériorité. Enfin, il existe des
séries publiées suggérant une amélioration chez les patients recevant les immunoglobulines
intraveineuses (Achiron 2000 n = 10, Cosi 1991 n = 11, Asura 1988 n = 9, Evoli 1993 n = 12).
Dans la myasthénie aiguë en poussées, les IgIV à la dose de 1 à 2 g/kg/cure auraient une efficacité
comparable à celle des échanges plasmatiques. L’administration des IgIV est plus facilement
réalisable et mieux tolérée que la plasmaphérèse.
Effet des IgIV dans la myasthénie aiguë en phase de poussées
Auteurs
Type d’étude
Posologie
Suivi
Gajdos
(2008)
Cochrane : 6 essais contrôlés
Hilkevich
(2001)
Ouverte
IgIV :
20.3
N = 11 patients mysthéniques 400 mg/kg/j pdt 5 j mois
sévères
Suivi par 400
mg/kg/mois
+ stéroïdes +
pyridostigmine
Achiron
(2000)
Ouverte
N = 10 patients myasthéniques
sévères
en
échec
des
thérapeutiques
conventionnelles
(corticostéroïdes, ciclosporine
et azathioprine)
Cosi
(1991)
Ouverte
IgIV :
N = 37 patients myasthéniques 400 mg/kg pdt 5 j
1/ versus placebo (n = 51)
2/
versus
échanges
plasmatiques pdt 2 sem
(n = 87)
3/ cross-over versus échanges
plasmatiques (n = 12)
4/ versus placebo pdt 42 j
(n = 15) puis ouverte pdt 6 sem
5/ versus méthylprednisolone
(n = 33)
6/ IgIV 1 g/kg pdt 2 j versus 1
g/kg en prise unique (n = 173)
IgIV :
1 an
400 mg/kg/j pdt 5 j
puis 400 mg/kg
toutes les 6 sem
60 j
Critères
d’évaluation
Efficacité
QMGS :
score
de
myasthénie
aigüe
quantitatif
Amélioration
selon
l’échelle
Oosterhuis
de
classification
des
degrés
de
sévérité
des
myasthénies
Amélioration
selon
l’échelle
d’Osserman
.variables de
la fatigue
.
longueur
des muscles
.
tests
fonctionnels
respiratoires
Amélioration
selon
Résultats
1/ Efficacité S
2/ NS
3/ NS
4/ NS mais tendance positive
dans l’étude ouverte
5/ NS
6/ NS
↓ S des doses de stéroïdes et
pyridostigmine (azathioprine)
2/11 : arrêt des corticoïdes
↓ S des grades de l’échelle
d’Osserman
↓ S des AC anti-récepteurs à
l’acétylcholine uniquement pdt la
phase d’induction de la rémission
mais pas pdt la phase de maintien
En 12 jours :
. 70.3 % : un degré d’amélioration
7
Auteurs
Type d’étude
Posologie
Suivi
aigües
. n = 26 patients dans une
longue phase stationnaire et
réfractaires
au
traitement
conventionnel
. n = 11 : patients dans une
phase aigüe de la maladie
Arsura
(1988)
Ouverte
N = 9 patients avec un début
d’aggravation de la myasthénie
aigüe qui se généralise
IgIV : 400mg/kg/j 220 j
pdt 5j
. n = 6 : 2 cures
. n = 2 : 3 cures
. n = 1 : 5 cures
+ n = 9 sous
anticholinesterase
pdt 2 mois et
n = 6
sous
corticoïdes pdt 2
mois.
Critères
Résultats
d’évaluation
l’échelle
dans l’échelle d’Oosterhuis
d’Oosterhuis . 58.7% : 2 degrés d’amélioration
En 60 j :
. 37.8% : persistence des 2 degrés
d’amélioration
Pas de différence (NS) entre les 2
types de patients en termes
d’amélioration
Puissance
. Après 20/23 cures : amélioration
S en 4 j en moyenne et maximale
musculaire
Capacité
en 8 j en moyenne.
vitale
Amélioration maintenue pdt 107 j
Temps pour en moyenne
lever la tête, .
AC
anti
récepteurs
à
l’acétylcholine : NS
chaque
jambe,
↓ S des doses de corticoïdes : 4/6
bras….
Echelle
d’Osserman
QMGS: quantified MG clinical score
OGCCMS: Oosterhuis global clinical classification of myasthenic severity
Bibliographie
Les référentiels de la Juste prescription du CEDIT (AP-HP), des Pharmaciens de CHU et des
Hospices Civils de Lyon ont été les documents de base du travail bibliographique.
La recherche bibliographique a été réalisée par interrogation systématique des banques de données
Medline, Embase et Pascal. Elle a identifié préférentiellement les essais cliniques et les revues de
synthèse publiés en langue française ou anglaise après janvier 1988.
1. Gajdos P, Chevret S, Toyka K. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev. 2008 Jan
23;(1):CD002277.
2. Gajdos P, Tranchant C, Clair B, Bolgert F, Eymard B, Stojkovic T, Attarian S, Chevret S. Treatment of myasthenia gravis
exacerbation with intravenous immunoglobulin: a randomized double-blind clinical trial. ; Arch Neurol. 2005 Nov;62(11):1689-93.
3. Zinman L, Ng E, Bril V. IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial. Neurology. 2007
Mar 13;68(11):837-41.
4. Gajdos P, Chevret S, Clair B, Tranchant C, Chastang C. Clinical trial of plasma exchange and high-dose intravenous
immunoglobulin in myasthenia gravis. Myasthenia Gravis Clinical Study Group. Ann Neurol. 1997 Jun;41(6):789-96.
5. Wolfe GI, Barohn RJ, Foster BM, Jackson CE, Kissel JT, Day JW, Thornton CA, Nations SP, Bryan WW, Amato AA, Freimer
ML, Parry GJ. Randomized, controlled trial of intravenous immunoglobulin in myasthenia gravis. Myasthenia Gravis-IVIG Study
Group. Muscle Nerve. 2002 Oct;26(4):549-52.
6. Ronager J, Ravnborg M, Hermansen I, Vorstrup S. Immunoglobulin treatment versus plasma exchange in patients with
chronic moderate to severe myasthenia gravis. Artif Organs. 2001 Dec;25(12):967-73
7. Hilkevich O, Drory VE, Chapman J, Korczyn AD. The use of intravenous immunoglobulin as maintenance therapy in
myasthenia gravis. Clin Neuropharmacol. 2001 May-Jun;24(3):173-6.
8. Achiron A, Barak Y, Miron S, Sarova-Pinhas I. Immunoglobulin treatment in refractory Myasthenia gravis. Muscle Nerve. 2000
Apr;23(4):551-5.
9. Cosi V, Lombardi M, Piccolo G, Erbetta A.Treatment of myasthenia gravis with high-dose intravenous immunoglobulin.
Acta Neurol Scand. 1991 Aug;84(2):81-4.
10. Arsura EL, Bick A, Brunner NG, Grob D.Effects of repeated doses of intravenous immunoglobulin in myasthenia gravis. Am
J Med Sci. 1988 May;295(5):438-43.
11. Evoli A, Palmisani MT, Bartoccioni E, Padua L, Tonali P. High-dose intravenous immunoglobulin in myasthenia gravis.
Ital J Neurol Sci. 1993 Apr;14(3):233-7.
8
Groupe de travail
Pr CHERIN Patrick, Interniste, Paris
Pr POUGET Jean, Neurologue, Marseille,
Pr CREANGE Alain, Neurologue, Paris,
Pr ANTOINE Jean-Christophe, Saint-Etienne,
Dr SERENI Carole, Neurologue, Paris
Dr CHIPAUX Mathilde, Afssaps, Paris
Groupe de lecture
Pr CLANET Michel, Neurologue, Toulouse,
Pr DULAC Olivier, Neurologue, Paris,
Pr EDAN Gilles, Neurologue, Rennes,
Pr GUILLEVIN Loïc, interniste, Paris,
Pr HACHULLA Eric, interniste, Lilles,
Dr LEGER Jean-Marc, Neurologue, Paris,
Dr MAGY Laurent, Neurologue, Limoges,
Pr TRANCHANT Catherine, Neurologue, Strasbourg,
Dr VIAL Christophe, Neurologue, Lyon,
Pr VERMESCH Patrick, Neurologue, Lilles,
Pr CONFAVREUX Christian, Neurologue, Lyon
Pr LEMASSON Gwendal, Neurologue, Bordeaux
Comité de qualification
Pr CAULIN Charles, Président, thérapeutique, Paris
Pr AULAGNER Gilles, pharmacien, représentant des
HCL, Lyon
Mme
BONGRAND
Marie-Claude,
pharmacien,
représentante des Pharmaciens de CHU, Marseille
Dr DUMARCET Nathalie, Afssaps
Dr CHASSANY Olivier, méthodologiste, Paris
Mme FAUCHER-GRASSIN Joëlle, pharmacien,
représentante des Pharmaciens de CHU Poitiers
Pr LAVILLE
Maurice, praticien hospitalier,
représentant des HCL, Lyon
Mme
MONTAGNIER-PETRISSANS
Catherine,
pharmacien, représentante de la Juste prescription de
l’AP-HP, Paris
M. LIEVRE Michel, pharmacologue, Lyon
Mme PIVOT, pharmacien, représentante des HCL
Lyon
Pr RICHÉ Christian, pharmacologue, Brest
M. ROPERS Jacques, Afssaps
Pr VICAUT Eric, médecin de santé publique, Paris
La Commission d’AMM du 24 Octobre 2008 présidée par le Pr Daniel VITTECOQ n’a pas émis
d’objection à ce référentiel, qui a également été visé par la Commission de la transparence de la HAS,
présidée par le Pr Gilles BOUVENOT.
Résumés-abstracts
Gajdos P, Chevret S, Toyka KIntravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev.
2008 Jan 23;(1):CD002277.
BACKGROUND: Myasthenia gravis is an autoimmune disease in which autoantibodies interfere with
neuromuscular transmission. As with other autoimmune diseases, people with myasthenia gravis would be
expected to benefit from intravenous immunoglobulin. OBJECTIVES: The objective of this review was to examine
the efficacy of intravenous immunoglobulin for treating exacerbations of myasthenia gravis or for chronic
myasthenia gravis. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials
register (March 2005) and MEDLINE (January 1966 to March 2005) using '
myasthenia gravis'and '
intravenous
immunoglobulin'as the search terms. SELECTION CRITERIA: We included all randomised or quasi-randomised
trials in which intravenous immunoglobulin was compared with no treatment, placebo or plasma exchange, in
people with myasthenia gravis. DATA COLLECTION AND ANALYSIS: One author extracted the data and the two
others checked these data and the source from which they were derived. For methodological reasons, no formal
meta-analysis was performed. MAIN RESULTS: We identified five randomised controlled trials, all of which
investigated short-term benefit. The first study of 87 participants with exacerbation found no statistically significant
difference between immunoglobulin and plasma exchange after two weeks. The second study of 12 participants
with moderate or severe myasthenia gravis treated in a crossover design trial found no statistically significant
difference in the efficacy of immunoglobulin and plasma exchange after four weeks. The third study with 15
participants with mild or moderate myasthenia gravis found no statistically significant difference in efficacy of
intravenous immunoglobulin and placebo after six weeks. The fourth study terminated early. It included 33
participants with moderate exacerbations of myasthenia gravis and showed no statistically significant difference in
the efficacy of intravenous immunoglobulin and methylprednisolone. The fifth trial including 173 people with
myasthenia gravis exacerbations, showed no superiority of intravenous immunoglobulin 1 g/kg on two
consecutive days over intravenous immunoglobulin 1 g/kg on a single day. AUTHORS'CONCLUSIONS: In
severe exacerbations of myasthenia gravis, one randomised controlled trial did not show a significant difference
between intravenous immunoglobulin and plasma exchange. Another showed no significant difference in efficacy
between 1 g/kg and 2 g/kg of intravenous immunoglobulin. A further trial showed no significant difference
9
between intravenous immunoglobulin and oral methylprednisolone. In chronic myasthenia gravis, there is
insufficient evidence from randomised trials to determine whether intravenous immunoglobulin is efficacious.
More research is needed to determine whether intravenous immunoglobulin reduces the need for steroids as
suggested by two case series.
Gajdos P, Tranchant C, Clair B, Bolgert F, Eymard B, Stojkovic T, Attarian S, Chevret S. Treatment of myasthenia
gravis exacerbation with intravenous immunoglobulin: a randomized double-blind clinical trial. Arch Neurol. 2005
Nov;62(11):1689-93.
BACKGROUND: The optimal dose of intravenous immunoglobulin (IVIG) in acute exacerbation of myasthenia
gravis remains unknown. Increasing the treatment duration might provide added efficacy. OBJECTIVE: To
determine the optimal dose of IVIG for treating myasthenia gravis exacerbation. DESIGN: Randomized doubleblind placebo-controlled multicenter trial designed to demonstrate superiority of the 2 g/kg dose over the 1 g/kg
dose of IVIG, conducted between November 13, 1996, and October 26, 2002. PARTICIPANTS: One hundred
seventy-three patients aged 15 to 85 years with acute exacerbation of myasthenia gravis. INTERVENTION:
Participants were randomly assigned to receive 1 g/kg of IVIG on day 1 and placebo on day 2 (group 1) vs 1 g/kg
of IVIG on 2 consecutive days (group 2). MAIN OUTCOME MEASURE: Improvement in the myasthenic muscular
score after 2 weeks. RESULTS: The mean improvements in the myasthenic muscular scores after 2 weeks were
15.49 points (95% confidence interval, 12.09-18.90 points) in group 1 and 19.33 points (95% confidence interval,
15.82-22.85 points) in group 2. However, the difference between the 2 groups was not significant (effect size,
3.84 [95% confidence interval, -1.03 to 8.71]; P = .12). CONCLUSION: This trial found no significant superiority of
2 g/kg over 1 g/kg of IVIG in the treatment of myasthenia gravis exacerbation.
Zinman L, Ng E, Bril V.IV immunoglobulin in patients with myasthenia gravis: a randomized controlled
trial. Neurology. 2007 Mar 13;68(11):837-41.
OBJECTIVE: We aimed to determine the effectiveness of IV immunoglobulin (IVIG) in the treatment of patients
with myasthenia gravis (MG) and worsening weakness in a randomized, placebo-controlled, masked study.
METHODS: Fifty-one patients with worsening weakness due to MG were randomized to infusion with 2 g/kg of
IVIG or an equivalent volume of IV dextrose 5% in water. The Quantitative Myasthenia Gravis (QMG) Score for
Disease Severity, a validated clinical composite scale, was calculated by a masked observer at baseline and days
14 and 28. RESULTS: In IVIG-treated patients, a clinically meaningful improvement in QMG Score for Disease
Severity was observed at day 14 and persisted at day 28. The greatest improvement occurred in patients with
more severe disease as defined by a QMG Score for Disease Severity greater than 10.5. CONCLUSION: This
study provides level 1 evidence for the effectiveness of IV immunoglobulin in patients with worsening weakness
due to myasthenia gravis.
Gajdos P, Chevret S, Clair B, Tranchant C, Chastang C.Clinical trial of plasma exchange and high-dose
intravenous immunoglobulin in myasthenia gravis. Myasthenia Gravis Clinical Study Group. Ann Neurol. 1997
Jun;41(6):789-96.
We have conducted a trial to randomly assess the efficacy and tolerance of intravenous immunoglobulin (i.v.Ig) or
plasma exchange (PE) in myasthenia gravis (MG) exacerbation and to compare two doses of i.v.Ig. Eighty-seven
patients with MG exacerbation were randomized to receive either three PE (n = 41), or i.v.Ig (n = 46) 0.4 gm/kg
daily further allocated to 3 (n = 23) or 5 days (n = 23). The main end point was the variation of a myasthenic
muscular score (MSS) between randomization and day 15. The MSS variation was similar in both groups (median
value, +18 in the PE group and +15.5 in the i.v.Ig group, p = 0.65). Similar efficacy, although slightly reduced in
the 5-day group was observed with both i.v.Ig schedules. The tolerance of i.v.Ig was better than that of PE with a
total of 14 side effects observed in 9 patients, 8 in the PE group and 1 in the i.v.Ig group (p = 0.01). Although our
trial failed to show a pronounced difference in the efficacy of both treatments, it exhibited a very limited risk for
i.v.Ig. i.v.Ig is an alternative for the treatment of myasthenic crisis. The small sample sizes in our trial, however,
could explain why a difference in efficacy was not observed. Further studies are needed to compare PE with i.v.Ig
and to determine the optimal dosage of i.v.Ig.
Wolfe GI, Barohn RJ, Foster BM, Jackson CE, Kissel JT, Day JW, Thornton CA, Nations SP, Bryan WW, Amato
AA, Freimer ML, Parry GJ. Randomized, controlled trial of intravenous immunoglobulin in myasthenia gravis.
Myasthenia Gravis-IVIG Study Group. Muscle Nerve. 2002 Oct;26(4):549-52.
We initiated a randomized, double-blinded, placebo-controlled trial of intravenous immunoglobulin (IVIG)
treatment in myasthenia gravis (MG). Patients received IVIG 2 gm/kg at induction and 1 gm/kg after 3 weeks vs.
5% albumin placebo. The primary efficacy measurement was the change in the quantitative MG Score (QMG) at
day 42. Fifteen patients were enrolled (6 to IVIG; 9 to placebo) before the study was terminated because of
10
insufficient IVIG inventories. At day 42, there was no significant difference in primary or secondary outcome
measurements between the two groups. In a subsequent 6-week open-label study of IVIG, positive trends were
observed.
Ronager J, Ravnborg M, Hermansen I, Vorstrup S. Immunoglobulin treatment versus plasma exchange in
patients with chronic moderate to severe myasthenia gravis. Artif Organs. 2001 Dec;25(12):967-73
The purpose of this study was to compare the efficacy of high-dose intravenous immunoglobulin (IVIG) treatment
with plasma exchange in patients suffering from moderate to severe myasthenia gravis (MG) in a stable phase.
There are no controlled studies comparing IVIG with plasma exchange in patients who despite
immunosuppressive treatment have persistent incapacitating MG symptoms. This was a controlled crossover
study. Twelve patients with generalized moderate to severe MG on immunosuppressive treatment for at least 12
months were included. The patients were evaluated clinically using a quantified MG clinical score (QMGS) before
and at follow-up visits after each treatment. One week after the treatments, the patients who received plasma
exchange treatment showed a significant improvement in QMGS compared to baseline but although some
improvement was seen after IVIG this did not reach statistical significance. Four weeks after both plasma
exchange and IVIG treatments, there was a significant improvement in QMGS compared to baseline. One week
and 4 weeks after treatment, no significant difference between the 2 treatments was found. Both treatments have
a clinically significant effect 4 weeks out in patients with chronic MG, but the improvement has a more rapid onset
after plasma exchange than after IVIG.
Hilkevich O, Drory VE, Chapman J, Korczyn AD. The use of intravenous immunoglobulin as maintenance therapy
in myasthenia gravis. Clin Neuropharmacol. 2001 May-Jun;24(3):173-6.
The standard therapy for myasthenia gravis (MG) includes steroids and immunosuppressants, which have
delayed onset of action and significant side effects. Plasmapheresis and intravenous immunoglobulin have been
used mostly for the treatment of severe exacerbations. In the present study we examined the use of intravenous
immunoglobulin as maintenance treatment in MG. We included 11 patients with generalized myasthenia gravis.
All had severe bulbar and respiratory involvement that required mechanical ventilation in three patients.
Intravenous immunoglobulin treatment was initiated at a dose of 400 mg/kg/d for 5 days and followed by
maintenance with 400 mg/kg once monthly. Regular medications were continued as necessary. There was
significant improvement in all patients, and none required mechanical ventilation over the treatment period of 20.3
months +/- 8.3 (mean +/- SD, total patient years of treatment = 18.7). Steroid and pyridostigmine doses were
reduced significantly and steroids were discontinued in two patients. There were no serious side effects related to
intravenous immunoglobulin. These results suggest that intravenous immunoglobulin maintenance therapy is a
valid modality in patients with MG.
Achiron A, Barak Y, Miron S, Sarova-Pinhas I. Immunoglobulin treatment in refractory Myasthenia gravis. Muscle
Nerve. 2000 Apr;23(4):551-5.
Failure to induce and maintain remission in severe exacerbations of myasthenia gravis (MG), despite optimal
care, is a common problem. We evaluated the efficacy and safety of high-dose intravenous immunoglobulin (IVIg)
therapy in an open-label study of 10 patients with severe generalized myasthenia and an acute deterioration
unresponsive to conventional therapy including high-dose corticosteroids, cyclosporine, and azathioprine.
Intravenous Ig at a loading dose of 400 mg/kg was administered daily for 5 consecutive days, with maintenance
IVIg treatment at a dose of 400 mg/kg, once every 6 weeks. Significant improvement occurred in all patients,
beginning at 6 +/- 2 days of treatment as measured by the Osserman scale, fatigue variables, muscle strength,
and respiratory function tests. No side effects were observed during induction of remission. Further IVIg
treatments were highly efficacious in maintaining the remission. The severity of the disease decreased by 2.5 +/0.8 grades of the Osserman scale over a period of 1 year (P <0.001), in parallel with reduction of
immunosuppressive therapy as well as a decrease in acetylcholine receptor antibody titers (P < 0.01).
Intravenous Ig therapy seems to be highly potent for inducing rapid improvement in refractory myasthenia during
acute deterioration as well as for maintaining remission.
Cosi V, Lombardi M, Piccolo G, Erbetta A. Treatment of myasthenia gravis with high-dose intravenous
immunoglobulin. Acta Neurol Scand. 1991 Aug;84(2):81-4.
We treated 37 patients affected by autoimmune generalized myasthenia gravis (MG) with high-dose intravenous
gammaglobulin (HDIVIg), 400 mg/kg per day on 5 consecutive days. A one-degree improvement of Oosterhuis
global clinical classification of myasthenic severity (OGCCMS), the disappearance of bulbar involvement or both
were recorded 12 days after the beginning of the treatment in 70.3% of the patients and persisted up to 60 days in
58.7%. A two-degree improvement of OGCCMS was recorded in 54.1% of the patients and it was maintained up
to 60 days in 37.8%. The percentage of improvement did not significantly differ between patients entering the
11
treatment in a long-standing, drug-refractory stationary phase of the illness (n = 26) and patients who received
HDIVIg in an acute phase of MG (n = 11). None of the patients experienced side effects. Our data indicates that
HDIVIg is an interesting, virtually riskless therapeutic choice for MG patients, and allows the planning of a
controlled trial versus plasma-exchange.
Arsura EL, Bick A, Brunner NG, Grob D. Effects of repeated doses of intravenous immunoglobulin in myasthenia
gravis. Am J Med Sci. 1988 May;295(5):438-43.
The authors administered repeated courses of intravenous immunoglobulin (IVIg) to nine patients at the onset of
an exacerbation of generalized myasthenia gravis (MG). Anticholinesterase medication (nine patients) and
corticosteroid dosage (six patients) had been kept constant for a 2-month period. Six patients received two
courses, two patients received three courses, and one patient received five courses. Twenty of 23 courses
resulted in satisfactory improvement beginning 4.3 +/- 1.2 days after start of IVIg and becoming maximal 8.2 +/2.0 days, with sustained improvement lasting 106.6 +/- 49.1 days. Vital capacity increased from an average of
1845.1 +/- 489 cc to 2894 +/- 762 cc (p less than 0.01) at peak effect. Four of nine patients had a decrease in
strength before improvement. There was no significant change in acetylcholine receptor antibody titers before or
after therapy. Side effects were minimal. Of the three patients who had nonsatisfactory course, two responded
well to additional IVIg. IVIg can produce repeated beneficial effects in patients with MG and may be useful as an
adjunct in the management of MG.
Evoli A, Palmisani MT, Bartoccioni E, Padua L, Tonali P. High-dose intravenous immunoglobulin in myasthenia
gravis. Ital J Neurol Sci. 1993 Apr;14(3):233-7.
The effects of high-dose intravenous immunoglobulin (i.v.Ig) in 12 MG patients were studied. All patients had
severe symptoms. In two cases anti-acetylcholine receptor antibodies (anti-AChR abs) were not detectable. I.v.Ig
was administered to 9 patients already on long-term immunosuppressive therapy and to 3 patients at the
beginning of azathioprine treatment. 10 patients (83%) improved; the duration of improvement was longer in
immunosuppressed patients. Anti-AChR abs generally decreased after infusion but we did not find a constant
correlation between reduction in ab titers and clinical improvement. Side effects included one case of severe
hemolysis. In our experience i.v.Ig therapy is effective in MG. The chief indication for its use appears to be the
treatment of deterioration of the disease
12
Syndrome de Lambert-Eaton : formes auto-immunes non paranéoplasiques
sous réserve de l’avis d’un centre de référence ou de compétence des maladies neuromusculaires.
1. PROTOCOLE THERAPEUTIQUE TEMPORAIRE
1 g/kg/j pendant 2 jours.
Contre-indications
de Gammagard®);
excipients et est
érable et
d'
hyperprolinémie.
intolérance.
IgIV.
- de s'
Sandoglobuline 120 mg/ml ® et 6ml/kg/h pour Kiovig® voire 8ml/kg/h chez les adultes atteints de
13
IgG Gammagard®) et
(3,4 mg/ml) et Tégéline® (0.8mg/ml);
de détecter d'
Le risque d'
Des cas d'
administration d'
IgIV impose :
Bien que ces cas d'
d'
Traitement associé
L'
vaccins.
IgIV, l'
animal n'
IV, et l'
enceinte qu'
14
15
2.
ARGUMENTAIRE
Il s'
agit d'
un syndrome auto-immun acquis, d'
une extrême rareté (prévalence est estimée à
1/100 000), provoqué par des anticorps dirigés contre les canaux calciques voltage-dépendants de la
terminaison nerveuse. Près de la moitié des cas sont paranéoplasiques, presque toujours associé à
un cancer pulmonaire anaplasique à petites cellules.
Les IgIV peuvent avoir un effet bénéfique transitoire en alternative à la 3.4 aminopyridine, qui reste un
traitement symptomatique de cette pathologie.
Elles n’ont montré leur efficacité que dans les formes auto-immunes non paranéoplasiques du
syndrome de Lambert-Eaton ; cette situation concerne 40% des syndromes de Lambert-Eaton
(environ 10 patients en France) : une étude comparative (Bain 1996, n = 9) versus placebo a mis en
évidence une amélioration statistiquement significative de la puissance musculaire.
Dans le syndrome de Lambert-Eaton, dans ses formes auto-immunes non paranéoplasiques,
l’administration d’IgIV est temporairement acceptable sous réserve de l’avis d’un centre de référence
ou de compétence des maladies neuromusculaires.
Effet des IgIV dans le syndrome de Lambert-Eaton
Auteurs
Maddison
(2005)
Bain
(1996)
Type d’étude
Posologie
Suivi
Cochrane
3 études dont 2 contrôlées
(avec
la
3.4
diaminopyridine) et une
étude crossover versus
placebo (avec IgIV : Bain
1996)
Crossover comparative IgIV :
8 sem
versus placebo
1 g/kg/j pdt
N =9
2j
Critères
d’évaluation
- AC anti chaine
de calcium
- Mesures de la
puissance
musculaire
Résultats
Etude crossover IgIV vs placebo :
. amelioration S dans les mesures de
puissance myométrique
. ↓ S des AC anti chaine de calcium
↓ S des AC anti chaine de calcium :
p = 0.028
↓
S
de
3
mesures
de
puissance musculaire : p = 0.017 à
0.038
Amélioration maximale en 2 à 4 sem
puis ↓ jusqu’à la 8ème sem.
Bibliographie
1. Illa I. IVIg in myasthenia gravis, Lambert Eaton myasthenic syndrome and inflammatory myopathies: current status. J Neurol.
2005 May;252 Suppl 1:I14-8
2. Maddison P, Newsom-Davis J.Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database Syst Rev. 2005 Apr
18;(2):CD003279.
3. Bain PG, Motomura M, Newsom-Davis J, Misbah SA, Chapel HM, Lee ML, Vincent A, Lang B. Effects of intravenous
immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome.
Neurology. 1996 Sep;47(3):678-83.
16
Groupe de travail
Groupe de lecture
HCL, Lyon
Mme
BONGRAND
Marie-Claude,
pharmacien,
Pr LAVILLE
Mme
Catherine,
l’AP-HP, Paris
Lyon
d’objection à ce référentiel qui a également été visé par la Commission de la transparence de la HAS,
Résumés-abstracts
Illa I.IVIg in myasthenia gravis, Lambert Eaton myasthenic syndrome and inflammatory myopathies: current
status. J Neurol. 2005 May;252 Suppl 1:I14-8
Intravenous immunoglobulin (IVIg) is an effective tool for the treatment of diseases with immune pathogenesis.
This article reviews the current knowledge of the benefits of treating with IVIg patients with myasthenia gravis
(MG), Lambert Eaton myasthenic syndrome (LEMS), dermatomyositis (DM), polymyositis (PM) and inclusion
body myositis (IBM). Myasthenia gravis: Treatment of MG with IVIg was reported to be beneficial in a number of
case series and two randomised controlled trials, in which efficacy was measured by clinical improvement using
myasthenic muscle score and decrease in anti-acetylcholine receptor antibodies (AchRAb). According to the
results, IVIg could be recommended for crisis and severe exacerbation. In many other clinical conditions, such as
response to treatment of mild or moderate exacerbation, changes in steroid dosage and before thymectomy, IVIg
has also been reported to be helpful, but no controlled trials to confirm its efficacy have been performed. LambertEaton myasthenic syndrome: A placebo-controlled crossover study reported a significant clinical improvement in
the amplitude of the resting CMAP following IVIg treatment. Further experience from case reports also indicates
that IVIg is useful in patients with LEMS, both as a short- and long-term treatment, especially when
immunosuppressive drugs are not fully effective. Inflammatory myopathies/dermatomyositis: In a double-blind
placebo-controlled crossover trial in patients with DM resistant to other treatments, IVIg was shown to produce a
significant increase of muscle strength as well as a marked improvement in immunopathological parameters in
repeated muscle biopsies (before and after IVIg). Thus, IVIg is an important therapy in patients with DM resistant
to other conventional therapies. Polymyositis: No randomised trials have been undertaken. One study showed
clinical improvement and a reduction in the need of prednisone in patients with chronic refractory PM. Inclusion
body myositis: Three controlled trials showed some muscle strength improvement, although the changes did not
reach statistical significance. However improvement in swallowing was repeatedly observed, suggesting that
some patients with severe dysphagia may derive a modest benefit from IVIg therapy. CONCLUSION: Controlled
trials indicate that in MG, LEMS, and DM, IVIg at a total dose of 2 g/kg is a highly useful therapy. Uncontrolled
trials and case reports indicate benefit in many different clinical situations, but further clinical investigation is
required.
17
Maddison P, Newsom-Davis J. Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database Syst
Rev. 2005 Apr 18;(2):CD003279.
BACKGROUND: Lambert-Eaton myasthenic syndrome is an autoimmune presynaptic disorder of neuromuscular
transmission. Treatments attempt to overcome the harmful autoimmune process, or to improve residual
neuromuscular transmission, in order to reverse muscle weakness. OBJECTIVES: The objective was to examine
the efficacy of treatment in Lambert-Eaton myasthenic syndrome. SEARCH STRATEGY: We searched the
Cochrane Neuromuscular Disease Group trials register (December 2004), MEDLINE (January 1966 to December
2004) and EMBASE (January 1980 to December 2004), and checked bibliographies and contacted authors to
identify additional published or unpublished data. SELECTION CRITERIA: All randomised or quasi-randomised
trials of adults and children with a diagnosis of Lambert-Eaton myasthenic syndrome, with or without small-cell
lung cancer, receiving any form of pharmacological or physical treatment. The primary outcome measure was
change in muscle strength scale score (Quantitative Myasthenia Gravis score), or limb muscle strength measured
by myometry. The secondary outcome measure was improvement in the mean amplitude of the resting
compound muscle action potentials. The mean amplitude used was the mean of all muscles tested. DATA
COLLECTION AND ANALYSIS: We identified three randomised controlled trials. MAIN RESULTS: Two controlled
trials of the effects of 3,4-diaminopyridine compared with placebo in a total of 38 patients with Lambert-Eaton
myasthenic syndrome were eligible, one of which was of crossover design. A third crossover trial compared
intravenous immunoglobulin treatment to placebo in nine patients.Two trials of 3,4-diaminopyridine reported a
significant improvement in muscle strength score, or myometric limb measurement following treatment, and a
significant improvement in resting compound muscle action potential amplitude following 3,4-diaminopyridine,
compared with placebo.A meta-analysis of the primary endpoint results was not possible because of marked
differences in primary outcome measures. However, a meta-analysis of the secondary endpoint was possible.
The overall weighted mean difference was 1.80 mV (95% confidence interval 0.82 to 2.78), favouring treatment.A
crossover trial reported a significant improvement in myometric limb strength and a non-significant improvement
in change in the mean resting compound muscle action potential amplitude when patients received intravenous
immunoglobulin compared to placebo infusions. Clinical improvement lasted for up to eight weeks. AUTHORS'
CONCLUSIONS: Limited evidence from randomised controlled trials showed that either 3,4-diaminopyridine or
intravenous immunoglobulin improved muscle strength scores and compound muscle action potential amplitudes
in patients with Lambert-Eaton myasthenic syndrome. There are insufficient data at present to quantify this
treatment effect. Other possible treatments have not been tested in randomised controlled trials.
Bain PG, Motomura M, Newsom-Davis J, Misbah SA, Chapel HM, Lee ML, Vincent A, Lang B. Effects of
intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton
myasthenic syndrome. Neurology. 1996 Sep;47(3):678-83.
Intravenous immunoglobulin improves many antibody-mediated autoimmune disorders, but its mode of action is
unknown. We investigated its effects on muscle strength and on the serum titer of the calcium-channel
autoantibodies that are likely to be pathogenic in the Lambert-Eaton myasthenic syndrome (LEMS). In a
randomized, double-blind, placebo-controlled crossover trial, serial indices of limb, respiratory, and bulbar muscle
strength and the serum titer of calcium-channel antibodies in nine patients were compared over an 8-week period,
using the area-under-the-curve approach, following infusion on two consecutive days of immunoglobulin at 1 g/kg
body weight/day (total dose 2.0 g/kg body weight) or placebo (equivalent volume of 0.3% albumin). Calciumchannel antibodies were measured by radioimmunoassay using 125I-omega-conotoxin MVIIC. Direct antiidiotypic actions of immunoglobulin were tested in this assay. Immunoglobulin infusion was followed by significant
improvements in the three strength measures (p = 0.017 to 0.038) associated with a significant decline in serum
calcium-channel antibody titers (p = 0.028). Improvement peaked at 2 to 4 weeks and was declining by 8 weeks.
Mean serum titers were unchanged at 1 week, however, and direct anti-idiotypic neutralization by immunoglobulin
was not demonstrable in vitro. We conclude that immunoglobulin causes a short-term improvement in muscle
strength in LEMS that probably results from the induced reduction in calcium-channel autoantibodies. The
reduction is not due to a direct neutralizing action of the immunoglobulin, but a delayed anti-idiotypic action
cannot be excluded. Improvement following intravenous immunoglobulin in other autoantibody-mediated
disorders may similarly be associated with decline in levels of pathogenic autoantibodies.
18
Myosites à inclusion avec dysphagie grave
I. PROTOCOLE THERAPEUTIQUE TEMPORAIRE
1 g/kg/j pendant 2 jours puis 1 fois par mois pendant 6 mois.
Contre-indications
de Gammagard®);
excipients et est
érable et
d'
hyperprolinémie.
intolérance.
IgIV.
- de s'
19
IgG Gammagard®) et
de détecter d'
Le risque d'
Des cas d'
administration d'
IgIV impose :
Bien que ces cas d'
d'
Traitement associé
L'
vaccins.
IgIV, l'
animal n'
IV, et l'
enceinte qu'
20
21
2.
ARGUMENTAIRE
Les myopathies inflammatoires (ou myosites) sont caractérisées par une inflammation des muscles
striés résultant d’une activation anormale et/ou excessive du système immunitaire, ce qui les
différencient des dystrophies musculaires progressives, congénitales ou myotoniques, des myopathies
métaboliques (myopathies mitochondriales, glycogénoses, lipidoses…), et de la myasthénie. Elles
peuvent être primitives ou d’origine infectieuse, toxique ou secondaire à une maladie de système
(collagénose, vascularite) ou à une néoplasie. La myosite sporadique à inclusions (sporadic inclusion
body myositis : s-IBM) est la plus fréquente des myopathies acquises ; elle est d'
évolution progressive
après l'
âge de 50 ans. Elle représenterait près de 16% des atteintes inflammatoires de l’adulte en
France. Il s'
agit d'
affections rares dont l'
incidence annuelle est estimée entre 5 et 10 cas par million
d'
habitants.
Le traitement des myosites à inclusion avec dysphagie repose sur les corticoïdes et les lgIV à courtterme (environ 6 mois). L’alternative est la chirurgie avec myotonies du crico-pharyngien.
Les études comparatives versus placebo publiées, montrent une amélioration des échelles
fonctionnelles chez certains patients, en fonction des échelles d’évaluation utilisées.
Effet des IgIV dans les myosites à inclusion
Auteurs
Type d’étude
Posologie
Suivi
Critères d’évaluation
Dalakas
(1997)
Comparative
double-aveugle
contre placebo
crosss-over
N = 19
IgIV
2 g /kg (2 doses
quotidiennes de 1 g /kg)
1 fois /mois pdt 3 mois
Période
de
sevrage
thérapeutique
d’au
moins 1 mois
Puis permutation des
traitements
-Temps de déglutition
mesuré sous
échographie
-Echelle
de
MRC
(Medical
Research
Council) évalue la force
musculaire
- Score de MVIC :
maximum voluntary
Isomeric contraction
Amélioration S de la
fonction de déglutition dans
le groupe IgIV par rapport
au placebo (p < 0,05)
Dalakas
(2001)
Comparative
double-aveugle
contre placebo
N = 36
Prednisone + IgIV
4 mois
(2 g /kg en 2 doses
quotidiennes de 1 g /kg)
versus prednisone +
placebo
Force musculaire
Scores MRC
Déglutition
Résultats NS
Walter
(2000)
Comparative
double-aveugle
contre placebo
cross-over
N = 22
IgIV
1 an
2 g /kg 1 fois /mois pdt 6
mois avec permutations
les 6 mois suivant
Groupe 1 : IgIV puis
placebo
Groupe 2 : Placebo puis
IgIV
Evaluation par le patient
de 14 activités dont la
déglutition (score NSS
global)
Echelle MRC
Données concernant la
déglutition
non
communiquées
Modification S des scores
NSS dans chaque groupe
entre score initial et score
post IgIV (gr1 de 24,4 à
30,6 ; gr2 de 30,5 à 33,1)
Echelle MRC : NS
Sparks
(2007)
N=4
IgIV
1 g /kg pdt 2j
puis 400 mg /kg 1 fois
/sem pdt 3 sem
-Evaluation quantitative
de la force musculaire de
10 groupes musculaires
-TOGD
-Biopsies musculaires
Cherin
(2002)
N = 4 avec
troubles
œsophagiens
menaçant
le
pronostic vital
IgIV
18 mois
2 g/kg 1x/mois pdt 6 à 4 ans
mois (8 mois pour
patient 3)
-Manométrie
oesophagienne
-Clinique (ablation de la
sonde
de
nutrition
entérale)
-seules (patient 2)
Résultats
S dans les modifications
à 6 mois entre gr1 et gr2
(IgIV > placebo, p < 0,05)
-Amélioration de la force
musculaire
(groupes
distaux comme proximaux)
-Amélioration de la motilité
œsophagienne et de la
force linguale chez les
patients
ayant
une
anomalie au TOGD
Patient 1 : amélioration
spectaculaire et ablation
sonde après la 3ème cure. 0
manifestation
œsophagienne à 4 ans.
22
Auteurs
Type d’étude
Posologie
Suivi
-+prednisone (patients 1
et 3)
NSS = neuromuscular symptom and disability functional
Résultats
spectaculaire après la 3ème
cure.
0
manifestation
progressive.
Ablation
sonde à 4 mois. 0
manifestation
après la 2ème cure. 0
manifestation
œsophagienne à 18 mois.
TOGD : transit oeso-gastro-duodénal
Bibliographie
1. Dalakas MC, Sonies B, Dambrosia J, Sekul E, Cupler E, Sivakumar K. Treatment of inclusion-body myositis with IVIg: a
double-blind, placebo-controlled study. Neurology. 1997 Mar;48(3):712-6.
2. Dalakas MC, Koffman B, Fujii M, Spector S, Sivakumar K, Cupler E.A controlled study of intravenous immunoglobulin
combined with prednisone in the treatment of IBM. Neurology. 2001 Feb 13;56(3):323-7.
3. Walter MC, Lochmüller H, Toepfer M, Schlotter B, Reilich P, Schröder M, Müller-Felber W, Pongratz D. High-dose
immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study. J Neurol. 2000
Jan;247(1):22-8.
4. Sparks S, Rakocevic G, Joe G, Manoli I, Shrader J, Harris-Love M, Sonies B, Ciccone C, Dorward H, Krasnewich D, Huizing
M, Dalakas MC, Gahl WA. Intravenous immune globulin in hereditary inclusion body myopathy: a pilot study.
BMC Neurol. 2007 Jan 29;7:3.
5. Cherin P, Pelletier S, Teixeira A, Laforet P, Simon A, Herson S, Eymard B. Intravenous immunoglobulin for dysphagia of
inclusion body myositis. Neurology. 2002 Jan 22;58(2):326 : no abstract available.
Groupe de travail
Groupe de lecture
HCL, Lyon
Mme
BONGRAND
Marie-Claude,
pharmacien,
Pr LAVILLE
Mme
Catherine,
l’AP-HP, Paris
Lyon
23
Résumés-abstracts
Dalakas MC, Sonies B, Dambrosia J, Sekul E, Cupler E, Sivakumar K. Treatment of inclusion-body myositis with
IVIg: a double-blind, placebo-controlled study. Neurology. 1997 Mar;48(3):712-6.
We randomized 19 patients with inclusion-body myositis (IBM) to a double-blind, placebo-controlled, crossover
study using monthly infusions of 2 g/kg intravenous immunoglobulin (IVIg) or placebo for 3 months. Patients
crossed over to the alternate treatment after a washout period. We evaluated responses at baseline and at the
end of each treatment period using expanded (0-10) MRC scales, the Maximum Voluntary Isometric Contraction
(MVIC) method, symptom and disability scores, and quantitative swallowing studies. We calculated the
differences in scores between IVIg and placebo from baseline to end of treatment. Of the 19 patients, 9 (mean
age, 61.2 years; mean disease duration, 5.6 years) were randomized to IVIg and 10 (mean age, 66.1 years; mean
disease duration, 7.4 years) to placebo. During IVIg the patients gained a mean of 4.2 (-16 to +39.8) MRC points,
and during placebo lost 2.7 (-10 to +8) points (p < 0.1). These gains were not significant. Similar results were
obtained with the MRC and MVIC scores when the patients crossed to the alternate treatment. Six patients had a
functionally important improvement by more than 10 MRC points that declined when crossed over to placebo.
Limb-by-limb analysis demonstrated that during IVIg the muscle strength in 39% of the lower extremity limbs
significantly increased compared with placebo (p < 0.05), while a simultaneous decrease in 28% of other limbs
was detected. The clinical importance of these minor gains is unclear. The duration of swallowing functions
measured in seconds with ultrasound improved statistically in the IVIg-randomized patients (p < 0.05) compared
with placebo. Although the study did not establish efficacy of IVIg, possibly because of the small sample size, the
drug induced functionally important improvement in 6 (28%) of the 19 patients. Whether the modest gains noted
in certain muscle groups justify the high cost of trying IVIg in IBM patients at a given stage of the disease remains
unclear.
Dalakas MC, Koffman B, Fujii M, Spector S, Sivakumar K, Cupler E. A controlled study of intravenous
immunoglobulin combined with prednisone in the treatment of IBM. Neurology. 2001 Feb 13;56(3):323-7.
OBJECTIVE: To investigate whether the combination of intravenous immunoglobulin (IVIg) with prednisone
improves muscle strength and alters endomysial inflammation in patients with sporadic inclusion body myositis (sIBM). BACKGROUND: In a previous controlled trial in s-IBM, IVIg did not significantly improve strength in spite of
modest benefits in some muscle groups. The possibility that prednisone may have a synergistic effect with IVIg
prompted another controlled trial. METHODS: Thirty-six patients with biopsy-proven IBM were randomized to
receive IVIg or placebo monthly for 3 months. Before infusions, all patients were started on high-dose prednisone
for 3 months. Primary outcome measures were differences in the 1) Quantitative Muscle Strength (QMT) testing;
and 2) modified Medical Research Council (MRC) scores, between the patients randomized to IVIg + prednisone
compared with those randomized to placebo + prednisone. Repeated open muscle biopsies were performed at
random in 24 patients to determine changes in the number of autoinvasive T cells and necrotic muscle fibers.
RESULTS: Nineteen patients were randomized to IVIg + prednisone and 17 to placebo + prednisone. No
significant change was noted in muscle strength, assessed by QMT and MRC, from baseline to the 2nd, 3rd, or
4th month after treatment between the two groups. The number of necrotic fibers was reduced in the IVIg
randomized group (p < 0.01), and the mean number of CD2+ cells was significantly decreased in both groups (p <
0.0001), denoting a steroid effect. CONCLUSION: IVIg combined with prednisone for a 3-month period was not
effective in IBM. Endomysial inflammation was significantly reduced after treatment, but the reduction was not of
clinical significance.
Walter MC, Lochmüller H, Toepfer M, Schlotter B, Reilich P, Schröder M, Müller-Felber W, Pongratz D. Highdose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study. J
Neurol. 2000 Jan;247(1):22-8.
Sporadic inclusion body myositis (s-IBM) is an acquired inflammatory muscle disease of unknown cause. In
general, s-IBM presents with slowly progressive, asymmetric weakness, and atrophy of skeletal muscle. There is
a mild transitory or nil responsiveness to standard immunosuppressive treatment. A controlled cross-over study of
22 s-IBM patients over 3 months showed a partial improvement in those treated with high-dose intravenous
immunoglobulin therapy (IVIG) versus placebo. The present study included 22 patients aged 32-75 years and with
a mean duration of disease of 5.2+/-3.6 years. They were randomized by a double-blind, placebo-controlled,
cross-over design to monthly infusions of 2 g/kg bodyweight IVIG or to placebo for 6 months each, followed by the
alternative treatment. After 6 and 12 months the response to treatment was evaluated, using a modified Medical
Research Council scale, Neuromuscular Symptom Score (NSS), the patient'
s own assessment of improvement,
24
arm outstretched time, and electromyography. No serious side effects were seen, in particular no viral infection
and no major cardiac or neurological complications. Overall there was no progression of the disease in 90% of
patients, unlike that which might have been expected in untreated patients. A mild and significant improvement
(11%) in clinical symptoms was found using NSS, but not with other test procedures. There was a trend to mild
improvement in treated patients when using other tests. Individual responses to treatment was heterogeneous.
The validity of this study may be reduced by mismatch of groups with regard to age at onset and variability in
disease expression. The findings of this study largely confirm those of a previous IVIG trial. Treatment with IVIG
may be mildly effective in s-IBM by preventing disease progression or inducing mild improvement. Long-term
studies are needed to evaluate further the benefit of IVIG therapy in s-IBM.
Sparks S, Rakocevic G, Joe G, Manoli I, Shrader J, Harris-Love M, Sonies B, Ciccone C, Dorward H, Krasnewich
D, Huizing M, Dalakas MC, Gahl WA. Intravenous immune globulin in hereditary inclusion body myopathy: a pilot
study. BMC Neurol. 2007 Jan 29;7:3.
BACKGROUND: Hereditary Inclusion Body Myopathy (HIBM) is an autosomal recessive, adult onset, noninflammatory neuromuscular disorder with no effective treatment. The causative gene, GNE, codes for UDP-Nacetylglucosamine 2-epimerase/N-acetylmannosamine kinase, which catalyzes the first two reactions in the
synthesis of sialic acid. Reduced sialylation of muscle glycoproteins, such as alpha-dystroglycan and neural cell
adhesion molecule (NCAM), has been reported in HIBM. METHODS: We treated 4 HIBM patients with
intravenous immune globulin (IVIG), in order to provide sialic acid, because IgG contains 8 micromol of sialic
acid/g. IVIG was infused as a loading dose of 1 g/kg on two consecutive days followed by 3 doses of 400 mg/kg
at weekly intervals. RESULTS: For all four patients, mean quadriceps strength improved from 19.0 kg at baseline
to 23.2 kg (+22%) directly after IVIG loading to 25.6 kg (+35%) at the end of the study. Mean shoulder strength
improved from 4.1 kg at baseline to 5.9 kg (+44%) directly after IVIG loading to 6.0 kg (+46%) at the end of the
study. The composite improvement for 8 other muscle groups was 5% after the initial loading and 19% by the end
of the study. Esophageal motility and lingual strength improved in the patients with abnormal barium swallows.
Objective measures of functional improvement gave variable results, but the patients experienced improvements
in daily activities that they considered clinically significant. Immunohistochemical staining and immunoblotting of
muscle biopsies for alpha-dystroglycan and NCAM did not provide consistent evidence for increased sialylation
after IVIG treatment. Side effects were limited to transient headaches and vomiting. CONCLUSION: The mild
benefits in muscle strength experienced by HIBM patients after IVIG treatment may be related to the provision of
sialic acid supplied by IVIG. Other sources of sialic acid are being explored as treatment options for HIBM.
Cherin P, Pelletier S, Teixeira A, Laforet P, Simon A, Herson S, Eymard B. Intravenous immunoglobulin for
dysphagia of inclusion body myositis. Neurology. 2002 Jan 22;58(2):326 : no abstract available.
Description de 4 cas de patients atteints de troubles oesophagiens menaçant le pronostic vital et dont les troubles
de la déglutition se sont améliorés de façon spectaculaire après administration d’IgIV seules ou en association à
un traitement corticoïde.
25
Polymyosite cortico-résistante en 2ème intention en cas d’échec, de
dépendance, d’intolérance et de contre-indication aux corticoïdes
La dose recommandée est de 2 g/kg/mois pendant 6 mois puis demi-dose pendant 6 mois.
Contre-indications
de Gammagard®);
excipients et est
érable et
d'
hyperprolinémie.
intolérance.
IgIV.
- de s'
26
IgG Gammagard®) et
de détecter d'
Le risque d'
Des cas d'
administration d'
IgIV impose :
Bien que ces cas d'
d'
Traitement associé
L'
vaccins.
IgIV, l'
animal n'
IV, et l'
enceinte qu'
27
28
2.
ARGUMENTAIRE
La polymyosite est une maladie rare se caractérisant par une inflammation et une dégénérescence
des fibres constituant les muscles squelettiques. Il s'
agirait d'
une atteinte du collagène, peut-être d'
une
maladie par hypersensibilité retardée (mécanisme auto-immunitaire : le malade fabrique des anticorps
contre ses propres tissus). La polymyosite touche environ 2 femmes pour 1 homme, on compte 6 cas pour
100 000 personnes.
Le seul traitement connu est la corticothérapie (traitement par cortisone); ce traitement stabilise la
maladie, mais ne la guérit pas. En cas d’échec, d’intolérance ou de dépendance aux corticoïdes, un
traitement immunosuppresseur est souvent proposé et l’usage des IgIV peut être efficace.
Il n’y a pas d’études contrôlées mais 20-30 publications d’études ouvertes sont toutes concordantes
avec 60-70% d’efficacité.
Une étude rétrospective utilisant la Tégéline® dans des dermatomyosites et polymyosites
corticorésistantes est en cours de publication : 63% d’efficacité + épargne cortisonique ont été
observés parmi les 32 polymyosites corticorésistantes, dépendantes ou intolérantes aux corticoïdes
inclues dans cette étude.
Une étude randomisée versus placebo dans les dermatomyosites et polymyosites cortico-résistantes
et résistantes aux immunosuppresseurs est en cours sur la demande de l’EMEA (laboratoire
Orphagen).
Effet des IgIV dans les polymyosites cortico-résistantes
Auteurs
Type d’étude
Posologie
Suivi
Critères
d’évaluation
IgIV :
51,4 +/--Force
1 g /kg pdt 2 j, 13,1
musculaire
renouvelés ts mois
-Troubles de
les mois pdt 4 pour lesla déglutition
à 6 mois
25
-Taux de CPK
patients
réponde
urs
Cherin Ouverte
(2002) N = 35
Après échec de :
- prednisone (n = 35),
- méthotrexate (n = 24),
- azathioprine (n = 13),
- cyclophosphamide (n = 4),
- cyclosporine (n = 7),
- chlorambucil (n = 1),
- plasmaphérèse (n = 8),
- lymphophérèse (n = 1)
- irradiation corporelle totale (n = 1)
Cherin Ouverte
IgIV :
N = 30 (22 PM et 8 DM)
(1993)
3 à 6 cures
Après échec de :
mensuelles de
- corticoïdes (n = 29),
2 g /kg /j
- immunosuppresseurs (n = 28),
-irradiation corporelle totale (n = 1)
Cherin Ouverte
IgIV :
(1991) N = 20 (12 PM, 6 DM, 2 myosite + 1g /kg /j pdt
connectivite)
2j :
Après échec de :
n = 13
ou 0,4 g /kg /j
- prednisone (n = 19),
pdt 5 j : n = 7
- méthotrexate (n = 10),
- azathioprine (n = 6),
- cyclophosphamide (n = 3),
- chlorambucil (n = 1),
- irradiation corporelle totale (n = 1)
DM = dermatomyosite
AC = anticorps
PM = polymyosite
BU = Bethesda Unit
Résultats
- Amélioration clinique à court terme:
25/35 (71,4 %): S
- Amélioration force musculaire S (p
< 0,01)
-↓
↓ S CPK avant la 4ème cure d’IgIV (p
< 0,01)
Score
de - Amélioration clinique : 18/30 S
force
- ↑ S du score global après la 3ème
musculaire
cure : p < 0,01
(score
max
théorique
:
88)
-Score
de - Amélioration clinique : 15/20
force
- Absence d’amélioration : 4/20
musculaire
- Aggravation : 1/20
-CPK
- Amélioration force
musculaire
après 3 cures : p < 0,01
- ↓ doses de corticoïdes après la
3ème cure : p< 0,05
-↓
↓ CPK jusqu’à la 4ème cure puis
stable
29
Bibliographie
1. Cherin P, Pelletier S, Teixeira A, Laforet P, Genereau T, Simon A, Maisonobe T, Eymard B, Herson S. Results and long-term
followup of intravenous immunoglobulin infusions in chronic, refractory polymyositis: an open study with thirty-five adult patients.
Arthritis Rheum.2002 Feb;46(2):467-74.
2. Chérin P, Herson S. Immunoglobulins or plasma exchange? New treatment methods in polymyositis and dermatomyositis:
plasma exchange and intravenous immunoglobulins. Ann Med Interne (Paris). 1993;144(8):521-5.
3. Cherin P, Herson S, Wechsler B, Piette JC, Bletry O, Coutellier A, Ziza JM, Godeau P.Efficacy of intravenous gammaglobulin
therapy in chronic refractory polymyositis and dermatomyositis : an open study with 20 adult patients
Am J Med. 1991 Aug;91(2):162-8
4. Mastaglia FL, Phillips BA, Zilko PJ. Immunoglobulin therapy in inflammatory myopathies.J Neurol Neurosurg Psychiatry. 1998
Jul;65(1):107-10
5. Koski CL, Patterson JV. Intravenous immunoglobulin use for neurologic diseases. J Infus Nurs. 2006 May-Jun;29(3
Suppl):S21-8.
6. Herson S, Cherin P, Coutellier A. The association of plasma exchange synchronized with intravenous gamma globulin
therapy in severe intractable polymyositis.
J Rheumatol. 1992 May;19(5):828-9.
7. Jann S, Beretta S, Moggio M, Adobbati L, Pellegrini G.High-dose intravenous human immunoglobulin in polymyositis resistant
to treatment. J Neurol Neurosurg Psychiatry. 1992 Jan;55(1):60-2.
Groupe de travail
Groupe de lecture
HCL, Lyon
Mme
BONGRAND
Marie-Claude,
pharmacien,
Pr LAVILLE
Mme
Catherine,
l’AP-HP, Paris
Lyon
30
Résumés-abstracts
Cherin P, Pelletier S, Teixeira A, Laforet P, Genereau T, Simon A, Maisonobe T, Eymard B, Herson S.Results
and long-term followup of intravenous immunoglobulin infusions in chronic, refractory polymyositis: an open study
with thirty-five adult patients. Arthritis Rheum.2002 Feb;46(2):467-74.
OBJECTIVE: Polymyositis is a rare inflammatory muscular disease of unknown cause. Corticosteroids and
immunosuppressive drugs are the first choice of therapy but are not always effective and may cause serious side
effects. Many studies have shown that polyvalent intravenous immunoglobulin (IVIG) may be of interest for the
treatment of dermatomyositis. We carried out an open, prospective study to evaluate the efficacy of IVIG in
subjects with polymyositis that was refractory to traditional treatments, and we evaluated the benefits of this
therapy over a long-term period of followup. METHODS: Thirty-five adult white patients (20 female, 15 male,
mean age 43.5 years [SD 16.8]) with chronic, refractory polymyositis were treated with high doses of IVIG, after
the patients had received the following traditional treatments: prednisone (n = 35), methotrexate (n = 24),
azathioprine (n = 13), cyclophosphamide (n = 4), cyclosporine (n = 7), chlorambucil (n = 1), plasmapheresis (n =
8), lymphopheresis (n = 1), and total body irradiation (n = 1). There had been no changes in the patients'
treatment in the 2 months before the initiation of IVIG therapy, and doses were not increased during IVIG
treatment. We used preparations of polyvalent human IVIG with increased concentrations of intact IgG. The
patients received 1 gm/kg/day for 2 consecutive days per month. The mean course of treatment was 4-6 months.
The clinical assessment involved the evaluation of proximal muscle power, muscle disability scale score, and
esophageal disorders. The biochemical evaluations carried out before each treatment period were compared by
Student'
s t-test and nonparametric Wilcoxon test. Results were considered to be significant at P = 0.05.
RESULTS: In the short-term, significant clinical improvement was noted in 25 of the 35 patients (71.4%). Mean
muscle power was estimated before and after IVIG therapy and was found to be significantly improved (P < 0.01).
All patients had a significant biochemical response. Mean creatine kinase levels during IVIG therapy decreased
significantly before the fourth IVIG perfusion (P < 0.01). Side effects, usually minor, were noted in 6 patients. This
benefit allowed the initial prednisone dose to be reduced by >50% in all patients. The mean (+/- SD) followup time
for the 25 patients who responded favorably to IVIG treatment was 51.4 +/- 13.1 months. Twelve of these 25
patients remained in full remission following their initial course of IVIG, resulting in complete stoppage of
medication in 5 patients or low doses of steroids in 7 patients. The condition of 6 patients remained improved and
no other drugs were prescribed, but the patients remained dependent on IVIG infusions. Seven of the 25 patients
who responded well to IVIG treatment relapsed at an average of 17.1 months (range 4-23 months) after the
discontinuation of IVIG. CONCLUSION: IVIG is an interesting therapy for the treatment of polymyositis, with
results showing that the condition of approximately 70% of the patients tested improved. After the discontinuation
of the IVIG therapy, the efficacy remained stable in 50% of the patients, with a followup of over 3 years.
Chérin P, Herson S. Immunoglobulins or plasma exchange? New treatment methods in polymyositis and
dermatomyositis: plasma exchange and intravenous immunoglobulins. Ann Med Interne (Paris). 1993;144(8):5215.
Plasma exchange (PE) and intravenous polyvalent immunoglobulins (IVIG) offer a new therapeutic approach to
polymyositis (PM) and dermatomyositis (DM). Plasma exchange. The largest open study of PE was reported by
Herson et al., in 57 patients with inflammatory myopathies (33 DM, 24 PM) who were resistant to classical
treatments. The patients were described as having acute (< 6 mois, n = 38) or subacute or chronic (n = 19)
disease. There were 41 females and 16 males with a mean age of 40.4 +/- 20.5 years. The mean number of PE
was 14.8 +/- 9.2. The score of muscle function improved in 54% of the patients. A significant improvement in the
muscle test was only seen in the acute forms, particularly in severe cases with impaired swallowing. The
difference was not significant in the subacute and chronic forms. Intravenous immunoglobulins. Several recent
publications have emphasized the importance of polyvalent IVIG in the treatment of inflammatory myopathies. In
our experience, 30 patients (21 females, 9 males, mean age 44.5 +/- 18) with PM (n = 22) or DM (n = 8) were
given IVIG after unsuccessful classical therapies including corticosteroids (n = 29), immunosuppressors (n = 28),
PE (n = 8), total body irradiation (n = 1), and lymphopheresis (n = 1). Three to 6 monthly cures of 2 g/kg/cure
polyvalent IVIG were given. Clinical improvement was significant as evaluated by muscle tests in 18 of the 30
patients. Global scores for the 30 patients rose from 44.2 +/- 12.7 to 65.3 +/- 17.9 points (for a theoretical
maximum of 88 points) after the third cure (p < 0.01).
Cherin P, Herson S, Wechsler B, Piette JC, Bletry O, Coutellier A, Ziza JM, Godeau P.Efficacy of intravenous
gammaglobulin therapy in chronic refractory polymyositis and dermatomyositis : an open study with 20 adult
patients. Am J Med. 1991 Aug;91(2):162-8
PURPOSE: Polymyositis and dermatomyositis are inflammatory muscular diseases of unknown cause. Many
interventions are available to treat patients with these conditions including corticosteroids, immunosuppressive
drugs, plasmapheresis, and total body irradiation. However, these therapies are not always effective, and they
may be associated with certain serious side effects. An attempt was made to evaluate the efficacy of polyvalent
31
intravenous immunoglobulin (IVIG) in patients with polymyositis or dermatomyositis refractory to traditional
treatment. PATIENTS AND METHODS: Twenty patients (16 women and 4 men; mean age 43 [16 SD] years), 14
with chronic refractory polymyositis and six with dermatomyositis, received high doses of IVIG because of the
failure of traditional treatments (prednisone [19], methotrexate [10], azathioprine [6], cyclophosphamide [3],
cyclosporine [3], chlorambucil [1], plasmapheresis [8], lymphopheresis [1], and total body irradiation [1]). In one
patient with positive results on picornavirus serologic testing, IVIG was the first treatment choice. IVIG therapy
was given with prednisone in 15 patients, with methotrexate in six patients, and with plasmapheresis in one
patient. There were no changes in treatment in the 2 months before the introduction of IVIG therapy and no
increases in dose during this treatment. Preparations of polyvalent human intravenous gammaglobulins with
increased intact immunoglobulin G were used. Thirteen patients received 1 g/kg daily for 2 days each month, and
seven patients received 0.4 g/kg daily for 5 days each month. The mean duration of treatment was 4 months.
RESULTS: Clinical assessment, which consisted of the measurement of proximal muscle power, and biochemical
studies were carried out before each treatment period. Significant clinical improvement was noted in 15 of the 20
patients. Mean muscle power estimated for the 20 patients before and after IVIG therapy was statistically
significantly reduced (p less than 0.01). Eighteen patients showed biochemical improvement, and two patients
with normal initial serum creatine kinase levels showed clinical improvement. Mean creatine kinase levels for the
20 patients during IVIG therapy showed a statistically significant decrease from the first IVIG perfusions (p less
than 0.01). Side effects of IVIG therapy were noted in four patients; however, these effects were mild. During IVIG
therapy, steroid doses were significantly reduced from the second or the third IVIG infusion (p less than 0.05).
CONCLUSION: IVIG is an efficacious new therapy for polymyositis and dermatomyositis and should play a role in
the treatment of these diseases, replacing or reducing steroid and immunosuppressive medications.
Mastaglia FL, Phillips BA, Zilko PJ. Immunoglobulin therapy in inflammatory myopathies. J Neurol Neurosurg
Psychiatry. 1998 Jul;65(1):107-10
A prospective open label trial of add on therapy with intravenous immunoglobulin (i.v.Ig) was carried out in 16
patients with inflammatory myopathy who had continued to deteriorate or had relapsed on conventional therapy.
The response was assessed using isometric myometry, functional scales, MRC grading, and serum creatine
kinase concentrations with a three month run in period before commencement of i.v.Ig. Five of seven patients with
isolated dermatomyositis or polymyositis and all four patients with an overlap syndrome responded to i.v.Ig with
partial or complete remission of disease and normalisation of serum creatine kinase concentrations. None of five
patients with inclusion body myositis showed any functional improvement although myometry scores improved in
some muscles in one case. It is concluded that i.v.Ig is an effective therapeutic option in patients with drug
resistant polymyositis or dermatomyositis. However, further controlled trials are required to confirm the efficacy of
this form of treatment and to establish optimal doses and administration regimes.
Koski CL, Patterson J. VIntravenous immunoglobulin use for neurologic diseases. J Infus Nurs. 2006 MayJun;29(3 Suppl):S21-8.
Intravenous immunoglobulin (IVIG) has been used primarily for immune deficiency patients, and its greatest
expansion is seen more and more in the treatment of autoimmune disorders, especially in neurology. The benefits
of IVIG treatment include its availability in all treatment centers and its ease of administration in an outpatient
setting. This article gives an overview of some autoimmune neurologic diseases and explores the clinical
evidence supporting the use of IVIG.
High-dose intravenous human immunoglobulin in polymyositis resistant to treatment.
Jann S, Beretta S, Moggio M, Adobbati L, Pellegrini G. J Neurol Neurosurg Psychiatry. 1992 Jan;55(1):60-2.
Two patients were treated with treatment-resistant polymyositis with intravenous immunoglobulin over four days
at a dose of 0.4 g/kg/day. Clinical recovery followed within two months. Serum creatine kinase (CK) activity
decreased to normal, and a clear improvement in muscle strength was observed. One patient showed neither
clinical relapses nor increase in serum CK activity after 20 months. The other showed a mild increase in serum
CK activity after 24 months and was successfully retreated with intravenous immunoglobulin. There were no
significant adverse side effects.
32
SYNDROME DE MILLER-FISHER
1.
PROTOCOLE THERAPEUTIQUE TEMPORAIRE
Les doses recommandées sont soit 0.4 g/kg pendant 5 jours, soit 1 g/kg pendant 2 jours
Contre-indications
de Gammagard®);
excipients et est
érable et
d'
hyperprolinémie.
intolérance.
IgIV.
- de s'
IgG Gammagard®) et
33
de détecter d'
Le risque d'
Des cas d'
administration d'
IgIV impose :
Bien que ces cas d'
d'
Traitement associé
L'
vaccins.
IgIV, l'
animal n'
IV, et l'
enceinte qu'
34
Ce protocole temporaire de traitement est limité à une durée de 4 ans.
35
2.
ARGUMENTAIRE
Le syndrome de Miller Fisher est une variante du Syndrome de Guillain-Barré caractérisée par une
ophtalmoplégie, une ataxie, et une aréflexie ostéotendineuse avec une faiblesse motrice relative des
extrémités. Il s’agit d’une maladie auto-immune avec des anticorps (AC anti-GQ1b) dirigés contre la
myéline se trouvant dans les nerfs périphériques.
Etant donné que les IgIV ont l’AMM dans le Guillain-Barré, que le syndrome de Miller-Fischer est une
forme de Guillain-Barré et qu’il y a peu d’études de bon niveau de preuve le concernant, le traitement
par IgIV est temporairement acceptable dans cette situation.
Effet des IgIV dans le syndrome de Fisher et l’encéphalite de Bickerstaff
Auteurs
Type d’étude
Résultats
Overell
(2007)
Cochrane
Pas de conclusion possible sur
Etudes rétrospectives de immunomodulateur dans ces syndromes
faible effectif
l’intérêt
d’un
traitement
Bibliographie
synthèse publiés en langue française ou anglaise.
Overell JR, Hsieh ST, Odaka M, Yuki N, Willison HJ. Treatment for Fisher syndrome, Bickerstaff'
s brainstem encephalitis and
related disorders.Cochrane Database Syst Rev. 2007 Jan 24;(1):CD004761
Groupe de travail
Groupe de lecture
HCL, Lyon
Mme
BONGRAND
Marie-Claude,
pharmacien,
Pr LAVILLE
Mme
Catherine,
l’AP-HP, Paris
Lyon
36
Résumé-abstract
Overell JR, Hsieh ST, Odaka M, Yuki N, Willison HJ. Treatment for Fisher syndrome, Bickerstaff'
s brainstem
encephalitis and related disorders. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD004761
BACKGROUND: Fisher syndrome is one of the regional variants of Guillain-Barré syndrome, characterised by
impairment of eye movements (ophthalmoplegia), incoordination (ataxia) and loss of tendon reflexes (areflexia). It
can occur in more limited forms, and may overlap with Guillain-Barré syndrome. A further variant is associated
with upper motor neuron signs and disturbance of consciousness (Bickerstaff'
s brainstem encephalitis). All of
these variants are associated with anti-GQ1b IgG antibodies. Intravenous immunoglobulin (IVIg) and plasma
exchange are often used as treatments in this patient group. This review was undertaken to systematically assess
any available randomised controlled data on acute immunomodulatory therapies in Fisher Syndrome or its
variants. OBJECTIVES: To provide the best available evidence from randomised controlled trials on the role of
acute immunomodulatory therapy in the treatment of Fisher Syndrome and related disorders. SEARCH
STRATEGY: We searched the Cochrane Neuromuscular Disease Trials register (March 2004), MEDLINE (from
January 1966 to November 2004), EMBASE (from January 1980 to November 2004), CINAHL (from January
1982 to November 2004) and LILACS (from January 1982 to November 2004) for randomised controlled trials,
quasi-randomised trials, historically controlled studies and trials with concurrent controls. We adapted this
strategy to search MEDLINE from 1966 and EMBASE from 1980 for comparative cohort studies, case-control
studies and case series. SELECTION CRITERIA: All randomised and quasi-randomised controlled clinical trials
(in which allocation was not random but was intended to be unbiased, e.g. alternate allocation, and nonrandomised controlled studies were to have been selected. Since no such clinical trials were discovered, all
retrospective case series containing five or more patients were assessed and summarised in the discussion
section. DATA COLLECTION AND ANALYSIS: All studies of Fisher Syndrome and its clinical variants were
scrutinised for data on patients treated with any form of acute immunotherapy. Information on the outcome was
then collated and summarised. MAIN RESULTS: We found no randomised or non-randomised prospective
controlled trials of immunotherapy in Fisher Syndrome or related disorders. We summarised the results of
retrospective series containing five or more patients in the discussion section. AUTHORS'CONCLUSIONS: There
are no randomised controlled trials of immunomodulatory therapy in Fisher Syndrome or related disorders on
which to base practice.
37
Syndrome de l’homme raide réfractaire aux anti-convulsivants ou
insuffisamment contrôlés par les anti-épileptiques
1 g/kg/j, 2j/mois pendant 3mois
Contre-indications
de Gammagard®);
excipients et est
érable et
d'
hyperprolinémie.
intolérance.
IgIV.
- de s'
38
IgG Gammagard®) et
de détecter d'
Le risque d'
Des cas d'
administration d'
IgIV impose :
Bien que ces cas d'
d'
Traitement associé
L'
vaccins.
IgIV, l'
animal n'
IV, et l'
enceinte qu'
39
Ce protocole temporaire de traitement est limité à une durée de 4 ans.
40
2.
ARGUMENTAIRE
Le syndrome de l'
homme raide (appelé aussi syndrome de Moersch-Woltman ou stiff-man) est
caractérisé par des épisodes apparentés à de la tétanie suivis d'
hypertonie progressive et
généralisée. Cette hypertonie, parfois douloureuse, prédomine au tronc et aux racines des membres.
Les accès sont souvent déclenchés par le froid ou par une émotion. L'
affection se manifeste chez
l'
adulte et évolue pendant des années. Une origine auto-immune est souvent évoquée devant la
présence d’anticorps anti-GAD et l’association à des maladies auto-immunes, mais le rôle précis de
ces anticorps reste à définir.
Les traitements immunomodulateurs, tels que les immunoglobulines et les échanges plasmatiques,
sont souvent utiles pour modifier l’histoire naturelle de la maladie ou diminuer les doses du traitement
symptomatique, afin d’en limiter les effets indésirables fréquents avec les posologies nécessaires à
l’amélioration des troubles.
Des séries de cas avaient suggéré l’efficacité des IgIV sur les symptômes et la qualité de vie. Un essai
randomisé a prouvé leur efficacité sur les symptômes et les capacités fonctionnelles en add-on sur le
traitement conventionnel (benzodiazépines ou autres antiépileptiques).
Il s’agit donc d’une situation temporairement acceptable chez des patients insuffisamment contrôlés
par les antiépileptiques.
Il est noté que l’effet des IgIV serait plus important en présence d’anticorps anti-GAD.
Effet des IgIV dans le syndrome de l’homme raide
Auteurs
Dalakas
(2001)
Type d’étude
Comparative
cross-over
versus
placebo
N = 16
Posologie
Suivi
IgIV :
1 an
1g/kg/j pdt 2j/mois
pdt 3mois
Critères
d’évaluation
- Scores de
raideur
Score
de
sensibilité
intense
AC
anti
GAD65
Résultats
- Scores de raideur : ↓ S (p =0.02)
- Scores de sensibilité intense : ↓ S
puis ↑ pdt la phase placebo
er
Patients ayant reçu le placebo en 1 :
scores inchangés puis ↓ S pdt la
phase IgIV (p=0.01)
11/16 : capable de marcher sans
assistance et ↓ fréquence des chutes
Ces effets sont durables : 6 semaines
à 1 an
Gerschlager
(2002)
N=6
Amato
(1994)
N=3
Karlson
(1993)
N=3
Patients
résistants
à
d’autres
thérapeutiques
N=3
Cantiniaux
(2006)
IgIV :
0.4g/kg/j pdt 5j/mois
avec des intervalles
entre 6 et 10
semaines
5/6 ont déjà reçu
des cures d’IgIV >
72 mois avant
IgIV :
0.4g/kg/j pdt 5j+0.5
à 2g/kg à 3-4 sem
d’intervalle
↓ AC anti GAD65
-Qualité de vie
↑ S de la qualité de vie, de l’échelle
Echelle analogue visuelle, du score SF36
analogue
visuelle
- Score SF36 :
douleur, état de
santé mental,
vitalité.
- Echelle de
sévèrité
des
troubles
- AC anti-GAD
Amélioration de la marche (sans
assistance), des douleurs de dos, de
la raideur, des spasmes
mais pas ↓ des AC anti GAD
IgIV :
0.4g/kg/j pdt 5j puis
1x/mois pdt 3mois
- AC anti-GAD
- EMG
Amélioration dans les 3 cas
- Baclofène +IgIV :
n=1
-Baclofène
intrathécal (IgIV
- AC anti-GAD
Amélioration dans les 3 cas
AC
antiamphiphysine
-EMG
41
Auteurs
Type d’étude
AC anti-GAD :
Posologie
Suivi
Critères
d’évaluation
-IRM
Résultats
inefficace): n = 1
-IgIV +
corticostéroïdes :
n=1
glutamic acid decarboxylase (inhibent la synthèse du GABA)
Bibliographie
1. Dalakas MC, Fujii M, Li M, Lutfi B, Kyhos J, McElroy B. High-dose intravenous immune globulin for stiff-person syndrome. N
Engel J Med. 2001 Dec 27;345(26):1870-6.
2. Cantiniaux S, Azulay JP, Boucraut J, Pouget J, Attarian S. Stiff man syndrome: clinical forms, treatment and clinical course.
Rev Neurol (Paris). 2006 Sep;162(8-9):832-9.
3. Amato AA, Cornman EW, Kissel JT.Treatment of stiff-man syndrome with intravenous immunoglobulin.
Neurology. 1994 Sep;44(9):1652-4.
4. Karlson EW, Sudarsky L, Ruderman E, Pierson S, Scott M, Helfgott SM. Treatment of stiff-man syndrome with intravenous
immune globulin.Arthritis Rheum. 1994 Jun;37(6):915-8.
5. Gerschlager W, Brown P. Effect of treatment with intravenous immunoglobulin on quality of life in patients with stiff-person
syndrome. Mov Disord. 2002 May;17(3):590-3.
Groupe de travail
Groupe de lecture
HCL, Lyon
Mme
BONGRAND
Marie-Claude,
pharmacien,
Pr LAVILLE
Mme
Catherine,
l’AP-HP, Paris
Lyon
42
Résumés-abstracts
Dalakas MC, Fujii M, Li M, Lutfi B, Kyhos J, McElroy BHigh-dose intravenous immune globulin for stiff-person
syndrome.. N Engl J Med. 2001 Dec 27;345(26):1870-6.
BACKGROUND: Stiff-person syndrome is a disabling central nervous system disorder with no satisfactory
treatment that is characterized by muscle rigidity, episodic muscle spasms, high titers of antibodies against
glutamic acid decarboxylase (GAD65), and a frequent association with autoimmune disorders. Because stiffperson syndrome is most likely immune-mediated, we evaluated the efficacy of intravenous immune globulin.
METHODS: We assigned 16 patients who had stiff-person syndrome and anti-GAD65 antibodies, in random
order, to receive intravenous immune globulin or placebo for three months, followed by a one-month washout
period and then by three months of therapy with the alternative agent. Efficacy was judged by improvements in
scores on the distribution-of-stiffness index and heightened-sensitivity scale from base line (month 1) to the
second and third month of each treatment phase. Direct and carryover effects of treatment were compared in the
two groups. RESULTS: Among patients who received immune globulin first, stiffness scores decreased
significantly (P=0.02) and heightened-sensitivity scores decreased substantially during immune globulin therapy
but rebounded during placebo administration. In contrast, the scores in the group that received placebo first
remained constant during placebo administration but dropped significantly during immune globulin therapy
(P=0.01). When the data were analyzed for a direct and a first-order carryover effect, there was a significant
difference in stiffness scores (P=0.01 and P<0.001, respectively) between the immune globulin and placebo
groups, and immune globulin therapy had a significant direct treatment effect on sensitivity scores (P=0.03).
Eleven patients who received immune globulin became able to walk more easily or without assistance, their
frequency of falls decreased, and they were able to perform work-related or household tasks. The duration of the
beneficial effects of immune globulin varied from six weeks to one year. Anti-GAD65 antibody titers declined after
immune globulin therapy but not after placebo administration. CONCLUSIONS: Intravenous immune globulin is a
well-tolerated and effective, albeit costly, therapy for patients with stiff-person syndrome and anti-GAD65
antibodies.
Cantiniaux S, Azulay JP, Boucraut J, Pouget J, Attarian S.Stiff man syndrome: clinical forms, treatment and
clinical course. Rev Neurol (Paris). 2006 Sep;162(8-9):832-9.
INTRODUCTION: Stiff-Man syndrome (SMS) is a rare neurological disease first described fifty years ago. There
are several clinical forms, which are frequently misdiagnosed. The aim of this study is to review three of the main
clinical forms. MATERIAL AND METHODS: Case reports concerning three women suffering from different forms
of SMS are presented, giving the main clinical features, their associations with other diseases, and the biological
and electrophysiological findings. RESULTS: The first patient presented a symmetric axial muscle rigidity, painful
spasms and contractions of the trunk and limbs associated with anti-GAD antibodies. The common form of SMS
was diagnosed and the patient was improved by intravenous immunoglobulin (IVIg). The second patient suffered
from contractions and spasms localized to the lower limbs. In this patient, anti-GAD antibodies were absent. The
Stiff-Leg syndrome was diagnosed and the patient was improved by intrathecal baclofen. The third patient
presented rigidity of limb and trunk muscles associated with signs of encephalitis. In this patient, only antiamphiphysin antibodies were present. The progressive encephalomyelitis with rigidity was diagnosed and the
patient was improved by IVIg associated with corticosteroid. CONCLUSION: Identifying patients with SMS makes
it possible to propose appropriate medical management. There are several forms of the disease, and the severity
of the evolution differs in each case. Treatment with GABA-ergic inhibitory drugs, IVIg and corticosteroid improve
both the symptomatology and the quality of life of these patients.
Amato AA, Cornman EW, Kissel JT.Treatment of stiff-man syndrome with intravenous immunoglobulin.
Neurology. 1994 Sep;44(9):1652-4.
Stiff-man syndrome (SMS) is a rare disorder characterized by progressive rigidity, stiffness, and spasms of axial
and extremity muscles. The etiology of SMS is unknown, but evidence suggests a possible autoimmune basis.
The recent successful use of intravenous immunoglobulin (IVIG) in treating various autoimmune neuromuscular
disorders led us to try IVIG in an uncontrolled pilot study on three patients. All three showed subjective and
objective improvement.
Karlson EW, Sudarsky L, Ruderman E, Pierson S, Scott M, Helfgott SM. Treatment of stiff-man syndrome with
intravenous immune globulin. Arthritis Rheum. 1994 Jun;37(6):915-8.
OBJECTIVE. To evaluate the efficacy of intravenous immune globulin (IVIG) in the treatment of stiff-man
syndrome (SMS). METHODS. An open, unblinded study of 3 patients with active disease and/or disease
refractory to treatment with diazepam and/or corticosteroids. RESULTS. All 3 bedridden patients improved
43
substantially shortly after infusion with IVIG and regained function. CONCLUSION. IVIG may be useful for the
treatment of SMS.
Gerschlager W, Brown P. Effect of treatment with intravenous immunoglobulin on quality of life in patients with
stiff-person syndrome. Mov Disord. 2002 May;17(3):590-3.
The therapeutic effects of intravenous immunoglobulin (IVIG) on the stiff-person syndrome (SPS) have been
described exclusively in case reports or open-label studies in terms of clinical outcomes. We investigate whether
IVIG improves quality of life (QoL) in the SPS. Six patients with the classic form of SPS completed a generic QoL
instrument, the SF-36, and a Visual Analogue Scale (VAS) before treatment as well as 2 weeks after completion
of a course of IVIG. There was significant improvement in the SF-36 subscores for pain, social functioning,
general mental health, and energy-vitality with treatment. The VAS also improved significantly. We conclude that
treatment with IVIG improves QoL in the SPS.
44
Vascularites systémiques ANCA positives en cas de rechute ou de
résistance à l'
association corticoïdes et immunosuppresseurs
La dose recommandée est de 2 g/kg chaque mois.
Contre-indications
de Gammagard®);
un des constituants de la préparation.
excipients et est
érable et
d'
hyperprolinémie.
intolérance.
IgIV.
- de surveiller attentivement le débit des perfusions ;
- de s'
45
IgG Gammagard®) et
de détecter d'
Le risque d'
Des cas d'
administration d'
IgIV impose :
Bien que ces cas d'
d'
Traitement associé
L'
vaccins.
IgIV, l'
animal n'
IV, et l'
enceinte qu'
46
47
2.
ARGUMENTAIRE
La pathogénie des vascularites systémiques associées aux anticorps anti-cytoplasme de
polynucléaires neutrophiles (ANCA) est incomplètement élucidée.
Parmi les vascularites ANCA-positives qui intéressent les vaisseaux de petit calibre, on distingue la
granulomatose de Wegener (GW), la polyangéite microscopique (MPA) et le syndrome de Churg et
Strauss (SCS). Au cours de ces pathologies, les ANCA constituent un outil précieux d'
aide au
diagnostic.
Le traitement de référence des vascularites ANCA-positives, repose sur l'
association de prednisone et
de cyclophosphamide. L'
efficacité de ce traitement est cependant tempérée par la survenue de
rechutes dans 20 à 50 % des cas et par la fréquence élevée des effets indésirables.
Une étude comparative versus placebo (Jayne 2000à ainsi que deux études ouvertes récentes Ito
Ihara 2006et Martinez 2007) ont montré de bons résultats des IgIV dans le traitement des vascularites
à ANCA, avec une diminution du score de BVAS (Birmingham vasculitis activity score), corrélée à une
diminution du titre des ANCA. L’étude de Martinez sur 22 patients avec de la Tegéline® a montré une
rémission complète au 24éme mois de traitement pour 8 patients.
L’usage des immunoglobulines est temporairement acceptable dans les vascularites à ANCA en cas
de rechute ou de résistance à l’association corticoïdes et immunosuppresseurs, dans l’attente d’un
dépôt d’extension d’AMM.
La place des IgIV dans la stratégie thérapeutique par rapport à l’infliximab et au rituximab, qui font
l’objet de PTT pour cette même indication, n’est pas définie à ce jour.
Effet des IgIV dans le traitement des vascularites systémiques ANCA positives
Auteurs Type d’étude
Posologie
Suivi
Jayne
(2000)
Comparative,
Sandoglobuline®
double
400 mg/kg/j pdt 5j
aveugle,
randomisée et
vs placebo
N= 34
12 mois
Jayne
(1993)
Ouverte
N=26
Sandoglobuline®
400 mg/kg/j pdt 5j
1 an.
Martinez
(2007)
Ouverte
N= 22
Tegeline®
24 mois
500 mg/j pdt 4 j
consécutifs
par
Résultats
- Critère de succès du - Succès du traitement : (p=0.015)
traitement : réduction de . IgIV : 14/17 patients
50% du score BVAS
. Placebo : 6/17 patients
- CRP
- ↓ S scores BVAS :
Nécessité
d’un . IgIV : J0 : 6.1
traitement
adjuvant :
M1 : 2.9
immunosuppresseurs
M3 : 2
. Placebo : J0 : 5.4
M1 : 4.53
M3 : 3.1
- ↓ CRP de J0 à J15 (p=0.02) et
de J0 à M1 (p=0.04) :
. IgIV: 3.5 et 4
. Placebo : 3.8 et 0
- NS sur le nbre de sujets avec
des ANCA positives
ttt
adjuvant
similaire
(prednisolone)
- Nbre d’effets indésirables :
. IgIV: 17
. Placebo : 6
- Etat clinique :
- Rémission totale : n=19
Score 2 : maladie active - Rémission partielle : n=6
Score
1:
rémission - 1 mort par choc septique
partielle
- ↓ VS : de 41 à 24 mm/h
Score
0:
rémission - ↓ ANCA : 17 à 7
totale
- ↓ CRP : de 35 à 10 mg/L
- ANCA
- de J10 à S4 : rash cutané : n =6
- CRP
- ↓ doses de cyclophosphamide
- VS
de 55 à 50 mg/j et de
prednisolone de 16 à 6 mg/j.
- CRP, score BVAS 2003 - A M6 :
permettant de définir :
. 1 ET
.Rémission
complète . 16 CR
48
Posologie
mois
mois
durant
Suivi
6
Résultats
(CR) : BVAS=0
. Rémission partielle
(PR) :
symptômes
cliniques et biologiques:
BVAS de 50%
.Echec
thérapeutique
(ET) : apparition d’un
nouvel effet secondaire
- Score SF36
. 2 PR
- A M9 : 13 CR
- A M24:
. 8 CR
. 1 PR
. ↓ du score BVAS de [3,25] à
[0,12]
. NS du score SF36 : de 39.11
à 39.94
.4/24 ANCA positives
- Rémission totale : n=0
- Rémission partielle n=5
- Administration répétée 1/M n’a
pas montré d’amélioration clinique
- CRP et ANCA de 50% en 1M
chez 3 sujets
- Améliorations cliniques non
corrélées aux valeurs de CRP et
ANCA
A M3 :
- ↓ GB : de 9820 à 7960
cellules/mm3 (p<0.01)
- ↓ CRP : de 95 à 57
mg/L(p<0.001)
- ↓ créat de 419 à 173 µmol/L
- ↓ BVAS score : de 20 à 8
(p<0.0001)
- ↓ S du titre des MPO-ANCA :
de 466 à 78.8 EU/mL
- Hypertension modérée +
œdèmes des extrémités résorbés
à l’arrêt du traitement chez 1
patient.
- Rémission totale : n=4 en 1an
. 2/4 nécessiteront après 1 an
un traitement adjuvant
- Rémission partielle : n=2
(nécessité
d’un
traitement
conventionnel)
- taux d’ANCA de S1 à S3 :
Patient 1 : de 38 à 10
Patient 4 : de 87.5 à 30
- Effet indésirable :
1 rash cutané spontanément
résolu
Richter
(1995)
Ouverte
N=15
ANCA positive
IgIV
30 000 mg/j pdt
5j
4 sem.
- Observations cliniques,
DEI index, ORL, MRT
- CRP, ANCA
Ito Ihara
(2006)
Ouverte
N=12
MPO-ANCA
sérique
Atteinte rénale
IgIV
3 mois
400 mg/kg/j pdt 5 j
- MPO-ANCA sérique,
CRP, taux de GB
- Fonction rénale : creat
- Score de l’activité de la
vascularite BVAS
Jayne
(1996)
N=6
ANCA positive
Sandoglobuline®
500 mg/kg/j
pdt 4 j
Arahata
(1999)
N=2
Patient 1 :
. âge = 34 ans
. SLE
. Syndrome
néphrotique
. MPO-ANCA
IgIV ?
?
associées à des
stéroïdes
+
immunosuppres
seurs
Tuso
(1992)
Patient 2 :
. âge = 39 ans
. SLE
. atteinte rénale
. Stéroïdes,
immunosuppres
seurs et
plasmaphérèse
inefficaces pdt
la crise rénale
N=2
Age : 66 et 14
16 à 48 Vascularite
définie
mois
selon l’état clinique : en
activité ou en rémission
totale ou partielle
- CRP
- ANCA activité
Fonction
hémodialyse
protéinurie
- MP0-ANCA
rénale : - Fonction rénale améliorée:
et . arrêt de l’hémodialyse
. ↓ protéinurie : de 4.4 à 0.5 g/j
- MPO-ANCA : ↓ de 48 à 5 EU/mL
IgIV : 12.5 g/j pdt
5j
Puis relais par
prednisolone
et
azathioprine
Ig IV :
500 mg/kg/j pdt 4 j
- Radio pulmonaire, C- Patient 1 :
ANCA, créatinine
. amélioration
de
la
radio
49
Posologie
Suivi
Résultats
ans
Résistance/intol
érance
aux
corticoïdes
et
Cyclophospham
ide
pulmonaire
. ↓ créat : 353.1 à 132 µmol/L
. ↓ C-ANCA : 162 à 62 SLI u/mL
Patient 2 :
. ↓ C-ANCA :
- A J4 : 81 à 61 SLI u/mL
ème
adm de 4 j : 79 à 43 SLI
- 2
u/mL
1 : Jayne DRW et al. ANCA and the prediction of relapse. Q. J. Med. 1995; 88:127-33
AC : anticorps
BVAS : Birmingham
vasculitis activity
score
Créat : concentration
de créatinine sérique
CRP : C-reactive
protein
DEI: Disease Extend
Index
GB : globules blancs
GR : globules rouges
Ht : hématocrite
Hosp. :
Hospitalisation
IU : unités
internationales
J : jour
M : mois
Nbre : nombre
Pla : groupe placebo
Pdt : pendant
S : significatif
Sem. : Semaine
Trt : traitement
VS : vitesse de
sédimentation
Bibliographie
1. Jayne DR, Chapel H, Adu D, Misbah S, O'
Donoghue D, Scott D, Lockwood CM. Intravenous immunoglobulin for ANCAassociated systemic vasculitis with persistent disease activity. QJM. 2000 Jul;93(7):433-9
2. Jayne DR, Lockwood CM.Pooled intravenous immunoglobulin in the management of systemic vasculitis. Adv Exp Med Biol.
1993;336:469-72.
3. Martinez V, Cohen P, Pagnoux C, Vinzio S, Mahr A, Mouthon L, Sailler L, Delaunay C, Sadoun A, Guillevin L; Intravenous
immunoglobulins for relapses of systemic vasculitides associated with antineutrophil cytoplasmic autoantibodies: results of a
multicenter, prospective, open-label study of twenty-two patients. French Vasculitis Study Group. Arthritis Rheum. 2008
Jan;58(1):308-17
4. Richter C, Schnabel A, Csernok E, De Groot K, Reinhold-Keller E, Gross WL. Treatment of anti-neutrophil cytoplasmic
antibody (ANCA)-associated systemic vasculitis with high-dose intravenous immunoglobulin. Clin Exp Immunol. 1995
Jul;101(1):2-7.
5. Ito-Ihara T, Ono T, Nogaki F, Suyama K, Tanaka M, Yonemoto S, Fukatsu A, Kita T, Suzuki K, Muso E. Clinical efficacy of
intravenous immunoglobulin for patients with MPO-ANCA-associated rapidly progressive glomerulonephritis. Nephron Clin
Pract. 2006;102(1):c35-42. Epub 2005 Sep 19.
6. Jayne DR, Lockwood CM. Intravenous immunoglobulin as sole therapy for systemic vasculitis. Br J Rheumatol. 1996
Nov;35(11):1150-3.
7. Arahata H, Migita K, Izumoto H, Miyashita T, Munakata H, Nakamura H, Tominaga M, Origuchi T, Kawabe Y, Hida A,
Taguchi T, Eguchi K.Successful treatment of rapidly progressive lupus nephritis associated with anti-MPO antibodies by
intravenous immunoglobulins. Clin Rheumatol. 1999;18(1):77-81.
8. Tuso P, Moudgil A, Hay J, Goodman D, Kamil E, Koyyana R, Jordan SC.Treatment of antineutrophil cytoplasmic
autoantibody-positive systemic vasculitis and glomerulonephritis with pooled intravenous gammaglobulin. Am J Kidney Dis.
1992 Nov;20(5):504-8.
50
Groupe de travail
Pr BARDIN Thomas, rhumatologue, Paris
Dr FLOUVAT Bernard, pharmacien
Pr JACQUOT Christian, pharmacologue, Paris
Dr MASSON Charles, rhumatologue, Angers
Pr CHAUVELOT-MOACHON Laurence,
pharmacologue, Paris
Dr ROUDIER Jean, rhumatologue, Marseille
Pr HATRON Pierre-Yves, interniste, Lille
HCL, Lyon
Mme
BONGRAND
Marie-Claude,
pharmacien,
Pr LAVILLE
Mme
Catherine,
l’AP-HP, Paris
Lyon
Résumés-abstracts
Jayne DR, Chapel H, Adu D, Misbah S, O'
Donoghue D, Scott D, Lockwood CMIntravenous immunoglobulin for
ANCA-associated systemic vasculitis with persistent disease activity.. QJM. 2000 Jul;93(7):433-9
Intravenous immunoglobulin (IVIg) is a potential alternative treatment for anti-neutrophil cytoplasm antibody
(ANCA)-associated systemic vasculitis (AASV) with less toxicity than conventional immunosuppressive agents.
This randomized, placebo-controlled trial aimed to investigate the efficacy of a single course of IVIg (total dose 2
g/kg) in previously-treated AASV with persistent disease activity in whom there was an intention to escalate
therapy. Vasculitic activity was monitored by the Birmingham vasculitis activity score (BVAS), C-reactive protein
(CRP) and ANCA levels. Treatment response was defined as a reduction in BVAS of more than 50% after 3
months, and there was an intention to keep doses of concurrent immunosuppressive drugs unchanged during this
period; follow-up continued to 12 months. Seventeen patients were randomized to receive IVIg and 17 to receive
placebo. Treatment responses were found in 14/17 and 6/17 of the IVIg and placebo groups, respectively
(p=0.015, OR 8.56, 95%CI 1.74-42.2). Following infusion of trial medication, greater falls in CRP were seen at 2
weeks (p=0.02) and 1 month (p=0.04) in the IVIg group. No differences were observed between ANCA levels or
cumulative exposure to immunosuppressive drugs, and after 3 months there were no differences in CRP levels or
disease activity between the IVIg and placebo groups. Seventeen adverse effects occurred after IVIg and six after
placebo: they were mostly mild, although reversible rises in serum creatinine occurred in four from the IVIg group.
A single course of IVIg reduced disease activity in persistent AASV, but this effect was not maintained beyond 3
months; mild, reversible side-effects following IVIg were frequent. IVIg is an alternative treatment for AASV with
persistent disease activity after standard therapy.
Jayne DR, Lockwood CM.Pooled intravenous immunoglobulin in the management of systemic vasculitis. Adv Exp
Med Biol. 1993;336:469-72.
Investigation into the therapeutic use of intravenous immunoglobulin (IVIg) in systemic vasculitis was prompted by
the detection of anti-idiotype antibodies reactive with ANCA in IVIg and the proven ability of IVIg to reduce the
incidence of coronary artery aneurysms in Kawasaki disease. The efficacy and safety of IVIg (Sandoglobulin) was
assessed in an open study of 26 patients with active systemic vasculitis. Eight weeks after IVIg 13 patients were
in full and 13 in partial remission, clinical benefit was maintained in 18 twelve months later and was reflected by
changes in C-reactive protein and ANCA.
Martinez V, Cohen P, Pagnoux C, Vinzio S, Mahr A, Mouthon L, Sailler L, Delaunay C, Sadoun A, Guillevin L;
French Vasculitis Study Group.Intravenous immunoglobulins for relapses of systemic vasculitides associated with
antineutrophil cytoplasmic autoantibodies: results of a multicenter, prospective, open-label study of twenty-two
patients. Arthritis Rheum. 2008 Jan;58(1):308-17
Objective: To evaluate, at 9 and 24 months, efficacy and safety of intravenous immunoglobulins (IVIg)
administered for 6 months to treat relapses of Wegener’s granulomatosis (WG), microscopic polyangiitis (MPA)
51
occurring under treatment or during the year following corticosteroids and/or immunosuppressants
discontinuation. Patients and methods: Enrolled patients received add-on IVIg (0.5 g/kg/d/4 d) monthly for 6
months and were assessed every 3−6 months. Corticosteroids could be maintained or reintroduced at relapse;
immunosuppressants could be continued but not reintroduced. At month 9 (end point) and 24 (follow-up) the
following information was collected: complete, or partial remission, relapse assessed with BVAS 2003, IVIg
tolerance and safety. Results: Twenty-two Caucasians patients were included: 19 WG, 3 MPA; 7 men, 15 women;
median duration of systemic vasculitis: 27 [range: 7–109] months; age 53 [range: 19–75] years; BVAS 11 [range:
3–25]; 21/23 were ANCA-positive at entry. At inclusion, 21/22 patients were taking steroids and/or
immunosuppressants; all relapses were treated with those drug(s) and IVIg. All patients initially responded to IVIg:
13 complete remissions, 1 partial remission, 7 had relapsed by month 9; 8/14 responses persisted at month 24.
Seven patients had minor side effects. Conclusion: IVIg were able to induce complete remissions of relapsed
ANCA-associated vasculitides in 13/22 patients at month 9. Because of their safety and good tolerance, IVIg
could be included in a therapeutic strategy comprising other drugs to treat relapses.
Richter C, Schnabel A, Csernok E, De Groot K, Reinhold-Keller E, Gross WL. Treatment of anti-neutrophil
cytoplasmic antibody (ANCA)-associated systemic vasculitis with high-dose intravenous immunoglobulin. Clin Exp
Immunol. 1995 Jul;101(1):2-7.
In this uncontrolled study 15 patients with ANCA-associated systemic vasculitis, who were poor responders to
conventional therapy, were treated with single or multiple courses of intravenous immunoglobulin (IVIG), 30 g/day
over 5 days. Clinical and serological evaluation was performed before and 4 weeks after IVIG. Six of the 15
patients experienced clinically significant benefit from IVIG. Improvement was confined to single organ
manifestations (skin, ENT findings), no improvement was seen with conjunctivitis and scleritis, pericarditis or
nephritis. No patient experienced complete remission after IVIG. Repeated courses of IVIG at 4-week intervals
were no more effective than single courses. In six anti-proteinase 3 (PR3)-positive patients pretreatment sera
were incubated with F(ab'
)2 fragments of the IVIG preparation in vitro to measure the inhibitory effect of IVIG on
anti-PR3 activity. An inhibition of anti-PR3 activity by 25-70% was observed; this did not correlate with clinical
effects. Approximately 40% of patients benefited from IVIG treatment, though complete remission of disease
activity did not occur. Neither clinical characteristics nor the inhibitory effect of the IVIG preparation on serum antiPR3 activity in vitro predicted clinical response to this treatment modality.
Ito-Ihara T, Ono T, Nogaki F, Suyama K, Tanaka M, Yonemoto S, Fukatsu A, Kita T, Suzuki K, Muso E. Clinical
efficacy of intravenous immunoglobulin for patients with MPO-ANCA-associated rapidly progressive
glomerulonephritis. Nephron Clin Pract. 2006;102(1):c35-42
BACKGROUND: To determine whether intravenous immunoglobulin (IVIg) can control disease activity in patients
with myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated rapidly progressive
glomerulonephritis (RPGN). METHODS: Twelve patients with serologically and histologically confirmed MPOANCA-associated RPGN (7 men, 5 women; mean age 71 +/- 3 years) received IVIg (400 mg/kg/day) alone for 5
days. The effects of IVIg were evaluated by white blood cell counts, serum C-reactive protein levels, Birmingham
Vasculitis Activity Score, rate of change in reciprocal creatinine (1/Cre), and plasma tumor necrosis factor-alpha
levels after IVIg administration. Corticosteroids with or without cyclophosphamide were commenced after IVIg.
RESULTS: After IVIg treatment, a significant decrease was observed in white blood cell count (p < 0.05), Creactive protein values (p < 0.001), and Birmingham Vasculitis Activity Score (p < 0.001) concomitant with the
amelioration of systemic symptoms. The rate of change in 1/Cre significantly improved (p < 0.05). Plasma tumor
necrosis factor-alpha levels that were significantly elevated in patients before IVIg compared with normal controls
(p < 0.0001), rapidly declined after IVIg with a significant reduction (p < 0.05). Three months post-treatment with
IVIg, all patients showed improvement of disease without serious infectious complications. CONCLUSION: IVIg is
a potential component of remission induction therapy for patients with MPO-ANCA-associated RPGN.
Jayne DR, Lockwood CM. Intravenous immunoglobulin as sole therapy for systemic vasculitis. Br J Rheumatol.
1996 Nov;35(11):1150-3.
High-dose, pooled, i.v. immunoglobulin (IVIg) is a potential, alternative treatment for Wegener'
s granulomatosis
(WG) and microscopic polyangiitis (MPA) which has shown promise in the treatment of refractory disease when
administered with continuing immunosuppression. This study of six new patients with antineutrophil cytoplasmic
antibody (ANCA)-positive vasculitis and early disease, without threatened vital organ function, examined the
therapeutic response to treatment with IVIg alone. IVIg was well tolerated and all six patients had early reductions
in disease activity. Four entered full, clinical remission which lasted for at least 1 yr, while in two the responses
were partial and transient, and they subsequently required conventional treatment. After 16-48 months of followup, two of the four patients in full remission relapsed, but the other two have remained well.
High-dose pooled immunoglobulin in the therapy of systemic vasculitis. Trans Assoc Am Physicians. Jayne DR,
Lockwood CM. 1991;104:304-12.
52
Arahata H, Migita K, Izumoto H, Miyashita T, Munakata H, Nakamura H, Tominaga M, Origuchi T, Kawabe Y,
Hida A, Taguchi T, Eguchi K. Successful treatment of rapidly progressive lupus nephritis associated with antiMPO antibodies by intravenous immunoglobulins. Clin Rheumatol. 1999;18(1):77-81.
We report a case of systemic lupus erythematosus (SLE) associated with crescentic glomerulonephritis and
myeloperoxidase-specific anti-neutrophil cytoplasmic antibodies (MPO-ANCA). A 34-year-old Japanese female
patient diagnosed with SLE developed rapidly progressive renal failure and nephrotic syndrome. Haemodialysis
was required to restore renal function. Methylprednisolone pulse therapy followed by plasmapheresis did not
suppress the progression of renal failure, so she was treated with high-dose intravenous immunoglobulin (IV-IG)
therapy, which was well tolerated and effectively prevented renal failure. A renal biopsy showed diffuse
proliferative lupus nephritis (WHO classification IVc) with predominant crescent formation and scant
subendothelial immune deposits. These findings indicate that, in addition to lupus nephritis, which usually results
from the deposition of circulating or locally formed immune complexes, MPO-ANCA may be involved in the
pathogenesis of crescentic glomerulonephritis. Furthermore, we propose that IV-IG is an effective therapy for
MPO-ANCA-related renal crisis in lupus nephritis.
Tuso P, Moudgil A, Hay J, Goodman D, Kamil E, Koyyana R, Jordan SC. Treatment of antineutrophil cytoplasmic
autoantibody-positive systemic vasculitis and glomerulonephritis with pooled intravenous gammaglobulin. Am J
Kidney Dis. 1992 Nov;20(5):504-8.
Antineutrophil cytoplasmic autoantibody (ANCA) is considered a serological marker for disease activity in patients
with ANCA(+) systemic vasculitis. Recently, ANCA has been implicated as a pathogenic antibody that may be
associated with neutrophil degranulation and release of lytic enzymes. Since intravenous gammaglobulin (IVIG) is
known to contain antiidiotypic antibodies to ANCA, which could decrease the activity of the later, we chose to treat
two patients with symptomatic ANCA(+) systemic vasculitis and glomerulonephritis with high-dose IVIG. The first
patient, a 66-year-old man, developed rapidly progressive renal failure despite treatment with intravenous (IV)
cyclophosphamide. The second patient, a 14-year-old boy, had relapsed 3 months after cessation of treatment
with prednisone and cyclophosphamide. Both patients improved dramatically after treatment with IVIG, with the
former recovering renal function within 11 days of therapy. In both patients, a concomitant reduction in serum
ANCA titers was also observed. The second patient is currently in a sustained remission 14 months after his last
IVIG dose on no other medication. These cases provide clinical evidence that IVIG has therapeutic benefit in
modifying the immune-mediated injury associated with ANCA(+) systemic vasculitis and glomerulonephritis. In
addition, IVIG may provide an additional safe therapeutic option to clinicians treating patient'
s with ANCA(+)
vasculitis and glomerulonephritis who are not responsive to or are experiencing toxicity from conventional
therapy.
53
Maladie de Willebrand acquise, notamment asscociée à une
gammapathie monoclonale IgG (MGUS IgG), en cas d’échec ou
d’intolérance à la desmopressine et/ou aux concentrés de vWF
La posologie recommandée est de 2 g/kg (1g/kg pendant 2j ou 0.4g/kg/j pendant 5j) répartie en 2 à 5
jours.
Les IgIV sont inefficaces en cas de MGUS IgM.
Une dose de 1 g/kg sur 24 h ou de 2 g/kg sur 48h peut être répétée toutes les 3 semaines en fonction
de l’activité du facteur de von Willebrand.
Contre-indications
de Gammagard®);
excipients et est
érable et
d'
hyperprolinémie.
intolérance.
IgIV.
- de s'
54
IgG Gammagard®) et
de détecter d'
Le risque d'
Des cas d'
administration d'
IgIV impose :
Bien que ces cas d'
d'
Traitement associé
L'
vaccins.
IgIV, l'
animal n'
IV, et l'
enceinte qu'
55
56
2.
ARGUMENTAIRE
La maladie de Willebrand acquise recouvre des entités physiopathologiques différentes caractérisées
par la baisse des concentrations plasmatiques des facteurs VIII et de Willebrand.
L’analyse des données de la littérature ne trouve que des études ouvertes ou rétrospectives de petits
effectifs montrant une efficacité des IgIV d’environ 30% chez une majorité de patients IgG MGUS
(Monoclonal Gammapathy of Undetermined Significance) non répondeurs à la desmopressine et/ou
aux concentrés de vWF.
Par ailleurs, les guidelines du NHLBI (National Heart, Lung and Blood Institute, USA) recommandent
l’utilisation des IgIV en dernière intention après échec de la desmopressine et/ou des concentrés de
vWF pour contrôler les saignements qui engagent le propostic vital.
Effet des IgIV dans les anticoagulations acquises par auto-AC
Auteurs
Type d’étude
Posologie
Critères
d’évaluation
IgIV :
Efficacité
Yamamoto Revue de
(2007)
44 études publiées entre 0,4 g /kg /j pdt 5 j
-AC
antifacteur
1965 et 2005
VIII
Rémission totale
Patients avec AC anti-F
(RT) : disparition
VIII ou syndrome de von
de l’AC
Willebrand acquis
Réponse partielle
(RP) : diminution
du titre d’AC d’au
moins 25 %
Echec :
autres
situations que RT
et RP
Mohri
(1998)
Macik
(1988)
Federici
(2005)
Federici
(1998)
Rétrospective
N = 25
Patients avec une maladie
de von Willebrand acquise
8/25 ont des AC anti vWF
de type IgG
N=2
Revue de quelques cas
et données
rétrospectives du registre
international des patients
atteints de maladie de von
Willebrand acquise
N = 10
Patients MGUS dont 5 IgG
MGUS et 2 IgM MGUS
Desmopressine
IgIV :
03 g/kg pdt 3j
IgIV :
1g/kg/j pdt 2j
Efficacité
- AC anti facteur VIII : RT et avec
bénéfice clinique IgIV seules 30 % (11
cas sur 35)
Ig IV + ttt immunosuppresseur 70 %
(33 /45)
-Syndrome de von Willebrand acquis.
Efficacité estimée à 30 %
Réponse rapide
Activités des
FVIII
vWF
Tolérance
Effets indésirables et complications
graves rares
4/8 (50%): non-répondeurs à la
desmopressine
1/16 (6%) : non répondeur
FVIII
vWF
IgIV efficaces chez 1 patient non
répondeur à la desmopressine
A J2 :
↑ FVIII et vFW
IgIV :
AC anti FVIII
1 g/kg/j pdt 2 j ou AC anti vWF
0,4 g/kg/j pdt 5 j et
doses
répétées
d’IgIV pdt 21 j
IgIV :
1 g/kg/j pdt 2 j puis 1
g/kg tous les 21j
chez 2 patients IgG
MGUS
Résultats
FVIII
vWF
Temps
saignement
MGUS : monoclobal gammopathy of uncertain signifiance
63/186 patients du registre ont reçu
des IgIV
21/63 (33%) ont bien répondu aux IgIV
13/21 (62%) des répondeurs ont des
AC anti FVIII et vWF.
Amélioration rapide des activités des
FVIII et vWF et du temps de
de saignement chez les patients IgG
MGUS
Pas d’amélioration chez les patients
IgM MGUS
57
Bibliographie
1. Yamamoto K, Takamatsu J, Saito H. Intravenous immunoglobulin therapy for acquired coagulation inhibitors: a critical review.
Int J Hematol. 2007 May;85(4):287-93.
2. Mohri H, Motomura S, Kanamori H, Matsuzaki M, Watanabe S, Maruta A, Kodama F, Okubo T.Clinical significance of
inhibitors in acquired von Willebrand syndrome. Blood. 1998 May 15;91(10):3623-9
3. Federici AB. Use of intravenous immunoglobulin in patients with acquired von Willebrand syndrome.
Hum Immunol. 2005 Apr;66(4):422-30
4. Macik BG, Gabriel DA, White GC 2nd, High K, Roberts H.The use of high-dose intravenous gamma-globulin in acquired von
Willebrand syndrome. Arch Pathol Lab Med. 1988 Feb;112(2):143-6.
5. Federici AB, Stabile F, Castaman G, Canciani MT, Mannucci PM.Treatment of acquired von Willebrand syndrome in patients
with monoclonal gammopathy of uncertain significance: comparison of three different therapeutic approaches. Blood. 1998 Oct
15;92(8):2707-11.
6. Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL, Rick ME, Sadler JE, Weinstein M, Yawn
BP. Von Willebrand disease (VWD) : evidence-based diagnosis and management guidelines, the National Heart, Lung, and
Blood Institute (NHLBI) Expert Panel Report (USA). Haemophilia 2008; 14 : 171-232.
Groupe de travail
Dr
ALADJIDI
Nathalie,
hémato-onco-pédiatre,
Bordeaux
Pr CHERIN Patrick, interniste, Paris
Dr CHIFFOLEAU Anne, biologiste, Nantes
Dr DEBRE Marianne, hémato-immuno-pédiatre, Paris
Dr DONADIEU Jean, hémato-onco-immuno-pédiatre,
Paris
Pr FAIN Olivier, interniste Paris
Pr GLOTZ Denis, néphrologue, Paris
Pr KESSLER Michèle, néphrologue, Nancy
Dr LARROCHE Claire, interniste, Paris
Dr MADELAINE Isabelle, Pharmacien, Paris
Pr POLLACK Benoît, hématologue, Grenoble
Dr ROTHSCHILD Chantal, hématologue, Paris
Pr SIE Pierre, Hématologue, Toulouse
Pr WAHL Denis, interniste et vasculaire, Nancy
Groupe de lecture
Pr BLETRY Olivier, interniste, Paris
Pr DHOTE Robin, interniste, Paris
Pr GODEAU Bertrand, interniste, Paris
Pr GUILLEVIN Loïc, interniste, Paris
Pr HACHULLA Eric, interniste, Paris,
Pr LECOMPTE Thomas, hématologue, Nancy
Pr LEVERGER Guy, hémato-immuno-pédiatre, Paris
Pr MILPIED Noël, hématologue, Bordeaux
Pr TRON François, hématologue, Rouen
Pr VIALLARD Jean-François, interniste, Bordeaux
Pr LE PARC Jean-Marie, Rhumatologue, Paris
HCL, Lyon
Mme
BONGRAND
Marie-Claude,
pharmacien,
Pr LAVILLE
Mme
Catherine,
l’AP-HP, Paris
Lyon
58
Résumés-abstracts
Yamamoto K, Takamatsu J, Saito HIntravenous immunoglobulin therapy for acquired coagulation inhibitors: a
critical review. . Int J Hematol. 2007 May;85(4):287-93.
Intravenous immunoglobulin (IVIG) therapy has been used for autoimmune diseases and disorders involving
autoantibodies, including coagulation inhibitors. In this review, we have evaluated the efficacy and safety of IVIG
therapy for acquired coagulation inhibitors, including factor VIII inhibitor, and for acquired von Willebrand
syndrome on the basis of 44 reports published between 1965 and 2005. Among 35 patients with factor VIII
inhibitor, we estimated the efficacy of IVIG therapy alone (which includes complete remissions and partial
responses with a clinical benefit) to be 30% (11 cases), whereas the response to combination therapy with IVIG
plus immunosuppressive agents (eg, corticosteroid, cyclophosphamide) seemed to be better (approximately 70%,
33/45 cases) than with IVIG therapy alone. In acquired von Willebrand syndrome, the efficacy of IVIG therapy was
estimated to be 30%. The response to IVIG therapy appears to occur rapidly, and coagulation inhibitors seem to
be neutralized immediately. Moreover, severe complications or side effects rarely occur during IVIG treatment.
IVIG therapy thus may be considered one choice for treating acquired coagulation inhibitors, although its efficacy
improves when used in combination with immunosuppressive agents.
Mohri H, Motomura S, Kanamori H, Matsuzaki M, Watanabe S, Maruta A, Kodama F, Okubo T. Clinical
significance of inhibitors in acquired von Willebrand syndrome. Blood. 1998 May 15;91(10):3623-9
Of 260 patients enrolled, 25 patients (9.6%) were associated with acquired von Willebrand syndrome (AvWS). We
studied 25 patients with AvWS, retrospectively. AvWS was diagnosed by reduced levels of von Willebrand factor
(vWF) (decrease of von Willebrand factor antigen [vWF:Ag] and von Willebrand ristocetin cofactor [vWF:RCoF]), a
decrease of ristocetin-induced platelet agglutination (RIPA), sometimes decreased high-molecular-weight
multimers, and prolonged bleeding time with neither prior nor family histories of bleeding problems and the
evidence of normal vWF:RCoF in their families. The inhibitor of vWF was determined by mixing patient plasma
with pooled normal plasma. Eight patients in this study had the inhibitors to vWF that were of the IgG class; the
subclasses were IgG1 (7 cases) and IgG2 (1 case). Multimeric analysis of vWF showed selective loss of large
multimers in most patients with AvWS similar to that of congenital type-2 von Willebrand disease (vWD). All
inhibitors blocked ristocetin-mediated vWF binding to platelets. Five out of 6 IgGs evaluated here recognized the
39/34-kD fragment (residues 480/481-718) and Fragment III (residues 1-1365) that implied binding domain of
glycoprotein Ib (GPIb), whereas 1 recognized Fragment I (residues 911-1365). A close relationship was found
between the presence of the inhibitor and bleeding tendency. Of the 7 patients with inhibitors, 6 patients (86%)
had a bleeding tendency, as well as 1 of the 15 patients without inhibitors (6%). The efficacy of treatment of
underlying diseases and/or therapy with deamino D-arginine vasopressin (DDAVP) for the treatment of AvWS
also depends on the presence of an inhibitor. Four of 8 patients with inhibitors (50%) had poor response to
treatment of the underlying disease and/or therapy with DDAVP, as well as 1 of the 16 patients without inhibitors
(6%). These results indicate that patients with AvWS developing inhibitors to vWF are likely to have bleeding
problems and might be resistant to treatment of underlying diseases and/or therapy with DDAVP for bleeding to
AvWS. We also showed evidence that intravenous immunoglobulin therapy (0.3 g/kg, 3 days) was effective to
correct a hemostatic defect and manage severe bleeding in a patient with AvWS developing inhibitors. We might
consider an additional treatment including expensive high-dose immunoglobulin therapy when uncontrollable
bleeding is continued after the treatment of the underlying diseases and/or therapy with DDAVP.
Federici AB. Use of intravenous immunoglobulin in patients with acquired von Willebrand syndrome. Hum
Immunol. 2005 Apr;66(4):422-30.
Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder with laboratory findings similar to those for
congenital von Willebrand disease. Unlike the congenital form, AVWS usually occurs in individuals with no
personal or family history of bleeding disorders. According to an international registry, AVWS is mainly associated
with lymphomyeloproliferative, immunologic, and cardiovascular disorders, as well as with solid tumors and other
miscellaneous conditions; however, the prevalence of AVWS in these underlying disorders is still unknown. von
Willebrand factor (VWF) is synthesized normally in most AVWS patients, and the low plasma VWF levels are from
its accelerated removal from plasma by five different mechanisms, including autoantibodies. Because of the
reduced half-life of endogenous-exogenous plasma VWF, bleeding of AVWS cannot be managed with
desmopressin or factor VIII/VWF concentrates. Clinical use of intravenous immunoglobulin (IVIg) in AVWS has
been reported since 1988. IVIg is most effective in AVWS with type immunoglobulin (Ig) G monoclonal
gammopathies of undetermined significance and in other cases with IgG autoantibodies. IVIg can correct factor
VIII and von Willebrand factor complex activities for about 15-20 days, and repeated injections induce remission
of AVWS in these patients. Prospective studies are required to evaluate the efficacy and safety of IVIg in AVWS.
59
Macik BG, Gabriel DA, White GC 2nd, High K, Roberts H. The use of high-dose intravenous gamma-globulin in
acquired von Willebrand syndrome. Arch Pathol Lab Med. 1988 Feb;112(2):143-6.
Acquired von Willebrand syndrome has been reported in patients with a variety of primary diseases, many
immunologic in nature. Usually, an autoantibody to von Willebrand factor can be identified. These patients often
experience severe hemorrhages requiring large doses of cryoprecipitate or factor VIII concentrates, thus exposing
them to viral and allergic complications. The success of intravenous gamma-globulin in the treatment of other
autoimmune diseases prompted us to treat two patients with acquired von Willebrand syndrome with high-dose
intravenous gamma-globulin. Two days after initiation of therapy, von Willebrand factor and factor VIII rose to
normal levels in both patients. Patient 1 underwent dental surgery, and patient 2 underwent a splenectomy
without increased bleeding and without additional factor coverage or desmopressin acetate therapy. Thus,
intravenous gamma-globulin is efficacious for acquired von Willebrand syndrome and obviates the need for
replacement therapy with its attendant complications.
Federici AB, Stabile F, Castaman G, Canciani MT, Mannucci PM.Treatment of acquired von Willebrand syndrome
in patients with monoclonal gammopathy of uncertain significance: comparison of three different therapeutic
approaches. Blood. 1998 Oct 15;92(8):2707-11.
Patients with monoclonal gammopathies of uncertain significance (MGUS) may develop an acquired bleeding
disorder similar to congenital von Willebrand disease, called acquired von Willebrand syndrome (AvWS). In these
patients, measures to improve hemostasis are required to prevent or treat bleeding episodes. We diagnosed 10
patients with MGUS and AvWS: 8 had IgGkappa (3) or lambda (5) MGUS and 2 IgM-kappa MGUS. Three
therapeutic approaches were compared in them: (1) desmopressin (DDAVP), (2) factor VIII/von Willebrand factor
(FVIII/vWF) concentrate, and (3) high-dose (1 g/kg/d for 2 days) intravenous Ig (IVIg). In patients with IgG-MGUS,
DDAVP and FVIII/vWF concentrate increased factor VIII and von Willebrand factor in plasma, but only transiently.
IVIg determined a more sustained improvement of the laboratory abnormalities and prevented bleeding during
surgery (short-term therapy). In addition to the standard 2-day infusion protocol, a long-term IVIg therapy was
performed in 2 patients with IgG-MGUS: repeated (every 21 days) single infusions of IVIg did improve laboratory
abnormalities and stopped chronic gastrointestinal bleeding. On the other hand, IVIg failed to correct laboratories
abnormalities in patients with IgM-MGUS. These comparative data obtained in a relative large and homogeneous
group of patients with AvWS and MGUS confirm that DDAVP and FVIII/vWF concentrates improve the bleeding
time (BT) and FVIII/vWF measurements only transiently, whereas IVIg provides a sustained treatment of AvWS
associated with IgG-MGUS, but not with IgM-MGUS
Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL, Rick ME, Sadler JE,
Weinstein M, Yawn BP.von Willebrand disease (VWD): evidence-based diagnosis and management guidelines,
the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia. 2008
Mar;14(2):171-232.
von Willebrand disease (VWD) is a commonly encountered inherited bleeding disorder affecting both males and
females, causing mucous membrane and skin bleeding symptoms, and bleeding with surgical or other
haemostatic challenges. VWD may be disproportionately symptomatic in women of child-bearing age. It may also
occur less frequently as an acquired disorder (acquired von Willebrand syndrome). VWD is caused by deficiency
or dysfunction of von Willebrand factor (VWF), a plasma protein that mediates platelet haemostatic function and
stabilizes blood coagulation factor VIII. The pathophysiology, classification, diagnosis and management of VWD
are relatively complex, but understanding them is important for proper diagnosis and management of patients with
VWD. These evidence-based guidelines for diagnosis and management of VWD from the National Heart, Lung,
and Blood Institute (NHLBI) Expert Panel (USA) review relevant publications, summarize current understanding of
VWD pathophysiology and classification, and present consensus diagnostic and management recommendations
based on analysis of the literature and expert opinion. They also suggest an approach for clinical and laboratory
evaluation of individuals with bleeding symptoms, history of bleeding or conditions associated with increased
bleeding risk. This document summarizes needs for further research in VWF, VWD and bleeding disorders,
including clinical research to obtain more objective information about bleeding symptoms, advancements in
diagnostic and therapeutic tools, and enhancement in the education and training of clinicians and scientists in
bleeding and thrombotic disorders. The NHLBI Web site (http://www.nhlbi.nih.gov/guidelines/vwd) has a more
detailed document, a synopsis of these recommendations, and patient education information.
60
Syndrome catastrophique des antiphospholipides en cas d’échec du traitement
anticoagulant IV associé à des corticostéroïdes en complément ou en
alternative à la plasmaphérèse
La dose usuelle est de 0.4 g/j/kg pendant 4-5 jours.
Contre-indications
de Gammagard®);
excipients et est
érable et
d'
hyperprolinémie.
intolérance.
IgIV.
Les complications potentielles peuvent être souvent évitées; il est souhaitable :
- de s'
61
IgG Gammagard®) et
de détecter d'
Le risque d'
Des cas d'
administration d'
IgIV impose :
Bien que ces cas d'
d'
Traitement associé
L'
vaccins.
IgIV, l'
animal n'
IV, et l'
enceinte qu'
62
63
2.
ARGUMENTAIRE
Le syndrome catastrophique des antiphospholipides, connu depuis une dizaine d'
années, se
différencie du syndrome classique des antiphospholipides par une cascade de thromboses affectant au
moins 3 organes. L'
atteinte rénale est constante, accompagnée souvent d'
hypertension artérielle, et
celle du système nerveux central est très fréquente.
L'
ensemble évolue souvent vers l'
insuffisance cardiaque ou rénale ou vers un syndrome de détresse
respiratoire. L’évolution est particulièrement grave : l'
atteinte des différents organes se fait en cascade,
en quelques jours ou semaines, conduisant le patient en service de soins intensifs. Le décès, survenu
dans 45 % des cas, relève, à des degrés divers, de l'
insuffisance rénale, cardiaque, hypophysaire, et
de l'
atteinte neurologique centrale souvent multiple.
La physiopathologie est mal connue : un lien statistique entre anticorps antiphospholipides et
manifestations thrombotiques existe, mais la responsabilité directe de ces anticorps dans l'
apparition
des thromboses n'
est pas prouvée.
Dans le syndrome catastrophique, prenant en compte les résultats de l’étude de Bucciarelli (2006) et
d’Asherson (1998) et en raison de la gravité de la situation et de l’absence d’alternative thérapeutique,
les IgIV peuvent être utilisées en cas d’échec à des traitements antithrombotiques associés à la
corticothérapie.
Le traitement de première intention est un traitement anticoagulant IV associé à des corticostéroïdes
et la plasmaphérèse.
En l’absence d’efficacité, un traitement de deuxième intention plasmaphérèse et/ou IgIV doit être
envisagé rapidement ou même d’emblée en cas de risque vital.
N.B. : Il existe un registre international incluant tous les cas de syndrome catastrophique :
http://www.med.ub.es/MIMMUN/FORUM/CAPS.HTM.
Effet des IgIV dans le syndrome des antiphospholipides en l’absence d’efficacité des anticoagulants
Auteurs
Type d’étude
Posologie
Résultats
Bucciarelli
(2006)
Cas rapportés
N = 250
Patients ayant eu le
syndrome
catastrophique des
antiphospholipides
242 épisodes de
syndrome
catastrophique ont été
analysés
IgIV : 51/242 (21%)
56% de survivants, 44 % de décès
Anticoagulants :
206/242 (85%)
↑ risque de décès quand présence d’un LED
↑ % survivants si patients traités par - anticoagulants
Corticostéroïdes IV : + corticostéroïdes
190/242 (78.5%)
+ EP : 77.8% de succès
- anticoagulants + corticostéroïdes + IgIV : 69 % de
Cyclophosphamide : succès
75/242 (40%)
Cyclophosphamide en combinaison avec les autres
Plasmaphérèse :
traitements : ↓ efficacité de la combinaison
73/242 (30%)
Séries de cas
Asherson
IgIV:8/50 (16%)
% de survivants : 50%
N = 50
(1998)
Anticoagulants :
- IgIV : 4 /8
Patients ayant eu un
35/50 (70%)
- plasmaphérèse : 13/20 (65%)
APS atastrophique avec Plasmaphérèse :
- anticoagulants : 22/35 (63%)
.anticoagulant lupique : 20/50 (40%)
- stéroïdes 19/35 (54%)
(94%),
Cyclophosphamide : - cyclophosphamide : 7/17 (41%)
.AC anticardiolipine
17/50 (34%)
- combinaison anticoagulants + stéroïdes +
(94%),
Splénectomie : 2/50 plasmaphérèse ou IgIV : 14/20 (70%)
. anti-dsDNA (87% des
(4%)
- combinaison anticoagulants + stéroïdes +
patients avec SLE),
plasmaphérèse ou IgIV + cyclophosphamide : 5/10
. AC antinuclear (58%),
(50%)
APA : AC antiphospholipides
LED : lupus erythémateux dissminé
EP : échanges plasmatiques
SLE : syndrome du lupus érythémateux
APS : antiphospholipide syndrome
64
Bibliographie
1. Bucciarelli S, Espinosa G, Cervera R, Erkan D, Gómez-Puerta JA, Ramos-Casals M, Font J, Asherson RA Mortality in the
catastrophic antiphospholipid syndrome: causes of death and prognostic factors in a series of 250 patients. European Forum on
Antiphospholipid Antibodies. Arthritis Rheum. 2006 Aug;54(8):2568-76.
2. Asherson RA, Cervera R, Piette JC, Font J, Lie JT, Burcoglu A, Lim K, Muñoz-Rodríguez FJ, Levy RA, Boué F, Rossert J,
Ingelmo M. Catastrophic antiphospholipid syndrome. Clinical and laboratory features of 50 patients.Medicine (Baltimore). 1998
May;77(3):195-207
3. Erkan D, Cervera R, Asherson RA.Catastrophic antiphospholipid syndrome: where do we stand? : Arthritis Rheum. 2003
Dec;48(12):3320-7 : pas d’abstract
Groupe de travail
Dr
ALADJIDI
Nathalie,
Bordeaux
Paris
Groupe de lecture
Pr BLETRY Olivier, interniste, Paris
HCL, Lyon
Mme
BONGRAND
Marie-Claude,
pharmacien,
Pr LAVILLE
Mme
Catherine,
l’AP-HP, Paris
Lyon
Résumés-abstracts
Bucciarelli S, Espinosa G, Cervera R, Erkan D, Gómez-Puerta JA, Ramos-Casals M, Font J, Asherson RA;
European Forum on Antiphospholipid Antibodies. Mortality in the catastrophic antiphospholipid syndrome: causes
of death and prognostic factors in a series of 250 patients. Arthritis Rheum. 2006 Aug;54(8):2568-76.
OBJECTIVE: To assess the main causes of death and the prognostic factors that influence mortality in patients
with the catastrophic antiphospholipid syndrome (CAPS). METHODS: We analyzed the case reports of 250
65
patients included in the CAPS Registry up to February 2005. To identify prognostic factors for CAPS, we
compared the main clinical and immunologic features and the types of treatment in the patients who died with
those features in the patients who survived. RESULTS: Recovery occurred in 56% of the episodes of CAPS and
death occurred in 44%. Cerebral involvement, consisting mainly of stroke, cerebral hemorrhage, and
encephalopathy, was considered the main cause of death, being present in 27.2% of patients, followed by cardiac
involvement (19.8%) and infection (19.8%). The only factor we identified that was prognostic of a higher mortality
rate was the presence of systemic lupus erythematosus (SLE). A higher recovery rate was associated with
combined treatment with anticoagulants (ACs) plus corticosteroids (CS) plus plasma exchange (PE) (77.8%),
followed by ACs plus CS plus PE and/or intravenous immunoglobulins (69%). In contrast, concomitant treatment
with cyclophosphamide did not demonstrate additional benefit. CONCLUSION: Cerebral involvement (mainly
consisting of stroke), cardiac involvement, and infections were considered the main causes of death in patients
with CAPS. The presence of SLE was related to a higher mortality rate. According to the results of the present
study, ACs plus CS plus PE should be the first line of therapy in patients with CAPS.
Asherson RA, Cervera R, Piette JC, Font J, Lie JT, Burcoglu A, Lim K, Muñoz-Rodríguez FJ, Levy RA, Boué F,
Rossert J, Ingelmo MCatastrophic antiphospholipid syndrome. Clinical and laboratory features of 50 patients..
Medicine (Baltimore). 1998 May;77(3):195-207
We analyzed the clinical and laboratory characteristics of 50 patients with catastrophic antiphospholipid syndrome
(APS) (5 from our clinics and 45 from a MEDLINE computer-assisted review of the literature from 1992 through
1996). Thirty-three (66%) patients were female and 17 (34%) were male. Twenty-eight (56%) patients had
primary APS, 15 (30%) had defined systemic lupus erythematosus (SLE), 6 (12%) had "lupus-like" syndrome, and
1 (2%) had rheumatoid arthritis. Mean age of patients in this series was 38 +/- 14 years (range, 11-74 yr). Three
(6%) patients developed the clinical picture of catastrophic APS under the age of 15 years, and 11 (22%) were 50
years old or more. In 11 (22%) patients, precipitating factors contributed to the development of catastrophic APS
(infections in 3, drugs in 3, minor surgical procedures in 3, anticoagulation withdrawal in 2, and hysterectomy in
1). The presentation of the acute multi-organ failure was usually complex, involving multiple organs
simultaneously or in a very short period of time. The majority of patients manifested microangiopathy--that is,
occlusive vascular disease affecting predominantly small vessels of organs, particularly kidney, lungs, brain,
heart, and liver--with a minority of patients experiencing only large vessel occlusions. Thrombocytopenia was
reported in 34 (68%) patients, hemolytic anemia in 13 (26%), disseminated intravascular coagulation in 14 (28%),
and schistocytes in 7 (14%). The following antibodies were detected: lupus anticoagulant (94%), anticardiolipin
antibodies (94%), anti-dsDNA (87% of patients with SLE), antinuclear antibodies (58%), anti-Ro/SS-A (8%), antiRNP (8%), and anti-La/SS-B (2%). Anticoagulation was used in 70% of the patients, steroids in 70%,
plasmapheresis in 40%, cyclophosphamide in 34%, intravenous gammaglobulins in 16%, and splenectomy in 4%.
Most patients, however, received a combination of nonsurgical therapies. Death occurred in 25 of the 50 (50%)
patients. In most, cardiac problems seemed to be the major cause of death. In several of these, respiratory failure
was also present, usually due to acute respiratory distress syndrome and diffuse alveolar hemorrhage. Among the
20 patients who received the combination of anticoagulation, steroids, and plasmapheresis or intravenous
gammaglobulins, recovery occurred in 14 (70%) patients. The use of ancrod and defibrotide appeared to be
effective in the 2 respective patients in whom they were used.
66
Immunoglobulines IV
Dermatomyosite cortico-résistante
La dose usuelle est de 2 g/kg/mois avec une réévaluation à 3 mois.
Contre-indications
de Gammagard);
excipients et est
érable et
d'
hyperprolinémie.
intolérance.
Les vraies réponses allergiques à ce médicament sont rares. Une intolérance aux Immunoglobulines
peut se développer dans les très rares cas de déficit en IgA où le patient possède des anticorps antiIgA.
Très rarement, les immunoglobulines humaines normales peuvent entraîner une chute brutale de la
pression artérielle associée à une réaction anaphylactique même chez des patients qui ont présenté
une bonne tolérance à une administration précédente d'
immunoglobulines humaines normales.
- de s'
67
IgG Gammagard®),
de la teneur en saccharose (1,67 g par g d’IgG : Sandoglobuline 1g, 3g, 6g, 12g et 2g/g d’IgG :
Tégéline®) en cas de diabète latent où une glycosurie passagère peut survenir, de diabète
ou de régime hypoglucidique ;
- en cas de restriction hydrosodée, de tenir compte de la teneur en sodium, notamment
Gammagard® (3,4 mg/ml) et Tégéline® (0.8mg/ml);
- de garder les patients sous observation pendant au moins 20 minutes après la fin de la perfusion
afin de détecter d'
intolérance. En cas de première perfusion d’IgIV, le patient doit
être maintenu sous observation pendant au moins 1 heure après la fin de la perfusion.
Le risque d'
Des cas d'
insuffisance rénale aiguë ont été rapportés chez des patients recevant des
immunoglobulines humaines normales. Dans la plupart des cas, des facteurs de risque ont été
identifiés, tels une insuffisance rénale pré-existante, un diabète, un âge supérieur à 65 ans, une
hypovolémie ou une obésité.
administration d'
IgIV impose :
· une hydratation correcte avant l’administration d’immunoglobulines humaines normales,
Bien que ces cas d'
d'
Traitement associé
L'
administration d'
immunoglobuline humaine normale peut entraver l'
efficacité des vaccins constitués
de virus vivants atténués tels que les vaccins contre la rougeole, la rubéole, les oreillons et la
varicelle. Après perfusion de ce médicament, attendre au minimum 6 semaines (de préférence 3 mois)
avant d'
administrer ce type de vaccins.
Si le patient a reçu des vaccins constitués de virus vivants atténués (rougeole, rubéole, oreillons,
varicelle) au cours des 2 semaines précédant la perfusion, un contrôle des anticorps protecteurs postvaccinaux peut être nécessaire en vue d'
immunoglobuline humaine normale, l'
augmentation transitoire de la
concentration de divers anticorps transférés peut être responsable de sérologies positives
temporaires.
68
animal n'
IV, et l'
ait été observée, les immunoglobulines humaines normales ne doivent être
administrées chez la femme enceinte qu'
Allaitement : Les protéines contenues dans l’immunoglobuline humaine normale étant des
constituants normaux du plasma humain, leur passage dans le lait maternel ne doit pas provoquer
d'
69
2.
ARGUMENTAIRE
Les dermatomyosites sont des maladies musculaires inflammatoires d'
étiologie inconnue. Des
désordres immunitaires participent à des degrés divers suivant le type de myopathie inflammatoire, à
la physiopathogénie de la maladie, comme en témoignent de nombreux arguments cliniques,
biologiques et expérimentaux. Ces myosites peuvent survenir à n'
importe quel âge, mais on observe
toutefois deux discrets pics de fréquence : chez l'
enfant entre 5 et 14 ans, où l'
on observe quasiexclusivement des dermatomyosites, et chez l'
adulte après 40 ans. Il s'
agit d'
une affection acquise,
même s'
il peut exister un terrain génétique parfois prédisposant.
Les dermatomyosites peuvent parfois s'
associer à d'
autres affections, notamment autres maladies
auto-immunes, pathologies tumorales, infections virales qu'
il faut rechercher systématiquement dans
le bilan de la maladie.
Les DM sont des connectivites rares dont l'
incidence annuelle est estimée entre 5 et 10 cas par million
d'
habitants et la prévalence de 6 à 7 cas pour 100 000 personnes. La prise en charge thérapeutique
des dermatomyosites repose sur des traitements immunomodulateurs, et la kinésithérapie une fois
passée la phase aiguë inflammatoire. La corticothérapie constitue le traitement de première intention,
active au long cours dans plus de 60 à 70% des cas.
L’analyse de la littérature concernant l’utilisation des immunoglobulines IV (IgIV) dans les
dermatomyosites cortico-résistantes fait état d’une étude randomisée comparative versus placebo
(Dalakas 1993) qui a montré une amélioration significative des symptômes neuromusculaires et de la
force musculaire chez une majorité des patients 9/12 (p<0.035). Une étude ouverte (Cherin 1991) a
mis en évidence une amélioration significative (p<0.01) chez 18/20 patients de la puissance
musculaire et une diminution significative des doses de corticostéroïdes après la 2ème ou 3ème dose
d’IgIV.
L’utilisation des IgIV dans les dermatomyosites cortico-résistantes est temporairement acceptable.
Effet des IgIV dans les dermatomyosites
Auteur
Type d’étude
Posologie
Suivi
Dalakas
(1993)
Comparative en
double-aveugle
versus placebo
N = 15 patients
résistants
aux
traitements
conventionnels
des
dermatomyosite
s (DM)
Ig IV :
2g /kg / mois pendant
3 mois n = 8 et
crossing over pour 3
mois
supplémentaires
Placebo : n = 7
6
mois
Cherin
(1991)
Ouverte
N = 20 patients
résistants
aux
traitements
conventionnels
(corticostéroïdes
et
immunosuppres
seurs) traités par
de fortes doses
d’IgIV
IgIV :
n = 13 : 1g/kg /jour
pendant 2 jours /mois
n = 7 : 0.4 g/kg/jour
pendant 5 jours/mois
4
mois
Critères
d’évaluation
Force
musculaire
Symptômes
neuromusculai
res
Modifications
des rashs
Résultats
Puissance
musculaire
proximale
Amélioration
du
bilan
biochimique
Puissance musculaire moyenne : p<
0.01
Force musculaire : groupe traité p
<0.018
Symptômes neuromusculaires :
P < 0.035
Après crossing over :
Patients traités : n = 12
. n = 9 : bonne amélioration
. n = 2 : amélioration moyenne
. n = 1 : pas d’amélioration
Patients placebo : n = 11
. n = 0 : bonne amélioration
. n = 3 : amélioration moyenne
. n = 3 : pas de changement
Pas d’effets indésirables
Bilan biochimique :
- amélioration : n = 18/20 patients
- créatine-kinase moyenne : p < 0.01
Effets indésirables : n = 4
↓ Doses des corticostéroïdes après
la 2ème ou 3ème dose d’IVIg P < 0.05
70
Bibliographie
1-Dalakas MC, Illa I, Dambrosia JM, Soueidan SA, Stein DP, Otero C, Dinsmore ST, McCrosky S. A controlled trial of high-dose
intravenous immune globulin infusions as treatment for dermatomyositis N Engl J Med. 1993 Dec 30;329(27):1993-2000
2-Cherin P, Herson S, Wechsler B, Piette JC, Bletry O, Coutellier A, Ziza JM, Godeau P. Efficacy of intravenous
gammaglobulin therapy in chronic refractory polymyositis and dermatomyositis : an open study with 20 adult patientsAm J Med.
1991 Aug;91(2):162-8
Groupe de travail
Professeur LEBBE Céleste, dermatologue, Paris
Professeur REVUZ Jean, dermatologue, Créteil
Professeur BEANI Jean-Claude, dermatologue,
Grenoble
Professeur DRENO Brigitte, dermatologue, Nantes
Docteur FLAGEUL Béatrice, dermatologue, Paris
Docteur JEAN-PASTOR Marie-Joseph dermatologue,
Marseille
Docteur Brigitte MILPIED-HOMSI, dermatologue,
Bordeaux
Docteur POLI Florence, dermatologue, Créteil
Groupe de lecture
SFD (Société Française de Dermatologie)
Docteur BOULINGUEZ Serge
Professeur CHOSIDOW Olivier, dermatologue, Paris
Docteur MAHE Emmanuel, dermatologue, Paris
Professeur HACHULLA Eric, dermatologue, Paris
Professeur TAIEB Alain, dermatologue, Bordeaux
Professeur CAMBAZART Frédéric, dermatologue,
Saint-Etienne
Professeur DELAPORTE Emmanuel, dermatologue,
Lille
Professeur RICHARD Marie-Aleth, dermatologue,
Marseille
Docteur VIGAN Martine, dermatologue, Besançon
Professeur BERNARD Philippe, dermatologue, Reims
Professeur JULLIEN Denis, dermatologue, Lyon
Professeur CLAUDY Alain, dermatologue, Lyon
HCL, Lyon
Mme
BONGRAND
Marie-Claude,
pharmacien,
Pr LAVILLE
Mme
Catherine,
l’AP-HP, Paris
Lyon
Dr ROSENHEIM Michel, médecin de santé publique,
Paris
71
La Commission d’AMM du 20 décembre 2007 présidée par le Pr Daniel VITTECOQ n’a pas émis
d’objection à ce référentiel, qui a également été visé par la Commission de la transparence de la
HAS, présidée par le Pr Gilles BOUVENOT.
Résumés-abstracts
A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis Dalakas
MC, Illa I, Dambrosia JM, Soueidan SA, Stein DP, Otero C, Dinsmore ST, McCrosky S. N Engl J Med. 1993 Dec
30;329(27):1993-2000
BACKGROUND. Dermatomyositis is a clinically distinct myopathy characterized by rash and a complementmediated microangiopathy that results in the destruction of muscle fibers. In some patients the condition becomes
resistant to therapy and causes severe physical disabilities. METHODS. We conducted a double-blind, placebocontrolled study of 15 patients (age, 18 to 55 years) with biopsy-proved, treatment-resistant dermatomyositis. The
patients continued to receive prednisone (mean daily dose, 25 mg) and were randomly assigned to receive one
infusion of immune globulin (2 g per kilogram of body weight) or placebo per month for three months, with the
option of crossing over to the alternative therapy for three more months. Clinical response was gauged by
assessing muscle strength, neuromuscular symptoms, and changes in the rash. Changes in immune-mediated
muscle abnormalities were determined by repeated muscle biopsies. RESULTS. The eight patients assigned to
immune globulin had a significant improvement in sores of muscle strength (P < 0.018) and neuromuscular
symptoms (P < 0.035), whereas the seven patients assigned to placebo did not. With crossovers a total of 12
patients received immune globulin. Of these, nine with severe disabilities had a major improvement to nearly
normal function. Their mean muscle-strength scores increased from 74.5 to 84.7, and their neuromuscular
symptoms improved. Two of the other three patients had mild improvement, and one had no change in his
condition. Of 11 placebo-treated patients, none had a major improvement, 3 had mild improvement, 3 had no
change in their condition, and 5 had worsening of their condition. Repeated biopsies in five patients of muscles
whose strength improved to almost normal showed an increase in muscle-fiber diameter (P < 0.04), an increase
in the number and a decrease in the diameter of capillaries (P < 0.01), resolution of complement deposits on
capillaries, and a reduction in the expression of intercellular adhesion molecule 1 and major-histocompatibilitycomplex class I antigens. CONCLUSIONS. High-dose intravenous immune globulin is a safe and effective
treatment for refractory dermatomyositis.
Efficacy of intravenous gammaglobulin therapy in chronic refractory polymyositis and dermatomyositis : an open
study with 20 adult patients. Cherin P, Herson S, Wechsler B, Piette JC, Bletry O, Coutellier A, Ziza JM, Godeau
P. Am J Med. 1991 Aug;91(2):162-8
PURPOSE: Polymyositis and dermatomyositis are inflammatory muscular diseases of unknown cause. Many
interventions are available to treat patients with these conditions including corticosteroids, immunosuppressive
drugs, plasmapheresis, and total body irradiation. However, these therapies are not always effective, and they
may be associated with certain serious side effects. An attempt was made to evaluate the efficacy of polyvalent
intravenous immunoglobulin (IVIG) in patients with polymyositis or dermatomyositis refractory to traditional
treatment. PATIENTS AND METHODS: Twenty patients (16 women and 4 men; mean age 43 [16 SD] years), 14
with chronic refractory polymyositis and six with dermatomyositis, received high doses of IVIG because of the
failure of traditional treatments (prednisone [19], methotrexate [10], azathioprine [6], cyclophosphamide [3],
cyclosporine [3], chlorambucil [1], plasmapheresis [8], lymphopheresis [1], and total body irradiation [1]). In one
patient with positive results on picornavirus serologic testing, IVIG was the first treatment choice. IVIG therapy
was given with prednisone in 15 patients, with methotrexate in six patients, and with plasmapheresis in one
patient. There were no changes in treatment in the 2 months before the introduction of IVIG therapy and no
increases in dose during this treatment. Preparations of polyvalent human intravenous gammaglobulins with
increased intact immunoglobulin G were used. Thirteen patients received 1 g/kg daily for 2 days each month, and
seven patients received 0.4 g/kg daily for 5 days each month. The mean duration of treatment was 4 months.
RESULTS: Clinical assessment, which consisted of the measurement of proximal muscle power, and biochemical
studies were carried out before each treatment period. Significant clinical improvement was noted in 15 of the 20
patients. Mean muscle power estimated for the 20 patients before and after IVIG therapy was statistically
significantly reduced (p less than 0.01). Eighteen patients showed biochemical improvement, and two patients
with normal initial serum creatine kinase levels showed clinical improvement. Mean creatine kinase levels for the
20 patients during IVIG therapy showed a statistically significant decrease from the first IVIG perfusions (p less
than 0.01). Side effects of IVIG therapy were noted in four patients; however, these effects were mild. During IVIG
therapy, steroid doses were significantly reduced from the second or the third IVIG infusion (p less than 0.05).
CONCLUSION: IVIG is an efficacious new therapy for polymyositis and dermatomyositis and should play a role in
the treatment of these diseases, replacing or reducing steroid and immunosuppressive medications
72
Immunoglobulines IV
En troisième intention dans le pemphigus après un traitement bien conduit :
- en première intention par des corticostéroïdes et des immunosuppresseurs,
- en seconde intention par du rituximab
La dose usuelle est de 2 g/kg/mois avec une évaluation de l’efficacité après 5-6 cycles.
Contre-indications
· chez les patients présentant un déficit en IgA et avec des anticorps circulants anti-IgA ; (à l’exception
de Gammagard);
excipients et est
érable et
d'
hyperprolinémie.
intolérance.
73
de s'
administration des IgIV par une perfusion lente
(0,5 ml/kg/h ( 0.5 ml/kg/h pour Sandoglobuline 120 mg/ml® et 1ml/kg/h maximum pour la Tégéline®)) ;
IgG
Gammagard), de la teneur en saccharose (1,67 g par g d’IgG : Sandoglobuline® 1g, 3g, 6g, 12g et
2g/g d’IgG : Tégéline®) en cas de diabète latent où une glycosurie passagère peut survenir, de diabète
ou de régime hypoglucidique ;
Le risque d'
Des cas d'
hypovolémie ou une obésité. Chez ces patients, l'
administration d'
IgIV impose :
· un dosage de la créatininémie,
Bien que ces cas d'
d'
Traitement associé
L'
administration d'
avant d'
temporaires.
74
animal n'
IV et l'
aucune réaction indésirable sur le fœtus
et le nouveau-né n'
d'
75
2.
ARGUMENTAIRE
Initialement, le pemphigus désigne un problème de la peau, la bulle. Progressivement, il a été
employé pour les dermatoses se caractérisant l'
apparition de bulles à l'
intérieur de l'
épiderme. On
distingue le pemphigus vrai et les pemphigoïdes. Le terme de pemphigoïde regroupe l'
ensemble des
dermatoses se caractérisant par des bulles différentes du pemphigus vrai. La caractéristique des
pemphigoïdes bulleux est leur volume généralement plus élevé que celui du pemphigus.
Il s’agit d’une infection rare (1 à 2 cas par million par an en France) dont on ne connaît pas la cause
avec certitude, mais pour laquelle on évoque une réaction auto-immune (l'
individu fabrique des
anticorps contre ses propres tissus, et dans ce cas, contre sa propre peau).
La prise de médicaments pourrait être à l'
origine de l'
apparition du pemphigus (inhibiteurs de l'
enzyme
de conversion, la D-pénicillamine) : il s’agit essentiellement de formes superficielles mais parfois de
formes profondes.
On distingue différents types de pemphigus :
• le pemphigus profond (pemphigus vulgaire) qui commence par l'
apparition de bulles sur les
muqueuses et tout particulièrement celles de la bouche ;
• le pemphigus superficiel (regroupant les variants séborrhéiques, érythémateux, foliacés et
herpétiformes) est de présentation clinique plus trompeuse. Il n’y a pas de lésions muqueuses et les
lésions cutanées sont des croûtes superficielles, voire des plaques érythémato-squameuses ;
• le pemphigus paranéoplasique est exceptionnel. Il est souvent cliniquement atypique. Les lésions
muqueuses sont diffuses et graves, les lésions cutanées trompeuses : éruption lichénoïde, lésions
évoquant un érythème polymorphe…
Le traitement de référence est :
. ouverture des bulles,
. bains à base d'
antiseptiques,
. administration de corticostéroïdes (cortisone) pendant une période pouvant aller de 6 mois à un an
. les immunosuppresseurs tels que la cyclosporine sont parfois utilisés ;
. certains médecins pratiquent également la plasmaphérèse, technique qui permet de prélever du plasma
(liquide contenu dans le sang) chez un donneur de sang ou chez un malade.
L’analyse de la littérature montre une efficacité des Immunoglobulines (IgIV) dans les pemphigus
cortico-résistants ou cortico-dépendants ou en cas de résistance aux immunosuppresseurs, à
l’infliximab ou en cas d’intolérance à ces traitements. L’ensemble des publications provient de la
même équipe et il n’y a pas d’étude randomisée double-aveugle. De plus, l’association des IgIV au
rituximab n’est pas validée par l’étude d’Ahmed (2006) et nécessiterait une comparaison versus
rituximab seul dans une étude comparative.
On observe une épargne significative des corticostéroïdes, une diminution significative des rechutes.
L’utilisation des IgIV dans les pemphigus peut se faire en 3ème intention après un traitement bien
conduit :
- en 1ère intention par des corticostéroïdes et des immunosuppresseurs,
- en seconde intention par du rituximab.
Aucune étude n’a mis en évidence une efficacité des IgIV en monothérapie.
76
Effet des IgIV dans le pemphigus
Auteur
Type d’étude
Posologie
Suivi
Enk
(1998)
Ouverte
N = 6 patients avec
pemphigus vulgaris et
foliaceus résistants aux
thérapies
conventionnelles
Ouverte
N = 7 patients avec
pemphigus
foliaceus
dépendants
aux
stéroïdes
IgIV : 2g/kg
toutes les 4
semaines
6 à 9 cycles
1 an
IgIV : 1-2
g/kg sur 3
jours toutes
les 4
semaines
- temps jusqu’à
l’arrêt des
stéroïdes
- nombre de
rechutes
Ahmed
(2002)
Ouverte
N = 11 patients avec
un pemphigus foliaceus
réfractaires
aux
thérapies
conventionnelles
IgIV : 2g/kg
par cycle de
4 semaines
Ahmed
(2001)
Ouverte
N = 21 patients avec un
pemphigus vulgaris en
échec
des
corticostéroïdes et des
immunosuppresseurs
IgIV : 2g/kg
toutes les 4
semaines
Engineer
(2000)
Méta-analyse
Rétrospective
pemphigus vulgaris en
échec
des
corticostéroïdes et des
immunosuppresseurs
ou
intolérants
aux
corticostéroïdes
Rétrospective
pemphigus
vulgaris
modéré à sévère et
dépendants
aux
corticostéroïdes
IgIV : 2 g/kg
tous les
mois
3 cycles
- réponse
clinique
durée
du
traitement
- nombre de
cycle d’IVIg
- fréquence des
rechutes et
récurrences
- épargne des
stéroïdes
- dose totale
d’IVIg
- durée des autres
traitements
conventionnels
- effets
indésirables
- fréquence et
récurrence des
rechutes
- durée du
traitement par
IgIV
-durée jusqu’à la
rémission
et
durée
de
la
rémission
-nombre
d’hospitalisation
s
-qualité de vie
Sami
(2002)
Sami N
2002
IgIV : 1 à 2
g/kg /cycle
6.2
ans
Critères
d’évaluation
- dose totale et
durée
de
la
corticothérapie
- nombre de
rechutes
Résultats
- Cicatrisation de toutes les
lésions
- pas de rechute au bout d’1 an
même après arrêt du traitement
- pas d’effets indésirables
sérieux
- durée moyenne : 2.8 mois
- ↓ de la dose de stéroïdes entre
le pré et le post traitement :
p = 0.005
- nombre de rechute : p =0.002
- durée de la corticothérapie :
p = 0.02
- Tous les patients ont été en
rémission pendant une période
de 18.6 mois en moyenne après
arrêt de la corticothérapie
- tous les critères sont
significativement améliorés
- Rémission de tous les patients
avec
une
épargne
des
corticostéroïdes et amélioration
de la qualité de vie
- Pas d’effets indésirables
sérieux
- l’arrêt du traitement par les IVIg
doit se faire progressivement
- tous les critères sont
significativement améliorés
- 19 % non répondeurs
- 81 %de répondeurs
Réponse au traitement si IGIV
associées à un autre traitement
Effet d’épargne cortisonique
significatif
- Rémission chez tous les
patients
↓
progressive
de
la
corticothérapie sur une période
moyenne de 4.3 mois
- ↓ de la dose de stéroïdes S
P = 0.004 et de la durée de la
corticothérapie : p =0.003
77
- ↓ du nombre de rechutes
p < 0.001
Levy
(2004)
Rétrospective
pemphigus
vulgaris
corticodépendant
ou
cortico-résistant
Ahmed
(2006)
Ouverte
N = 11 patients avec
pemphigus
vulgaris
résistant
aux
corticoïdes
et
aux
immunosuppresseurs
- 8/12 rémission complète
Rituximab :
375
mg/m²/sem
pendant 3
semaines
puis
IgIV : 2g/kg
la 4 ème
semaine
Puis
rituximab +
IgIV tous les
mois
pendant 4
mois
37
mois
- taux
des AC
sérique
Réduction
de
la
corticothérapie : 75% et ↓ des
immunosuppresseurs : 2/3
- Rémission persistante après
traitement :
. à 6 mois : 6/10
. à 1 an : 5/8
- Amélioration de tous les
patients entre 3 et 6 cycles de
rituximab
-9/11 rémissions (22 à37 mois)
- 2 rechutes
- corrélation entre le taux d’AC/
évolution clinique et la déplétion
en lymphocytes B
Bibliographie
1- Enk AH, Knop J. Adjuvant therapy of pemphigus vulgaris and pemphigus foliaceus with intravenous immunoglobulins
Hautarzt. 1998 Oct;49(10):774-6
Sami N, Qureshi A, Ahmed AR. Steroïd sparing effect of intravenous immunoglobulin therapy in patients with pemphigus
foliaceus Eur J Dermatol. 2002 Mar-Apr;12(2):174-8
3-Ahmed AR, Sami N. Intravenous immunoglobulin therapy for patients with pemphigus foliaceus unresponsive to conventional
therapy J Am Acad Dermatol. 2002 Jan;46(1):42-9
4- Ahmed AR. Intravenous immunoglobulin therapy in the treatment of patients with pemphigus vulgaris unresponsive to
conventional immunosuppressive treatment J Am Acad Dermatol. 2001 Nov;45(5):679-90
5- Engineer L, Bhol KC, Ahmed AR. Analysis of current data on the use of intravenous immunoglobins in management of
pemphigus vulgaris J Am Acad Dermatol. 2000 Dec;43(6):1049-57
6-Sami N, Qureshi A,Ruocco E, Ahmed AR. Corticosteroïd-sparing effect of intravenous immunoglobin therapy in patients with
pemphigus vulgaris Arch Dermatol. 2002 Sep;138(9):1158-62
7-Levy A, Doutre MS, Lesage FX, Richard MA, Picard-Dahan C, Beylot-Barry M, Bernard P, Crickx B, Descamps V. Treatment
of pemphigus with intravenous immunoglobulinAnn Dermatol Venereol. 2004 Nov;131(11):957-61
8- Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. Treatment of pemphigus vulgaris with rituximab and intravenous immune
globulinN Engl J Med. 2006 Oct 26;355(17):1772-9
78
Groupe de travail
Grenoble
Marseille
Bordeaux
Docteur Sébastien BARBAROT, Dermatologue, Nantes
Professeur Christophe BEDANE, Dermatologue,
Limoges
Groupe de lecture
Saint-Etienne
Lille
Professeur RICHARD MARIE-Aleth, dermatologue,
Marseille
HCL, Lyon
Mme
BONGRAND
Marie-Claude,
pharmacien,
Pr LAVILLE
Mme
Catherine,
l’AP-HP, Paris
Lyon
Paris
Résumés-abstracts
Adjuvant therapy of pemphigus vulgaris and pemphigus foliaceus with intravenous immunoglobulins
Enk AH, Knop J. Hautarzt. 1998 Oct;49(10):774-6
High dose intravenous immunoglobulins (IVIG) have been shown to be effective in different autoimmune
diseases. We report on the use of IVIG in patients with pemphigus vulgaris (PV) or pemphigus foliaceus (PF)
resistant to conventional therapy. Six patients who presented with a relapse of their disease following
conventional immunosuppressive treatment with prednisolone and azathioprine were additionally treated with 2
g/kg of IVIG every four weeks. Six to nine cycles of this therapy were given to each patient. All patients showed
healing of their blisters without evidence of relapse even when steroids and immunosuppressants were tapered.
None of the patients relapsed within one year of follow-up, although IVIG treatment was discontinued. Side effects
of IVIG treatment were moderate with only slight evidence of headaches. We suggest that adjuvant treatment of
PV and PF resistant to conventional immunosuppressive strategies is a useful addition to our therapeutic arsenal
in both diseases.
Steroïd sparing effect of intravenous immunoglobulin therapy in patients with pemphigus foliaceus. Sami N,
Qureshi A, Ahmed AR. Eur J Dermatol. 2002 Mar-Apr;12(2):174-8
Pemphigus foliaceus (PF) is a rare autoimmune cutaneous blistering disease, with only skin involvement.
Systemic corticosteroids and immunosuppressive agents are the mainstay of therapy. However, some patients
develop multiple side effects to systemic corticosteroids, when they are used in high doses over prolonged
periods. In some patients, immunosuppressive agents are not effective or contraindicated. In such patients,
79
alternative treatment modalities are needed. The purpose of this study is to demonstrate the use of intravenous
immunoglobulin (IVIg) therapy in seven patients with severe PF, who were steroid-dependent. The following
information was recorded in each patient, before and after IVIg therapy initiation: total dose and total duration of
prednisone therapy, and number of relapses. In addition, the highest dose and side effects of prednisone therapy,
and duration of observation were documented. After the initiation of IVIg treatment, doses of systemic
corticosteroids were gradually reduced and eventually discontinued over a mean period of 2.8 months.
Thereafter, IVIg was used as monotherapy. A statistically significant difference was noted between pre-IVIg
therapy and after the initiation of IVIg therapy in the total dose (p = 0.005), and total duration of prednisone
treatment (p = 0.02), and the number of relapses (p = 0.002). In all seven patients, IVIg produced an effective
clinical response and demonstrated a steroid-sparing effect. In patients with PF, who are steroid-dependent and
in whom use of conventional immunosuppressive agents is contraindicated, IVIg appears a safe and effective
agent to induce and maintain a prolonged clinical remission.
Intravenous immunoglobulin therapy for patients with pemphigus foliaceus unresponsive to conventional therapy
Ahmed AR, Sami N. J Am Acad Dermatol. 2002 Jan;46(1):42-9
BACKGROUND: Pemphigus foliaceus (PF) is a chronic autoimmune blistering skin disease that is commonly
treated with oral corticosteroids and immunosuppressive therapy. In some patients, PF can be refractory to
treatment and the resultant side effects of prolonged immune suppression can be potentially fatal. Alternative
therapies are needed. OBJECTIVE: The purpose of this study is to report treatment outcomes with IVIg therapy in
11 patients with severe PF refractory to prednisone and other immunosuppressive therapy. METHODS: Selection
criteria included documentation of a biopsy and immunopathology in 11 patients who were resistant to treatment
or experienced side effects to conventional therapy. IVIg was administered according to a defined protocol. The
parameters used to assess clinical response to IVIg included time observed for effective control of disease,
duration of IVIg maintenance therapy, total duration of IVIg, number of IVIg cycles, systemic drug therapy, and the
frequency of recurrences and relapses. The pre-IVIg and post-IVIg data were statistically analyzed by means of
the SAS UNIVARIATE and 2-sided Wilcoxon sign rank and sign tests. RESULTS: All patients had an effective
clinical response and remained in clinical remission for a mean period of 18.6 months after discontinuation of IVIg
therapy. Serious side effects from IVIg use were not observed. CONCLUSION: IVIg therapy appears to have
potential as a biologic alternative agent in inducing and maintaining clinical remissions in patients with PF who are
resistant to more standard conventional treatment. IVIg is effective as monotherapy and may be needed for a
period of several months to achieve a long-term clinical remission.
Intravenous immunoglobulin therapy in the treatment of patients with pemphigus vulgaris unresponsive to
conventional immunosuppressive treatment. Ahmed AR. J Am Acad Dermatol. 2001 Nov;45(5):679-90
BACKGROUND: Severe pemphigus vulgaris (PV) is conventionally treated with high-dose oral prednisone,
usually in combination with an immunosuppressive agent (ISA). Some patients experience significant side effects,
which are sometimes fatal, from prolonged immunosuppression. OBJECTIVE: Intravenous immunoglobulin (IVIg)
was administered to 21 patients with severe cutaneous and mucosal PV who had not responded to the prolonged
use of oral prednisone and multiple ISAs. METHODS: A preliminary dose-determination study tested 7 additional
volunteers to ascertain the optimal IVIg dose of 2 g/kg per cycle. Parameters to assess clinical outcome were
recorded before and after IVIg therapy. Variables tested were highest dose, total dose, and duration of
prednisone and ISAs, their side effects, frequency of recurrence and relapse, duration of IVIg therapy, clinical
response, induction and duration of remission, number of hospitalizations, total days of hospital stay, and quality
of life. RESULTS: Use of IVIg monotherapy resulted in effective control of disease and produced a sustained
remission in the 21 patients. The patients became free of lesions and remained so after finishing IVIg therapy.
IVIg had a steroid-sparing effect and produced a high quality of life. Serious side effects from the use of IVIg were
not observed. IVIg needs to be gradually withdrawn after achievement of clinical control. CONCLUSION: In
patients with PV who do not respond to conventional immunosuppressants, IVIg appears to be an effective
treatment alternative. Its early use is of significant benefit in patients who may experience life-threatening
complications from immunosuppression. IVIg is effective as monotherapy.
Analysis of current data on the use of intravenous immunoglobins in management of pemphigus vulgaris.
Engineer L, Bhol KC, Ahmed AR. J Am Acad Dermatol. 2000 Dec;43(6):1049-57
!
!" !
#immunosuppressive adjuvant
agents, are frequently used in treating patients with pemphigus vulgaris (PV). The severe, catastrophic, and
potentially fatal side effects of these agents highlight the need for the development of safe alternatives for PV
therapy. Intravenous immunoglobulin (IVIG) therapy has recently been reported to be effective in the treatment of
PV. OBJECTIVE: Our purpose was to do a retrospective analysis of the available literature on the use of IVIG in
the treatment of PV. We also wished to determine whether the cumulative evidence permits making preliminary
conclusions regarding the potential role of IVIG in the overall management of PV. METHODS: A review of the
English-language, peer-reviewed literature was conducted for reports on IVIG use in treatment of PV. The
80
available information on 21 patients was used to assess different dimensions of clinical efficacy. RESULTS: A
minimum dose of 2 g/kg per cycle given at regular monthly intervals for a minimum of 3 cycles seems be effective
in inducing a rapid clinical remission in patients with severe, recalcitrant PV. However, this should not be
perceived as a "standard" dose. Tapering and eventual discontinuation of other agents were possible in many
patients. Long-term follow-up was not provided to examine the influence of IVIG on the clinical course of disease,
its efficacy as monotherapy, and the benefit of using it as maintenance therapy to keep the patient in prolonged
clinical remission. In 4 of the 21 patients (19%), use of IVIG was of no clinical benefit. This failure of efficacy was
primarily due to inadequate use. IVIG demonstrated beneficial effect in 17 of 21 patients (81%). CONCLUSION:
IVIG may be a safe and effective agent in the management of severe, recalcitrant PV. Multicenter controlled
studies, using different dose regimens, with lengthy follow-up periods are necessary to clearly define the
emerging beneficial role of IVIG.
Corticosteroïd-sparing effect of intravenous immunoglobin therapy in patients with pemphigus vulgaris. Sami N,
Qureshi A,Ruocco E, Ahmed AR. Arch Dermatol. 2002 Sep;138(9):1158-62
BACKGROUND: Pemphigus vulgaris (PV) is a rare, potentially fatal autoimmune mucocutaneous blistering
disease. The prolonged use of systemic corticosteroids, though clinically effective in high doses, can result in
multiple debilitating adverse effects. Immunosuppressive agents, used as adjuvants and as corticosteroid-sparing
agents, are not effective in all patients and are contraindicated in some. Therefore, alternative treatment
modalities are needed to provide effective control of PV in such patients. OBJECTIVE: To demonstrate the
corticosteroid-sparing effect of intravenous immunoglobulin (IVIg) therapy in patients with moderate to severe PV.
DESIGN: A retrospective analysis in a cohort of 15 patients with moderate to severe PV who were treated with
IVIg therapy. All 15 patients were corticosteroid dependent, and the use of other systemic conventional
immunosuppressive agents was contraindicated. The patients were followed up over a mean period of 6.2 years.
SETTING: Ambulatory tertiary medical care facility of a university-affiliated hospital. INTERVENTION: All 15
patients received an IVIg dose of 1 to 2 mg/kg per cycle. MAIN OUTCOME MEASURES: The following
information was documented in each of the 15 patients before and after the initiation of IVIg therapy: total dosage
and total duration of prednisone therapy and number of relapses. Also, the highest dosage and adverse effects of
prednisone therapy, as well as the total duration of observation, were recorded. RESULTS: All 15 patients had a
satisfactory clinical response to IVIg therapy. The use of systemic prednisone was gradually discontinued over a
mean period of 4.3 months. A statistically significant difference was noted in the total dose of prednisone (P
=.004), total duration of prednisone therapy (P =.003), and number of relapses (P<.001) before and after the
initiation of IVIg therapy. CONCLUSIONS: Intravenous immunoglobulin therapy has a demonstrable
corticosteroid-sparing effect. It is a safe and effective alternative treatment modality in patients with PV who are
dependent on systemic corticosteroids or who develop significant adverse effects as a result of their use.
Treatment of pemphigus with intravenous immunoglobulin. Levy A, Doutre MS, Lesage FX, Richard MA, PicardDahan C, Beylot-Barry M, Bernard P, Crickx B, Descamps V. Ann Dermatol Venereol. 2004 Nov;131(11):957-61
INTRODUCTION: The interest of intravenous immunoglobulins (Igi.v.) in the treatment of pemphigus is
discussed. Pemphigus is not a recognized indication for this treatment by the CEDIT (French Committee for the
assessment and diffusion of technological innovations). The aim of this study was to assess the efficacy of Igi.v.
in the treatment of severe corticosteroid-dependent or resistant pemphigus. MATERIAL AND METHODS: A
retrospective study using a standardized questionnaire was conducted in the various departments of dermatology
among the "Groupe Bulles" of the French Society of Dermatology. The study collected the following information
from 12 patients suffering from pemphigus and treated with Igi.v.: 1) general demographical data; 2)
characteristics of the pemphigus; 3) different treatments applied, and 4) efficacy and side effects of treatments.
RESULTS: Among the 12 patients studied at the end of treatment with Igi.v., 8 were in complete remission (1
fleetingly for 2 months and 1 preceding initiation of Igi.v.), and 2 were improved (1 temporarily for 4 months). A
reduction in corticosteroid therapy was possible in 75 p. 100 of cases (9 patients). During treatment with Igi.v.,
immunosuppressors were combined with oral corticosteroids in 3 cases. It was possible to reduce their dose 1
one case and to stop them in another case. No major side effect related to treatment with Igi.v. was observed. Six
months and one year after the treatment, complete remission rates were respectively 6/10 and 5/8. One patient
relapsed more than one year after the end of Igi.v. treatment. CONCLUSIONS: Although very expensive,
treatment with Igi.v. appears of interest in the treatment of severe corticosteroid-dependent or resistant
pemphigus. Moreover tolerance is excellent. The results of our study warrant confirmation in a prospective study.
Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. Ahmed AR, Spigelman Z,
Cavacini LA, Posner MR. N Engl J Med. 2006 Oct 26;355(17):1772-9
BACKGROUND: Pemphigus vulgaris is a potentially fatal autoimmune mucocutaneous blistering disease.
Conventional therapy consists of high-dose corticosteroids, immunosuppressive agents, and intravenous immune
globulin. METHODS: We studied patients with refractory pemphigus vulgaris involving 30% or more of their bodysurface area, three or more mucosal sites, or both who had inadequate responses to conventional therapy and
81
intravenous immune globulin. We treated the patients with two cycles of rituximab (375 mg per square meter of
body-surface area) once weekly for 3 weeks and intravenous immune globulin (2 g per kilogram of body weight) in
the fourth week. This induction therapy was followed by a monthly infusion of rituximab and intravenous immune
globulin for 4 consecutive months. Titers of serum antibodies against keratinocytes and numbers of peripheralblood B cells were monitored. RESULTS: Of 11 patients, 9 had rapid resolution of lesions and a clinical remission
lasting 22 to 37 months (mean, 31.1). All immunosuppressive therapy, including prednisone, could be discontinued
before ending rituximab treatment in all patients. Two patients were treated with rituximab only during recurrences
and had sustained remissions. Titers of IgG4 antikeratinocyte antibodies correlated with disease activity.
Peripheral-blood B cells became undetectable shortly after initiating rituximab therapy but subsequently returned
to normal values. Side effects that have been associated with rituximab were not observed, nor were infections.
CONCLUSIONS: The combination of rituximab and intravenous immune globulin is effective in patients with
refractory pemphigus vulgaris.
82
Immunoglobulines IV
Pemphigoïde cicatricielle avec une atteinte muqueuse étendue ou atteinte
oculaire ne répondant pas à l’association dapsone ou corticoïdes et
immunosuppresseurs bien conduite (3 à 6 mois d’Immunosuppresseurs) ou en
cas d’intolérance à ces traitements
La dose usuelle est de 2 g/kg/mois ou cycle avec une évaluation de l’efficacité après 5-6 cycles.
Contre-indications
· chez les patients présentant un déficit en IgA et avec des anticorps circulants anti-IgA ; (à l’exception
de Gammagard);
excipients et est
érable et
d'
hyperprolinémie.
Sécurité d’emploi et mises en garde
administration. Le débit recommandé
(voir paragraphe Mode d'
administration) doit être scrupuleusement observé et les patients doivent
rester sous surveillance pendant toute la durée de la perfusion afin de détecter d'
éventuels signes
d'
intolérance.
83
de s'
administration des IgIV par une perfusion lente
(0,5 ml/kg/h ( 0.5 ml/kg/h pour Sandoglobuline 120 mg/ml® et 1ml/kg/h maximum pour la Tégéline®)) ;
IgG
Gammagard), de la teneur en saccharose (1,67 g par g d’IgG : Sandoglobuline® 1g, 3g, 6g, 12g et
2g/g d’IgG : Tégéline®) en cas de diabète latent où une glycosurie passagère peut survenir, de diabète
ou derégime hypoglucidique ;
Le risque d'
Des cas d'
hypovolémie ou une obésité. Chez ces patients, l'
administration d'
IgIV impose :
· un dosage de la créatininémie,
Bien que ces cas d'
d'
IgIV, celles contenant du saccharose comme stabilisant représentent la plus large part
Traitement associé
L'
administration d'
avant d'
84
temporaires.
animal n'
IV et l'
aucune réaction indésirable sur le fœtus
et le nouveau-né n'
d'
85
2.
ARGUMENTAIRE
Classiquement, on distingue deux types de pemphigoïde :
- La pemphigoïde bulleuse qui touche les personnes âgées (âge moyen entre 60 et 70 ans). Son
incidence annuelle est en France d’environ 70 nouveaux cas.
Cette dermatose aboutit à la formation de boutons de coloration rouge ressemblant à de l'
urticaire. À
cela s'
ajoutent de petites cloques c'
est-à-dire des vésicules ou des cloques plus volumineuses (bulles)
à peu près symétriques et se disposant sur l'
ensemble des membres et du tronc.
- La pemphigoïde cicatricielle quant à elle apparaît essentiellement chez les femmes après 70 ans.
Une des caractéristiques de cette dermatose est son évolution vers des cicatrices. Les muqueuses
sont concernées également et essentiellement celles des yeux, et de la bouche. Les cicatrices
touchent les conjonctives (membrane de protection située à la face antérieure du globe oculaire et à la
partie interne des paupières). Elles sont quelquefois à l'
origine d'
une cécité. La pemphigoïde
cicatricielle concerne plus rarement la peau, entraînant des érosions chroniques essentiellement au
niveau de la tête et du cou.
La stratégie thérapeutique actuellement recommandée est :
- dapsone (traitement de référence)
- alternative : sulfasalazine ou les cyclines.
- dans les atteintes muqueuses graves (atteinte oculaire ou laryngée) : association avec des
immunosuppresseurs (cyclophosphamide) et corticoïdes.
L’analyse de la littérature montre que la majorité des publications provient de la même équipe. Le
nombre total de patients est difficile à évaluer en raison de la possibilité de plusieurs cycles d’IgIV
pour obtenir une efficacité du traitement. En effet, le traitement par les IgIV doit être prolongé, il faut
au moins 4 cycles pour obtenir une efficacité. La durée de rémission varie entre 12 et 72 mois. On
observe une amélioration et une stabilité clinique chez une majorité de patients : 8/8 patients
stabilisés (Letko 2004), réponse clinique chez 15/15 patients (Sami 2002), 8/10 et 10/10 stabilisés et
amélioration de l’acuité visuelle (Sami 2004 et Foster 1999).
L’utilisation des IgIV est temporairement acceptable dans la pemphigoïde cicatricielle avec atteinte
muqueuse étendue ou oculaire ne répondant pas à l’association bien conduite de dapsone ou
corticoïdes et immunosuppresseurs (3 à 6 mois d’immunosuppresseurs) ou en cas d’intolérance à ces
traitements.
Le traitement par immunoglobulines IV doit être prolongé pendant au moins 5 à 6 cycles pour en
évaluer son efficacité.
Les IgIV sont un traitement de fond. Le traitement des poussées inflammatoires oculaires reste les
immunosuppresseurs en bolus.
86
Effet des IgIV dans les pemphigoïdes cicatricielles
Auteur
Type d’étude
Letko
(2004)
Ouverte :
- Groupe A : n = 8
patients ayant une
pemphigoïde oculaire
cicatricielle
traités
par
IVIG
et
antérieurement par
des
immunosuppresseurs
- Groupe B : n = 8
patients traités par
des
immunosuppresseurs
conventionnels
Posologi
e
IgIV :
2g/kg
toutes les
2à4
semaines
jusqu’à
améliorati
on
Sami
(2002)
Ouverte
n = 15 patients
traités
antérieurement par
des corticoïdes et
immunosuppresseurs
pour une
pemphigoïde
cicatricielle et
résistants à ces
traitements
IgIV de 1
à2
g/kg/cycle
Sami
(2004)
Ouverte
n = 10 patients avec
un pemphigoïde
oculaire cicatricielle
IgIV
Foster
(1999)
Ouverte
une pemphigoïde
cicatricielle atteignant
les yeux et résistants
aux thérapies
conventionnelles
IgIV :
23g/kg/cycl
e sur 3
jours
toutes les
2à6
semaines
Ahmed
(2001)
Rétrospective
une pemphigoïde
orale
n = 12
patients
traités par
les
thérapies
conventio
nnelles
n = 8
patients
IgIV
Suivi
Groupe
A : 24
mois
Groupe
B : 45
mois
48 mois
6 ans
Critères
d’évaluation
- durée entre
le début du
traitement et
la rémission
-récurrence
- progression de
la maladie
- inflammation
de l’oeil
Résultats
- nombre
d’effets
indésirables
- fréquence et
récurrence
des rechutes
- dose de
prednisone
utilisée et
durée de la
corticothérapie
- qualité de vie
- acuité
visuelle
- progression
de la maladie
telles que la
fibrose et la
cécité
- nombre de
cycles d’IVIg
-durée totale
du traitement
- durée
moyenne de
traitement
- acuité
visuelle,
symptômes
oculaires
- amélioration
clinique
-durée
de
traitement
- fréquence
des rechutes
- rémission
- effets
indésirables
- progression
- qualité de vie
- Résultats : 11 à50 cycles (moyenne
25)
- Réponse clinique chez tous les
patients (4.8 mois)
-Rémission : 12 à72 mois (moyenne
24)
- différence significative de tous les
critères d’évaluation en comparant pré
et post-traitement par IVIg
- pas d’effets indésirables avec les IVIg
- Durée moyenne entre le début du
traitement et la rémission : p < 0.01
. Groupe A : 4 mois
. Groupe B : 8.5 mois
- Récurrence : p < 0.05
. Groupe A : Pas de récurrence
. Groupe B : 1 récurrence en moyenne
chez 5 patients
- progression de la maladie :
. groupe A : pas de progression chez
les 8 patients (stade 2)
. groupe B :
Pas de progression chez 4 patients
(stade 2) et progression chez les 4
autres (stade 3)
- inflammation des yeux : p< 0.05
- nombre de cycles entre 20 et 42 et la
durée moyenne de traitement entre 25
et 43 mois.
- 8 patients ont suivi le protocole
complet : amélioration de l’acuité
visuelle et pas de progression de la
maladie.
Rémission maintenue pendant 24 à 48
mois
- 2 patients ont arrêté le traitement et
ont perdu la vue
- Minimum 4 cycles pour un effet
- Pour 3 patients, il a fallu 12 cycles
- durée moyenne de traitement : 19
mois
- stabilité de l’acuité visuelle : 10/10
- amélioration clinique chez tous les
patients
- Pour tous les critères d’évaluation :
différence S entre les 2 groupes
87
Bibliographie
1- Letko E, Miserocchi E, Daoud YJ, Christen W, Foster CS, Ahmed AR. A non randomized comparison of the clinical outcome
of ocular involvement in patients with mucous membrane (cicatricial) pemphigoïd between conventional immunosuppressive
and intravenous immunoglobulin therapies.Clin Immunol. 2004 Jun;111(3):303-10
2- Sami N, Bhol KC, Razzaque Ahmed A. Intravenous immunoglobulin therapy in patients with multiple mucosal involvement in
mucous membrane pemphigoïd Clin Immunol. 2002 Jan;102(1):59-67
3-Sami N, Letko E, Androudi S, Daoud Y, Foster CS, Ahmed AR. Intravenous immunoglobulin therapy in patients with ocularcicatricial pemphigoïd : a long term follow-up Ophthalmology. 2004 Jul;111(7):1380-2
4-Ahmed AR, Colon JE. Comparison between intravenous immunoglobin and conventional immunosuppressive therapy
regimens in patients with severe oral pemphigoïd : effects on disease progression in patients nonresponsive to dapsone
therapy.Arch Dermatol. 2001 Sep;137(9):1181-9
5-Foster CS, Ahmed AR. Intravenous immunoglobulin therapy for ocular cicatricial pemphigoid : a preliminary study
Ophthalmology. 1999 Nov;106(11):2136-43
Groupe de travail
Grenoble
Docteur Sébastien BARBAROT, Dermatologue, Nantes
Professeur Christophe BEDANE, Dermatologue, Limoges
Marseille
Bordeaux
Groupe de lecture
Saint-Etienne
Lille
Professeur RICHARD MARIE-Aleth, dermatologue,
Marseille
HCL, Lyon
Mme
BONGRAND
Marie-Claude,
pharmacien,
Pr LAVILLE
Mme
Catherine,
l’AP-HP, Paris
Lyon
Paris
.
88
Résumés-abstracts
A non randomized comparison of the clinical outcome of ocular involvement in patients with mucous membrane
(cicatricial) pemphigoïd between conventional immunosuppressive and intravenous immunoglobulin therapies.
Letko E, Miserocchi E, Daoud YJ, Christen W, Foster CS, Ahmed AR. Clin Immunol. 2004 Jun;111(3):303-10
The purpose of this study was to compare the clinical outcomes of intravenous immunoglobulin (IVIg) therapy to
conventional immunosuppressive therapy in patients with mucous membrane pemphigoid (MMP), also known as
cicatricial pemphigoid (CP), whose disease progressed to involve the eye. Before ocular involvement, all the
patients in this study were diagnosed and treated with immunosuppressive agents, for biopsy-proven MMP,
affecting the skin and/or mucous membranes, other than the conjunctiva. Eight patients in group A were treated
with IVIg after the diagnosis of ocular cicatricial pemphigoid (OCP) was established. The efficacy and safety of
IVIg therapy were compared to a clinically similar group of eight patients treated with conventional
immunosuppressive therapy (group B). The inclusion criteria for both groups were: (1). presence of MMP at
extraocular sites confirmed by biopsy before entry into the study; (2). entry into the study occurred when ocular
involvement was noted and confirmed by biopsy; (3). presence of conventional immunosuppressive therapy at the
time of ocular involvement; (4). a minimum of 18 months of follow-up after diagnosis of ocular involvement. The
mean length of the therapy, after the onset of ocular involvement, was 24 months (range 16-30) in group A and 45
months (range 21-90) in group B. The median time between initiation of therapy and clinical remission in group A
and group B was 4 and 8.5 months, respectively. This difference was statistically significant (P < 0.01). No
recurrence of ocular inflammation was recorded in any of the patients in group A. On the contrary, at least one
recurrence (median 1) was recorded in five patients in group B (range 0-4). This difference was statistically
significant (P < 0.05). All eight patients in group A and group B presented to the ophthalmologist in stage 2 of
OCP at the time of the initial visit. At the last follow-up visit, no progression to advanced stages of OCP was
recorded in all eight patients in group A. On the contrary, only four patients in group B remained in stage 2 of
OCP at the last follow-up exam. The conjunctival scaring progressed from stage 2 to stage 3 in the remaining four
patients of group B. At the last follow-up visit, both eyes of each patient in group A were free of inflammation.
Some level of conjunctival inflammation at the last follow-up visit was noted in five patients in group B (range 01.5, P < 0.05). Both groups of patients were studied during the same time period. The results of this study suggest
that ocular involvement in patients with MMP may be considered an indication for initiating IVIg therapy, since it
was more effective in arresting progression of OCP, when compared to conventional immunosuppressive therapy.
These data indicate that IVIg produced a faster control of the acute inflammation and that no recurrences were
observed during the follow-up. This clinical difference could be because of the reduced production of pathogenic
antibody, and/or restoration of the immunoregulation, which may have been disturbed.
Intravenous immunoglobulin therapy in patients with multiple mucosal involvement in mucous membrane
pemphigoïd. Sami N, Bhol KC, Razzaque Ahmed A. Clin Immunol. 2002 Jan;102(1):59-67
Mucous membrane pemphigoid (MMP), also known as cicatricial pemphigoid (CP), is an autoimmune
mucocutaneous, blistering disease which can lead to blindness and/or death from sudden asphyxiation,
secondary to a scarring process. Conventional therapy for the treatment of MMP consists of high-dose systemic
corticosteroids and/or immunosuppressive agents. Some patients do not respond to these treatments and
develop multiple serious side effects, which can be potentially fatal. In such patients, alternative treatment
modalities are needed. This study presents the use of intravenous immunoglobulin (IVIg) therapy in 15 patients
with severe MMP whose disease was nonresponsive to the prolonged use of high-dose systemic corticosteroids
and immunosuppressive agents and who developed multiple side effects to them. All 15 patients received an IVIg
dose of 1-2 g/kg/cycle. The following objective parameters were used to assess the clinical outcome pre- and
post-IVIg therapy: number of side effects, frequencies of recurrences and relapses, duration and total dosage of
prednisone therapy, and the quality of life. The differences in these variables between the pre- and post-IVIg data
were statistically analyzed using the SAS UNIVARIATE software running the two-sided Wilcoxon signed-rank and
sign tests. A statistically significant difference was observed between pre- and post-IVIg therapy data when
comparing the aforementioned variables. All 15 patients had an effective clinical response, were able to
discontinue previous systemic therapies, and eventually achieved a prolonged clinical remission. IVIg improved
the quality of life in all 15 patients and demonstrated a steroid-sparing effect. No serious side effects were
observed. IVIg therapy is a safe and effective alternative modality in the treatment of patients with nonresponsive
and progressive MMP and can induce a sustained clinical remission.
89
Intravenous immunoglobulin therapy in patients with ocular-cicatricial pemphigoïd : a long term follow-up
Sami N, Letko E, Androudi S, Daoud Y, Foster CS, Ahmed AR. Ophthalmology. 2004 Jul;111(7):1380-2
OBJECTIVE: To report the clinical outcome and long-term follow-up of 10 patients with progressive ocularcicatricial pemphigoid (OCP), nonresponsive to conventional therapy and treated with IV immunoglobulin (IVIg)
therapy, reported earlier as a preliminary study. DESIGN: Noncomparative, prospective, interventional case
series according to a defined protocol for IVIg therapy. PARTICIPANTS: Ten patients, with a diagnosis of OCP
present bilaterally confirmed by both biopsy and immunofluorescence studies and who had failed conventional
therapy and had objectively demonstrated a positive response to IVIg therapy in a preliminary study, published in
1999. MAIN OUTCOME MEASURES: Comparison of objective clinical outcome parameters before and after IVIg
therapy, including visual acuity (VA) and prevention of progression of subepithelial conjunctival fibrosis and
blindness. RESULTS: All 10 patients initially demonstrated signs of clinical improvement with IVIg therapy. The
total number of IVIg cycles ranged from 20 to 42 (mean, 32), and the total duration of IVIg therapy ranged from 25
to 43 months (mean, 35). Eight patients who completed the protocol had an improvement in their VA and did not
have further progression of subepithelial conjunctival fibrosis. These 8 patients have been maintained in a
sustained remission for a total follow-up period ranging from 24 to 48 months (mean, 35) after the discontinuation
of IVIg therapy. Two patients did not complete the protocol. Both had initially demonstrated a positive clinical
response. One patient had worsening of the OCP and, after IVIg therapy, was abruptly and involuntarily
withdrawn. In the second patient, deterioration occurred after ocular surgery. Intravenous immunoglobulin therapy
was not provided postoperatively. These 2 patients who did not complete the protocol lost vision.
CONCLUSIONS: Intravenous immunoglobulin therapy is an effective treatment in OCP in patients nonresponsive
to conventional therapy. In 8 patients who completed the protocol, progression of the disease was not observed.
A gradual withdrawal of IVIg therapy, as described in the protocol, may be beneficial in maintaining a sustained
clinical remission. Abrupt cessation or discontinuation can result in a severe recurrence that may possibly
progress to blindness.
Comparison between intravenous immunoglobin and conventional immunosuppressive therapy regimens in
patients with severe oral pemphigoïd : effects on disease progression in patients nonresponsive to dapsone
therapy. Ahmed AR, Colon JE. Arch Dermatol. 2001 Sep;137(9):1181-9
CONTEXT: Mucous membrane pemphigoid has a wide clinical spectrum. The clinical context was to determine
whether pemphigoid disease that initiates in the oral cavity progresses to involve other mucosae and to determine
the influence of systemic therapy on such progression. OBJECTIVE: To determine the clinical outcomes and
disease progression in patients with oral pemphigoid for whom dapsone therapy was impossible. DESIGN:
Retrospective analysis of a cohort of 20 patients with immunopathologic-proven oral pemphigoid studied between
September 1, 1994, and October 31, 2000. Twelve patients received conventional therapy that consisted of a
combination of oral prednisone with an immunosuppressive agent. Eight patients in whom such therapy was
contraindicated received intravenous immunoglobulin therapy. Patients were followed up for 33 to 62 months
(mean follow-up, 47.5 months). SETTING: Patients were treated in an ambulatory tertiary medical care facility of a
university-affiliated hospital. PATIENTS: The 20 patients had pemphigoid disease limited to the oral cavity only at
the initial clinical presentation and when enrolled in the study. MAIN OUTCOME MEASURES: The following
variables were compared between the 2 groups of patients: (1) duration of treatment, (2) frequency of relapses,
(3) induction of remission, (4) adverse effects of therapy, (5) extra oral involvement, and (6) quality of life.
RESULTS: Using the aforementioned factors, the group treated with intravenous immunoglobulin had statistically
significant shorter treatment duration, fewer relapses, higher remission rate, fewer adverse effects, no extraoral
involvement, and a better quality of life compared with the group who received conventional therapy.
CONCLUSIONS: Intravenous immunoglobulin is a safe and effective modality to treat mucous membrane
pemphigoid. It seems to be a good option for patients who cannot be treated with dapsone and in whom
conventional therapy is contraindicated or results in the development of serious adverse effects. In patients with
progressive mucous membrane pemphigoid, intravenous immunoglobulin therapy may arrest disease
progression.
Intravenous immunoglobulin therapy for ocular cicatricial pemphigoid : a preliminary study. Foster CS, Ahmed AR.
Ophthalmology. 1999 Nov;106(11):2136-43
OBJECTIVE: To report the effects of intravenous immunoglobulin treatment of ten patients with progressive
ocular cicatricial pemphigoid who did not respond to conventional immunomodulatory regimens. DESIGN:
Noncomparative, interventional case series. PARTICIPANTS: Ten patients with biopsy-proven progressive
cicatricial pemphigoid affecting the eyes who did not respond adequately to other local and systemic
immunosuppressive treatment regimens. INTERVENTION: Intravenous infusions of pooled human
immunoglobulin, 2 to 3 g/kg body weight/cycle, divided over 3 days, and repeated every 2 to 6 weeks. MAIN
OUTCOME MEASURES: Reduction in conjunctival inflammation, prevention of progression of subepithelial
conjunctival fibrosis, improvement in ocular symptoms (discomfort, photophobia), improved visual acuity,
reduction in extraocular mucosal lesions. RESULTS: Clinical deterioration was arrested and resolution of chronic
conjunctivitis was documented in all ten patients. Maximum therapeutic effect was observed and maintained after
90
a minimum of 4 cycles of therapy; three patients required 12 cycles before disease control. The duration of
therapy in these ten patients has been 16 to 23 months (mean, 19.3 months) with no treatment-induced side
effects. Extraocular mucosal lesion resolution has occurred in all but one patient, Visual acuity has stabilized or
improved in all ten patients, and subjective complaints of discomfort and photophobia have decreased in all
patients. CONCLUSIONS: Intravenous immunoglobulin immunomodulatory therapy can be a safe and effective
therapy for otherwise treatment-resistant ocular cicatricial pemphigoid.
91
Situation non acceptable
Neutropénie auto-immune
ARGUMENTAIRE
La neutropénie auto-immune assez commune chez les jeunes enfants, est due à des anticorps dirigés
contre des cibles antigéniques (= glycoprotéines) spécifiques des polynucléaires neutrophiles. Cette
forme devient habituellement moins sévère avec l'
âge.
Elle est définie par nombre absolu de PNN au-delàde l’âge de 1 an :
- légère : 1 000 à 1 500/mm3,
- modérée : 500 à1000/mm3,
- sévère : < 500/mm3.
Elle est rare chez l’adulte, pauci-symptomatique, chronique et sans régression spontanée.
La plupart des études rapportant l’utilisation d’IgIV datent des années 1980. Les publications portent
sur des cas rapportés avant la mise à disposition du GCSF, excepté une étude allemande de 1998
(BUX) portant sur 240 enfants. Dans cette étude les IgIV ne sont pas comparées au GCSF.
Il n’y a plus d’intérêt à administrer des IgIV dans cette situation depuis l’arrivée du GCSF, qui
représente le traitement de référence.
Effet des IgIV dans les neutropénies autoimmunes
Auteurs
Type d’étude
Posologie
Suivi
Résultats
Bux
(1998)
Ouverte
N = 240
Enfants de 5-15 mois
IgIV :
n =20 : 0.4 à 1 g/ kg pdt 3 à
5j
50 % d’efficacité :
↑ transitoire des neutrophiles pdt 1
sem
Hilgartner
(1987)
Ouverte
N=6
Enfants < 2 ans
Réponse en moyenne après 3g/kg
d’IgIV au bout de 5 à 7 j en moyenne
avec une durée de l’effet de 14j
(moyenne).
Kurtzberg
(1987)
Ouverte
N = 16
Age : 9 mois à 22 ans
n = 2 patients avec
neutropénie auto-immune
N =2
. N1 : agranulocytose
auto-immune
. N2 : neutropénie autoimmune avec infections
récidivantes
N=3
enfants corticorésistants ou
de contre-indication aux
corticoïdes
IgIV :
1g/kg/j jusqu’au taux de
neutrophiles > 1000/mm3
environ 5j puis 1g/kg/dose
en maintien pdt 14j
IgIV :
N1 = 1: 0, 4 g/kg/j pdt 5j
N2 = 1 : 1g/kg/j pdt 2j
Beris
(1985)
Ventura
(1986)
Sorensen
(1988)
N=2
n = 1 : enfant de 12 ans
neutropénique
avec
infections récidivantes
IgIV :
N1 :18g/j pdt 4j
N2 :18g/j pdt 2j
N1 : ↑ transitoire des neutrophiles
N2 : idem mais ↑ plus modérée
8 mois
IgIV :
0.4 g/kg/j pdt 5 j tous les 2- 3-4
3 semaines quand le taux mois
de neutrophiles ↓ et <
2500/mm3
IgIV :
8
1g/kg/j pdt 3j et 1g/kg mois
toutes les 4 sem (maintien)
+ corticoïdes 20-30 mg/j
pdt 6 mois
↑ neutrophiles >2500/mm3
N1 : maintien du taux de neutrophiles
pdt 8 mois
N2 : rechute au bout de 6 mois
↑ transitoire des neutrophiles
Maintien du taux chez 1/3 après 8
doses d’IgIV.
↑ neutrophiles > 8000/ mm3
A 8 mois : taux de neutrophiles : 10002000/mm3
92
Auteurs
Bussel
(1983)
Type d’étude
N=2
Enfants (14 mois et 13
mois) neutropéniques avec
infections récidivantes
Posologie
Suivi
IgIV :
5
N1 : 0.5g/kg/ j pdt 3j puis mois
0.5g/kg/sem pdt 3 sem
N2 : 0.45 g/kg/j
Résultats
3
↑ neutrophiles >3000/mm dans les 7j
suivant la dose d’IgIV
N1 : ↓ neutrophiles en 3 sem puis ↑
après dose d’IgIV
N2 : stabilisation des neutrophiles à
3
1000/mm
↓ AC anti neutrophiles chez N1 et N2
Bibliographie
1. Bux J, Behrens G, Jaeger G, Welte K. Diagnosis and clinical course of autoimmune neutropenia in infancy: analysis of 240
cases.Blood. 1998 Jan 1;91(1):181-6
2. Hilgartner MW, Bussel J. Use of intravenous gamma globulin for the treatment of autoimmune neutropenia of childhood and
autoimmune hemolytic anemia. Am J Med. 1987 Oct 23;83(4A):25-9.
3. Kurtzberg J, Friedman HS, Chaffee S, Falletta JM, Kinney TR, Kurlander R, Matthews TJ, Schwartz RS. Efficacy of
intravenous gamma globulin in autoimmune-mediated pediatric blood dyscrasias.AM J MED. 1987 OCT 23;83(4A):4-9.
4. Béris P, Audétat F, Beyner F, Pittet D, Jeannet M, Miescher PA.High intravenous doses of immunoglobulins for treatment of
autoimmune neutropenias. Schweiz Med Wochenschr. 1985 Oct 26;115(43):1512-4.
5. Ventura A, Florean P, Pascone R, Perini R, Pocecco M, Lepore L. Intravenous immunoglobulin in immune neutropenia. Helv
Paediatr Acta. 1986 Mar;41(6):495-500.
6. Sorensen RU, Kallick MD. J Clin Apher. Clinical uses of intravenous immune globulin: immunoglobulin replacement therapy
and treatment of autoimmune cytopenias. 1988;4(2-3):97-103.
7. Bussel J, Lalezari P, Hilgartner M, Partin J, Fikrig S, O'
Malley J, Barandun S. Reversal of neutropenia with intravenous
gammaglobulin in autoimmune neutropenia of infancy. Blood. 1983 Aug;62(2):398-400.
Groupe de travail
Dr
ALADJIDI
Nathalie,
Bordeaux
Paris
Groupe de lecture
Pr KESSLER Michèle, néphrologue , Nancy
93
HCL, Lyon
Mme
BONGRAND
Marie-Claude,
pharmacien,
Pr LAVILLE Maurice, praticien hospitalier,
Mme
Catherine,
l’AP-HP, Paris
Lyon
Résumés-abstracts
Bux J, Behrens G, Jaeger G, Welte K. Diagnosis and clinical course of autoimmune neutropenia in infancy:
analysis of 240 cases. Blood. 1998 Jan 1;91(1):181-6
Primary autoimmune neutropenia (AIN) is caused by granulocyte-specific autoantibodies and occurs
predominantly in infancy. Clinical presentation and diagnosis have not been well established, resulting in
burdening diagnostic investigations and unnecessary treatment with granulocyte colony-stimulating factor (GCSF). In the present study, clinical, laboratory, and immunologic data of 240 infants with primary AIN were
evaluated. Suspected association with parvovirus B19 infection was investigated using serologic and DNA-based
methods. Primary AIN was mainly diagnosed at the age of 5 to 15 months but was observed as early as day 33 of
life. In 90% of the cases, AIN was associated with benign infections despite severe neutropenia. Spontaneous
remission, shown by 95% of the patients, usually occurred within 7 to 24 months. Autoantibodies in the patient'
s
sera were not always present, and screening had to be repeated several times until antibody detection
succeeded. About 35% of the autoantibodies showed preferential binding to granulocytes from NA1 and NA2
homozygous donors. Bone marrow was typically normocellular or hypercellular, with a variably diminished
number of segmented granulocytes. A significant association with parvovirus B19 infection was not found.
Symptomatic treatment with antibiotics was sufficient in most patients. Eighty-nine percent of the patients
received antibiotics (cotrimoxazole) for prophylaxis of infections. For severe infections or for surgical preparation,
G-CSF, corticosteroids, and intravenous IgG were administered, resulting in increased neutrophil counts in 100%,
75%, and 50% of the patients treated, respectively. In combination with the detection of granulocyte-specific
antibodies, the typical clinical picture allowed diagnosis of AIN without burdening investigations. Treatment with
G-CSF was found to be a reliable alternative to temporarily increase the neutrophil count.
Hilgartner MW, Bussel J. Use of intravenous gamma globulin for the treatment of autoimmune neutropenia of
childhood and autoimmune hemolytic anemia. Am J Med. 1987 Oct 23;83(4A):25-9.
Intravenous gamma globulin (IVIG) was used to treat autoimmune neutropenia of childhood and autoimmune
hemolytic anemia, two autoimmune disorders not previously treated with this modality. Six children younger than
two years of age, who presented with severe infections and persistent absolute neutrophil counts (300/mm3),
were treated with 1 g of gamma globulin per kilo body weight until counts reached more than 1,000/mm3. The
average response occurred with a dose of 3.0 g/kg within five to seven days and lasted an average of 14 days
before counts decreased to baseline levels. Four patients with autoimmune hemolytic anemia were also treated
with IVIG, 1 g/kg for five to seven days (average dose of 5 g/kg), for severe Coombs'
-positive hemolytic anemia.
Response of the hemolytic anemia to IVIG was excellent in one patient and good in two patients. No response
occurred in the fourth patient. Response was slower in these patients than in patients treated for immune
thrombocytopenic purpura (ITP). The average total amount of gamma globulin required for a response is
markedly different: 1 g/kg for ITP, 3.0 g/kg for autoimmune neutropenia, and 5 g/kg for hemolytic anemia.
Possible mechanisms of action include blockade of reticuloendothelial system Fc receptors, suppression of
autoantibody production, and/or interference in the binding of autoantibodies to target cells.
94
Kurtzberg J, Friedman HS, Chaffee S, Falletta JM, Kinney TR, Kurlander R, Matthews TJ, Schwartz RS. EFFICACY
Am J Med. 1987 Oct
23;83(4A):4-9.
OF INTRAVENOUS GAMMA GLOBULIN IN AUTOIMMUNE-MEDIATED PEDIATRIC BLOOD DYSCRASIAS.
Sixteen pediatric patients diagnosed with a variety of autoimmune-mediated hematocytopenias were treated with
one to 50 courses of intravenous gamma globulin (IVIG), pH 4.25, over the course of one to 30 months. Thirteen
patients had immune thrombocytopenic purpura (ITP), two had autoimmune neutropenia, and one had
autoimmune hemolytic anemia. In one patient, chronic ITP was associated with systemic lupus erythematosis,
and in a second patient, acute ITP was the presenting manifestation of infection with human immunodeficiency
virus. Initial therapy consisted of 400 mg/kg/dose daily for five days for the first seven patients treated, and 1,000
mg/kg/dose daily for two days for the remaining nine patients. In 15 of 16 patients, there was a response to IVIG
therapy. In nine of 16 patients, maintenance IVIG therapy for two to more than 30 months was required. Minimal
toxicity was experienced in four of 210 separate infusions. Data are presented to support the use of IVIG in the
management of childhood autoimmune disorders.
Béris P, Audétat F, Beyner F, Pittet D, Jeannet M, Miescher PA. High intravenous doses of immunoglobulins for
treatment of autoimmune neutropenias. Schweiz Med Wochenschr. 1985 Oct 26;115(43):1512-4.
Two patients respectively with acute agranul ocytosis and with chronic neutropenia were treated with high-dose
immunoglobulins. In the first case, immunologic tests revealed the presence of antigranulocytic autoantibodies: all
other tests (antinuclear antibodies, anti-DNA antibodies, immune complexes, latex) were negative. In the second
case, all the above mentioned tests were negative. In both patients, neutrophil number returned to normal after
the second immunoglobulin injection. Eight months after treatment, the neutrophil count was normal in the first
patient and anti-granulocyte tests had become negative. In the second patient there was a late recurrence of
neutropenia. The diagnosis of autoimmune neutropenia is difficult to confirm. In the case of peripheral "idiopathic"
neutropenia, with infectious complications, high-dose immunoglobulin administration thus appears justified
regardless of the results of the immunologic tests. This therapy also has the advantage of avoiding side effects of
steroid treatment or of splenectomy.
Ventura A, Florean P, Pascone R, Perini R, Pocecco M, Lepore L. Intravenous immunoglobulin in immune
neutropenia. Helv Paediatr Acta. 1986 Mar;41(6):495-500.
Three patients with immune neutropenia successfully treated with high dose intravenous IgG (IV IgG) are
described. In the first case, the neutropenia had not responded to standard steroid therapy; in the second case,
very high doses of steroids were required in order to obtain and maintain remission. In the last case, the steroids
were contraindicated because of an underlying immunologic disorder. We suggest that these 3 forms of immune
neutropenia might be a good indication for IV IgG treatment.
Sorensen RU, Kallick MD. Clinical uses of intravenous immune globulin: immunoglobulin replacement therapy
and treatment of autoimmune cytopenias. J Clin Apher. 1988;4(2-3):97-103.
Intravenous immune globulin (IVIG) is indicated for IgG replacement in antibody deficiency syndromes and as
immunoregulatory therapy in some autoimmune diseases. Two case histories illustrate both aspects of IVIG
therapy. 1. Patient 1 is a 24-year-old male with agammaglobulinemia. He was successively treated with monthly
IMIG, paternal plasma, and then over the last 5 years, IVIG. On IgG doses of 250 mg/kg q/4 weeks, IgG trough
levels remained below 200 mg IgG/dl. IgG half-life was reduced. Although asymptomatic for prolonged periods of
time, he eventually developed clinically evident inflammatory bowel disease. Optimal IVIG replacement therapy
requires normal IgG half-life and adequate IgG trough levels. 2. Patient 2 is a 12-year-old girl with autoimmune
neutropenia, recurrent skin infections, and ileitis unresponsive to antibiotics and to steroid therapy. IVIG at a dose
of 3,000 mg/IgG/kg over 3 days significantly increased her neutrophil count. Subsequently, she has required
1,000 mg/kg of IVIG q/4 weeks for maintenance. Antineutrophil autoantibodies have persisted. There is synergism
of IVIG with high doses of corticosteroids. The mechanism of action of IVIG seems to involve a blockage of the
RES system. IVIG therapy is safe even at high doses for most patients. However, anaphylactic reactions have
been observed in IgA-deficient patients with IgE anti-IgA antibodies. The full spectrum of therapeutic applications
of IVIG is still being explored. For some patients self-infusion of IVIG at home is an appealing treatment
alternative.
Bussel J, Lalezari P, Hilgartner M, Partin J, Fikrig S, O'
Malley J, Barandun SReversal of neutropenia with
intravenous gammaglobulin in autoimmune neutropenia of infancy.. Blood. 1983 Aug;62(2):398-400.
Intravenous gammaglobulin (IVIgG) was used to treat autoimmune neutropenia of infancy in two males with
repeated infections. The neutrophil count increased significantly in both patients with the initial IVIgG therapy; 1
95
patient went into remission. The neutrophil count in the other remained above baseline for 3 wk, and a
subsequent booster infusion also caused the neutrophil count to increase. The patients have remained clinically
well since their treatment began. Serial studies of antineutrophil antibody and serum lysozyme, performed to
elucidate the mechanism of action, suggested decreased neutrophil destruction, perhaps by Fc receptor
blockade, as well as decreased synthesis of antineutrophil antibody. Neutrophil function was not impaired after
the neutrophil count increased. Many patients with immune neutropenia have a benign course, but those who
have significant infections could be treated, acutely or prophylactically, with intravenous gammaglobulin.
96
Echecs récidivants de FIV avec ou sans anticorps anti-phospholipides
ARGUMENTAIRE
Dans cette situation, il faut d’abord rechercher la cause des avortements. Les IgIV n’ont pas fait la
preuve certaine de leur efficacité. Les études sont contradictoires.
Effet des IgIV dans les avortements précoces récidivants
Auteurs
Type d’étude
Posologie
Résultats
Clark
(2006)
Méta-analyse
3 essais randomisés chez 172
femmes en échecs de FIV
Stephen
son
(2000)
Comparative versus placebo
N = 51
échecs de FIV
IgIV :
% de naissance : 15% IgIV gpe
versus 12% : NS
0.5g/kg
le jour du transfert d’embryon
ou dans les 72h avant
Balasch
(1996)
Ouverte
N = 12
échecs
d’implantation
de
l’embryon
Ouverte
N = 10
au moins 7 échecs de FIV les
couples partagent au moins 3
HLA loci - test de cross-match
négatif
Ouverte
N = 29
échecs de FIV
IgIV :
% d’implantation : 0 implantation
0.4g/kg/j
pdt
5
j
de
stimulation ovarienne 5à 7 j
avant transfert d’embryon
IgIV :
% de naissance : 7/10 succès
30g x 2 : 1 dose avant la dont 2 grossesses gémellaires
ponction des ovules puis la
2ème dose dès l’existence
d’un poul foetal
Elram
(2005)
Coulam
(1994)
% de naissance : ↑ S du % de
naissance : p = 0.012
IgIV :
9/16 : grossesses
0.5g /kg après implantation 1/13 : grossesse
tous
les
28j
jusquà S : p = 0.02
l’accouchement ou 28-32ème
- femmes produisant > 3 sem
embryons
/
cycle
après
stimulation : n = 16
- < 3 embryons / cycle : n = 13
Bibliographie
1. Clark DA, Coulam CB, Stricker RB. Is intravenous immunoglobulins (IVIG) efficacious in early pregnancy failure? A critical
review and meta-analysis for patients who fail in vitro fertilization and embryo transfer (IVF). J Assist Reprod Genet. 2006
Jan;23(1):1-13.
2. Elram T, Simon A, Israel S, Revel A, Shveiky D, Laufer N.Treatment of recurrent IVF failure and human leukocyte antigen
similarity by intravenous immunoglobulin. Reprod Biomed Online. 2005 Dec;11(6):745-9.
3. Coulam CB, Goodman C. Increased pregnancy rates after IVF/ET with intravenous immunoglobulin treatment in women with
elevated circulating C56+ cells. Early Pregnancy. 2000 Apr;4(2):90-8.
4. Balasch J, Creus M, Fábregues F, Font J, Martorell J, Vanrell JA. Intravenous immunoglobulin preceding in vitro fertilizationembryo transfer for patients with repeated failure of embryo transfer. Fertil Steril. 1996 Mar;65(3):655-8.
97
5. Stephenson MD, Fluker MR. Treatment of repeated unexplained in vitro fertilization failure with intravenous immunoglobulin:
a randomized, placebo-controlled Canadian trial..Fertil Steril. 2000 Dec;74(6):1108-13.
Groupe de travail
Dr
ALADJIDI
Nathalie,
Bordeaux
Paris
Groupe de lecture
HCL, Lyon
Mme
BONGRAND
Marie-Claude,
pharmacien,
Pr LAVILLE
Mme
Catherine,
l’AP-HP, Paris
Lyon
Résumés-abstracts
Clark DA, Coulam CB, Stricker RB. Is intravenous immunoglobulins (IVIG) efficacious in early pregnancy failure?
A critical review and meta-analysis for patients who fail in vitro fertilization and embryo transfer (IVF). J Assist
Reprod Genet. 2006 Jan;23(1):1-13.
PROBLEM: Intravenous Immunoglobulins (IVIG) are widely used off label in the treatment of early reproductive
failure. As IVIG is expensive, and may have side-effects, evidence of efficacy is needed. Previous results have
suggested that the pre-conception treatment of primary recurrent abortion patients might be effective, but the data
set has been too small for adequate statistical power. More recently it has been suggested that IVIG may improve
the success rate of in vitro fertilization and embryo transfer (IVF) in patients with prior IVF failures, but clinical
trials have given conflicting results that need explanation. Systematic reviews generating inconclusive results
have focused on methodological rigor to the exclusion of biological plausibility. METHODS: Review of current
basic science of design, measurement, and evaluation of clinical trials and basic science mechanisms providing a
rationale for treatment. Meta-analysis of published randomized controlled and cohort-controlled trials (updated
with two unpublished data sets) evaluating IVIG treatment in IVF failure patients. Live birth rate was used as the
most relevant endpoint. The ability of different sources of IVIG to suppress natural killer (NK) cell activity was
determined using a standard (51)Cr-release assay in vitro. RESULTS AND CONCLUSIONS: Meta-analysis of
three published randomized controlled trials (RCTs) of IVIG in IVF failure patients shows a significant increase in
the live birth rate per woman (p = 0.012; Number Needed to Treat for 1 additional live birth, NNT = 6.0 women).
Using live birth rate per embryo transferred, and adding data from two cohort-controlled trials to the meta-analysis
98
further supports this conclusion (overall p = 0.000015, NNT = 3.7 women). Relevant variables appear to include
properties and scheduling of the IVIG, and selection of patients with abnormal immune test results. Different IVIG
preparations vary significantly in their ability to suppress NK activity in vitro. A rationale for use of IVIG is provided
by a review of mechanisms of IVIG action and mechanisms underlying failure of chromosomally normal embryos.
Elram T, Simon A, Israel S, Revel A, Shveiky D, Laufer N. Treatment of recurrent IVF failure and human
leukocyte antigen similarity by intravenous immunoglobulin. Reprod Biomed Online. 2005 Dec;11(6):745-9.
This study sought to assess the efficacy of intravenous immunoglobulin (IVIg) in improving pregnancy rates and
outcome, in a select group of patients with repeated IVF failure and human leukocyte antigen (HLA) similarity.
Couples suffering from recurrent IVF failure, defined as at least seven attempts at embryo transfer with no
successful implantations, who were found to share at least three HLA loci, and a negative cross-match test, were
included in the study. The treatment consisted of two 30 g IVIg doses: one before oocyte retrieval, and a second
as soon as a fetal pulse was identified on ultrasound. Ten couples comprised the study group. In total, these
couples had undergone 98 IVF cycles with no successful pregnancies prior to initiation of the study. Following a
total of 18 IVIg courses, seven women conceived, two women twice. Up to date, five women have delivered at
least one live fetus, at 27 weeks or later. One woman is currently in the early third trimester of a twin pregnancy,
and one woman had a late abortion at 19 weeks. The results suggest that couples with recurrent IVF failure and
HLA similarity, may benefit from IVIg treatment.
Coulam CB, Goodman C. Increased pregnancy rates after IVF/ET with intravenous immunoglobulin treatment in
women with elevated circulating C56+ cells. Early Pregnancy. 2000 Apr;4(2):90-8.
.
Intravenous (IV) immunoglobulin (Ig) has been previously shown to increase pregnancy rates after previously
failed in vitro fertilization (IVF) embryo (ET) attempts in women who are efficient embryo producers (fertilize at
least 50% of oocytes retrieved and generate at least 3 embryos/cycle). Women experiencing implantation failure
have a higher frequency of elevated percentage of circulating CD56+ (natural killer) cells (>12%) than fertile
women (3-12%). To evaluate the effects of IVIg on pregnancy rates in women with elevated percentage of
circulating CD56+ cells, 32 women who had previously failed IVF/ET (>12 embryos transferred without
pregnancy) were studied. Pregnancy and live birth rates with and without IVIg were compared in the same
woman. All 32 women had previously failed to conceive after at least 12 ET, were efficient embryo producers and
had persistently elevated plasma concentrations of CD56+ cells. Each woman received IVIg 500mg/kg prior to
ET. If serum hCG concentrations were positive for pregnancy, IVIg was continued at 500mg/kg/mo until 28 weeks
gestation. Pregnancy rates with and without IVIg were 56% and 9% (P<0.0001). The rate of live birth was 38%
with IVIg and 0% without IVIg (P<0.0001). IVIg enhances pregnancy and live birth rates in women with elevated
circulating CD56+ cells who have a history of implantation failure. Despite technologic advances leading to
enhancement of fertilization rates after in vitro fertilization (IVF) (1, 2) implantation rates after embryo transfer (ET)
have not increased significantly (3) over the last 20 years (4). Implantation rates after IVF/ET are influenced by
the quality of the embryos and receptivity of the endometrium (3-9). Endometrial receptivity involves both
hormonal (10-13) and immunologic (14-29) factors. Among the immunologic factors that play a crucial role in
successful implantation are natural killer (NK) cells (14-18). NK cells present within the decidua that express
CD56(but lack CD 16) have been associated with successful implantation (14-18). A deficiency of decidual
CD56+ CD16- cells (18) and an increase in circulating CD56+ cells (25, 26) have been observed in women
experiencing implantation failure. Women experiencing implantation failure after IVF and multiple ET have been
successfully treated with intravenous (IV) immunoglobulin (Ig) (27). IVIg reduces activation of NK cells and NK
killing activity both in vitro (29) and in vivo (30-31). This reduction in activation of NK cells is essential for normal
implantation to occur (14). To further define the role of IVIg for treatment of implantation failure, pregnancy and
live birth rates were compared before and after IVIg treatment in women undergoing IVF/ET who had elevated
levels of circulating CD56+ cells.
Coulam CB, Krysa LW, Bustillo M .Intravenous immunoglobulin for in-vitro fertilization failure. Hum Reprod. 1994
Dec;9(12):2265-9.
The aim of this study was to determine the effectiveness of intravenous (i.v.) immunoglobulin (Ig) for treatment of
individuals experiencing failure after in-vitro fertilization (IVF) and embryo transfer. A total of 29 women with
unexplained infertility who failed to become pregnant after IVF/embryo transfer were divided into two groups
based on performance in previous IVF cycles: 16 women had fertilization of > or = 50% of oocytes retrieved
and/or produced > or = 3 embryos each cycle and 13 had fertilization of < 50% of oocytes retrieved and/or
produced < 3 embryos each cycle. Each woman had received at least 12 transferred embryos (95th percentile for
successful IVF patients) or had experienced two or more biochemical pregnancies without ultrasonic confirmation
of implantation during previous IVF/embryo transfer attempts. All women received i.v. Ig 500 mg/kg prior to the
next embryo transfer. Only one of the 13 (8%) women with suboptimal fertilization and embryo yield became
pregnant in the treatment cycle. Of 16 women who had previously had fertilization of at least 50% of oocytes
retrieved and produced at least three embryos, nine (56%) became pregnant in the treatment cycle. The
difference in pregnancy rates between the two groups is significant (P = 0.02). Intravenous Ig is useful in the
99
treatment of unexplained IVF failure in women who have oocyte fertilization rates > or = 50% and generate at
least three embryos per cycle.
Balasch J, Creus M, Fábregues F, Font J, Martorell J, Vanrell JA. Intravenous immunoglobulin preceding in
vitro fertilization-embryo transfer for patients with repeated failure of embryo transfer. Fertil Steril. 1996
Mar;65(3):655-8.
OBJECTIVE: To determine the effectiveness of immunotherapy with high-dose IV immunoglobulin preceding IVFET for patients with repeated failure of ET. DESIGN: Prospective, observational. SETTING: Assisted
Reproduction Unit of the Hospital Clínic i Provincial in Barcelona, a tertiary care setting. PATIENTS: Twelve
consecutive tubal infertility patients experiencing repeated unexplained IVF-ET failure including at least three ETs
replacing three to four fresh embryos each. Two women shared three or more human leukocyte antigens (HLA)
with the husband. INTERVENTION: During the subsequent new IVF-ET cycle, each patient received 400 mg/kg
IV immunoglobulin daily for 5 days during ovarian stimulation, that is, 5 to 7 days before ET. MAIN OUTCOME
MEASURES: Clinical pregnancies. RESULTS: No implantation occurred. There were no side effects.
CONCLUSIONS: High-dose IV immunoglobulin is not a useful tool for IVF-ET failure.
Stephenson MD, Fluker MRTreatment of repeated unexplained in vitro fertilization failure with intravenous
immunoglobulin: a randomized, placebo-controlled Canadian trial..Fertil Steril. 2000 Dec;74(6):1108-13.
OBJECTIVE: To evaluate the effect of intravenous immunoglobulin (IVIG) on pregnancy outcome in couples with
repeated unexplained in vitro fertilization (IVF) failure. DESIGN: Prospective, randomized, double blind, placebocontrolled clinical trial. SETTING: A university-based and a free-standing IVF program. PATIENT(S): Fifty-one
couples with a history of repeated unexplained IVF failure who were preparing for another fresh IVF cycle or
replacement of cryopreserved embryos. INTERVENTION(S): Eligible women underwent a standard IVF
stimulation using a long luteal phase GnRH analog protocol. Cryopreserved embryos were replaced after
endometrial preparation with oral micronized estradiol and subsequent vaginal progesterone. The women were
randomly selected to receive IVIG (500 mg/kg) or an equivalent volume of normal saline. The first infusion was
given on the day of embryo transfer or during the preceding 72 hours. The second infusion was given 4 weeks
later if a clinical pregnancy was confirmed by ultrasound. MAIN OUTCOME MEASURE(S): Live-birth rates.
RESULT(S): Overall, the live-birth rates were 4/26 (15%) for the IVIG group and 3/25 (12%) for the placebo group
(P=0. 52). There were 39 fresh IVF cycles, which yielded a clinical pregnancy rate of 28%, with live-birth rates of
4/21 (19%) for the IVIG group and 3/18 (17%) for the placebo group (P=0.59). CONCLUSION(S): In this
randomized clinical trial, IVIG did not improve the live-birth rate in couples with repeated unexplained IVF failure,
stringently defined by known determinants of IVF outcome.
100
Syndrome d’activation macrophagique (SAM) secondaire à une infection
à EBV, SAM dans le cadre d’un lupus en poussées (hors-infection), SAM
associé à un cancer notamment un lymphome
ARGUMENTAIRE
Le SAM est classé dans les désordres histiocytaires qui comprennent les maladies du macrophage
avec le SAM ou lymphohistiocytose hémophagocytaire.
Deux groupes de SAM sont individualisés :
les SAM primaires ou génétiquement déterminés, rares chez l’adulte et dont la plus fréquente
est la lymphohistiocytose hémophagocytaire familiale,
les SAM secondaires ou acquis concernant les enfants et les adultes, compliquant de
nombreuses pathologies : infections, néoplasies, maladies inflammatoires ou auto-immunes
systémiques ou médicaments.
Le SAM qu’il soit familial ou acquis est la résultante d’une réponse immune hautement stimulée mais
inefficace, mettant parfois en jeu le pronostic vital si elle n’est pas freinée par un traitement approprié.
Le traitement de référence est :
. SAM secondaire à une infection à EBV : étoposide (VP 16),
. SAM associé à un cancer notamment un lymphome : chimiothérapie,
. SAM associé à un lupus en poussées hors infection : corticothérapie.
Groupe de travail
Dr
ALADJIDI
Nathalie,
Bordeaux
Paris
Groupe de lecture
HCL, Lyon
Mme
BONGRAND
Marie-Claude,
pharmacien,
Pr LAVILLE
Mme
Catherine,
l’AP-HP, Paris
Lyon
101
Prévention des infections chez le grand prématuré
Prophylaxie des infections nosocomiales
Les études les plus nombreuses ont été faites pour l’indication prophylaxie des infections
nosocomiales et partent de l’hypothèse que les infections nosocomiales sont plus fréquentes en
néonatologie et plus spécifiquement chez le prématuré. Les immunoglobulines sont transmises par la
mère à partir de la 32ème semaine.
Les IgIV sont inefficaces en prévention des infections nosocomiales à staphylocoque. La Cochrane de
2004 a montré que l’administration d’IgIV versus placebo chez des prématurés entraine une
diminution minime de 3 à 4 % des septicémies et des infections graves mais reste sans effet sur les
comorbidités associées (hémorragie intra ventriculaire, entérocolite, mortalité). L’étude française
prospective multicentrique de Magny a montré une légère augmentation du taux de mortalité dans le
groupe traité.
Prophylaxie des infections à VRS
Les IgIV sont inefficaces dans la prophylaxie des infections à VRS. Les immunoglobulines spécifiques
anti VRS ont démontré une efficacité en prophylaxie mais n’ont jamais été commercialisées en
France.
Le traitement de référence est un anticorps monoclonal : le palivizumab (Synagis®), qui a l’AMM dans
la prévention des infections à VRS et n’a aucune activité démontrée en curatif.
Effet des IgIV dans la prévention des infections chez le grand prématuré
Auteurs
Type d’étude
Posologie
Suivi
Critères
d’évaluation
Fuller
(2006)
COCHRANE
4 études randomisées,
contrôlées en double
aveugle vs placebo
- Inf. Resp VRS
- IgIV
- Synagis
Stevens
(2000)
Cohorte historique
multicentrique
N=1029
Age<32 sem.
Risque d’infections à VRS
Comparative
randomisée double aveugle
vs placebo
N=235
Age<32 sem.
IgIV
Magny
(1991)
- Taux de mortalité
- Nbre de jours d’hosp.
et
de
jours
de
ventilation
Jusqu'
à
l’age de
1 an
Résultats
NS du nombre de J
d’hosp.
et
de
dépendance à l’O2
NS du nombre de
jours de ventilation
- Inefficacité des IgIV
IgIV
500 mg à J0,1,2,3,
17 & 31
- Mortalité liée à une
infection
- Nbre d’enfants ayant
1 ou plus infections
nosocomiales
- Nbre d’enfants sous
trt Antibio
Ohlsson
(2004)
COCHRANE
Méta analyse: 19 études
randomisées vs placebo
N=5000
Age<37 sem.
Poids<2.5 kg
IgIV : 120 mg/kg à 1
g/kg de 1 à 7 doses
Gammagard®
Sandoglobuline®
Gamimmune®
- Durée d’hosp. et
évolution
des
septicémies
et
infections.
Fanaroff
(1994)
Comparative
multicentrique vs placebo
N= 2416
Sandoglobuline®
700 mg/kg tous les
14 jours jusqu'
à
- ↓ du nbre d’infections
nosocomiales
NS
infections
nosocomiales :
. IgIV : 55
. Pla : 68
- NS sur la durée du trt
antibio :
. IgIV : 12.2 j
. Pla : 11.8 j
- Taux de mortalité liée à
une infection :
. IgIV : 7
. Pla : 5
- Gpe IgIV : ↓ de 3-4%
des septicémies et des
infections graves
NS du taux de
mortalité
NS de la durée
d’hospitalisation.
- pas de du nbre d’inf.
nosocomiales
- pas de
du taux de
102
Auteurs
Type d’étude
Poids : 0.501 à 1.5 kg
Comparative
randomisée multicentrique
vs placebo
N=81
Age< 33 sem.
[IgG] cordon< 4g/L
VRS : virus respiratoire syncytial
Inf. : infection
Sandberg
(2000)
Posologie
atteindre un poids
de 1.8 kg
IgIV
1 g/kg à J : 0, 3, 7,
14, 21 et 81
Suivi
Critères
d’évaluation
Résultats
mortalité & morbidité
- Nbre d’infection et - NS de la mortalité et
taux de mortalité
du
nbre
d’épisodes
infectieux
Resp : respiratoire
Bibliographie
1. Fuller H, Del Mar C. Immunoglobulin treatment for respiratory syncytial virus infection. Cochrane Database Syst Rev. 2006
Oct 18;(4):CD004883
2. Stevens TP, Sinkin RA, Hall CB, Maniscalco WM, McConnochie KM. Respiratory syncytial virus and premature infants born
at 32 weeks'gestation or earlier: hospitalization and economic implications of prophylaxis. Arch. Pediatr Adolesc Med. 2000
Jan;154(1):55-61.
3. Magny JF, Bremard-Oury C, Brault D, Menguy C, Voyer M, Landais P, Dehan M, Gabilan JC. Intravenous immunoglobulin
therapy for prevention of infection in high-risk premature infants: report of a multicenter, double-blind study. Pediatrics. 1991
Sep;88(3):437-43.
4. Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight infants. Cochrane
Database Syst Rev. 2004;(1)
5. Sandberg K, Fasth A, Berger A, Eibl M, Isacson K, Lischka A, Pollak A, Tessin I, Thiringer K. Preterm infants with low
immunoglobulin G levels have increased risk of neonatal sepsis but do not benefit from prophylactic immunoglobulin G. J
Pediatr. 2000 Nov;137(5):623-8.
6.Fanaroff AA, Korones SB, Wright LL, Wright EC, Poland RL, Bauer CB, Tyson JE, Philips JB 3rd, Edwards W, Lucey JF, et al.
A controlled trial of intravenous immune globulin to reduce nosocomial infections in very-low-birth-weight infants. National
Institute of Child Health and Human Development Neonatal Research Network. N Engl J Med. 1994 Apr 21;330(16):1107-13.
Groupe de travail
Pr BERNARD Louis, infectiologue, Paris
Dr BARRE Jérôme, pharmacologue, Paris
Pr BEYTOUT Jean, infectiologue, Clermont-Ferrand
Pr BINGEN Edouard, microbiologiste, Paris
Pr CHIDIAC Christian, infectiologue, Lyon
Dr DANIS Martin, parasitologue, Paris
Pr DEBORD Thierry, infectiologue, Paris
Pr DUBREUIL Luc, microbiologiste, Lille
Pr FLORET Daniel, réanimateur pédiatrique, Lyon
Dr GALPERINE Tatiana, infectiologue, Paris
Dr GAUZIT Rémy, réanimateur, Paris
Dr KOUZAN Serge, pneumologue, Bethune
Dr LECOMPTE Thanh, infectiologue, Nancy
Dr MAZUE Guy, vétérinaire, Paris
Dr MERAD- TAOUFIK Mansouriah, interniste, Paris
Dr PAREZ Nathalie, pédiatre, Paris
Dr PEAN Yves, biologiste, Paris
Paris
Pr ROUVEIX Bernard, Paris
Pr SALMON, infectologue, Paris
Dr SOLLET Jean-Pierre, réanimateur, Paris
Dr SOUSSY Claude-James, bactériologue, Paris
Pr STAHL Jean-Paul, infectiologue, Grenoble
Dr HEARD Isabelle, biologiste, Paris
Pr MORINET Frédéric, microbiologiste, Paris
Dr LEPORT Catherine, interniste, Paris
HCL, Lyon
Mme
BONGRAND
Marie-Claude,
pharmacien,
Pr LAVILLE
Mme
Catherine,
l’AP-HP, Paris
103
Lyon
Paris
Résumés-abstracts
Virus respiratoire syncitial
Fuller H, Del Mar C.Immunoglobulin treatment for respiratory syncytial virus infection. Cochrane Database Syst
Rev. 2006 Oct 18;(4):CD004883
BACKGROUND: Respiratory syncytial virus (RSV) bronchiolitis and pneumonia hospitalize hundreds of
thousands of infants every year. Treatment is largely supportive therapy, (for example, oxygen, fluids and
occasionally mechanical ventilation). Ribavirin, an antiviral agent, is licensed for severe RSV infection, although
systematic reviews find it of no benefit. Passive protection against RSV can be achieved through monthly
intramuscular injection of the humanized monoclonal anti-RSV antibody palivizumab (Synagis), and yields a 55%
reduction in RSV hospitalisation in susceptible infants. This review assesses immunoglobulin treatment of RSV
infection rather than its role as a prophylactic measure. OBJECTIVES: To assess the efficacy of adding human or
humanized immunoglobulin therapy to supportive therapy in infants hospitalized with laboratory-determined RSV
infection. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL)
(The Cochrane Library, Issue 1, 2006), MEDLINE (1966 to Week 4, January 2006) and EMBASE (1980 to
September 2005). We also ran searches of reference lists of relevant trials and review articles and searches of
personal files. We did not impose any language restrictions. SELECTION CRITERIA: We selected randomised
controlled trials (RCTs) that compared immunoglobulin treatment with a placebo control in children hospitalized
for RSV infection with bronchiolitis or pneumonia or other lower respiratory tract infection (LRTI) with laboratorydocumented RSV infection. The primary outcomes of interest were mortality, length of hospitalisation, length of
ventilation and oxygen dependence. Secondary outcome measures were pulmonary function and rehospitalisations for recurrent breathing difficulties in subsequent years. Any adverse effects of the treatments
were also noted, for example, hypersensitivity reactions. DATA COLLECTION AND ANALYSIS: Data were
extracted but cross-comparison was not possible due to the shortage of studies and lack comparative
measurements. MAIN RESULTS: Four papers fitted the search criteria. None demonstrated statistically significant
benefit of intravenous immunoglobulin (IVIG) treatment added to supportive care compared with supportive care
alone. The evidence does not support a role for RSVIG in such a setting, with the doses used in the studies.
AUTHORS'CONCLUSIONS: The evidence on the role of respiratory syncytial virus immunoglobulin (RSVIG) in
treating RSV severe infections is limited. Future research might consider using stronger titres of neutralising
antibodies; and further analyse severely ill children (who might respond differentially compared to those less ill,
but yet hospitalised).
Stevens TP, Sinkin RA, Hall CB, Maniscalco WM, McConnochie KM. Respiratory syncytial virus and premature
infants born at 32 weeks'gestation or earlier: hospitalization and economic implications of prophylaxis. Arch
Pediatr Adolesc Med. 2000 Jan;154(1):55-61.
OBJECTIVES: To assess the risk of hospitalization associated with respiratory syncytial virus (RSV) and to
estimate the economic impact of RSV prophylaxis with either RSV immune globulin (RSV-Ig) or RSV monoclonal
antibody (palivizumab) on a cohort of preterm infants born at 32 weeks'gestation or earlier. DESIGN: Historical
cohort study. SETTING: A 12-county neonatal network served by the regional center in Rochester, NY.
PARTICIPANTS: One thousand twenty-nine infants born at 32 weeks'gestation or earlier followed up until 1 year
of corrected age. MAIN OUTCOME MEASURES: Rate of hospitalization with an RSV-associated illness; cost per
hospitalization prevented resulting from either form of RSV prophylaxis. RESULTS: The probability of
hospitalization with an RSV-associated illness for infants born at 32 weeks'gestation or earlier was estimated at
11.2%. The incidence of RSV hospitalization increased with decreasing gestational age (13.9% vs 4.4% for
infants born at < or =26 weeks'gestation vs those born at 30-32 weeks'gestation). Infants requiring respiratory
support at 36 weeks of postconceptual age (PCA) or older had a higher hospitalization rate (16.8% vs 6.2%),
longer hospital stays, and higher hospital charges than infants requiring respiratory support at less than 36 weeks
of PCA. For infants requiring respiratory support at less than 36 weeks of PCA, the incidence of RSV
hospitalization still increased with decreasing gestational age (10.2% vs 4.3% for infants < or =26 weeks'
gestation vs those 30-32 weeks'gestation). Analysis indicated that both forms of RSV prophylaxis would increase
104
the net cost of care for all groups. Palivizumab was more cost-effective than RSV-Ig for preventing RSV
hospitalization among infants who required respiratory support at less than 36 weeks of PCA, especially those
born at 26 weeks'gestation or earlier. Overall, RSV-Ig was more cost-effective than palivizumab for infants
requiring respiratory support at 36 weeks of PCA or older. CONCLUSIONS: This analysis suggests that available
forms of RSV prophylaxis would increase the net cost of care not only for the entire cohort but for each of the
subgroups studied. However, the RSV hospitalization rate and the cost-effectiveness of prophylaxis varied
markedly by subgroup.
Prévention des infections nosocomiales
Magny JF, Bremard-Oury C, Brault D, Menguy C, Voyer M, Landais P, Dehan M, Gabilan JC.Intravenous
immunoglobulin therapy for prevention of infection in high-risk premature infants: report of a multicenter, doubleblind study. Pediatrics. 1991 Sep;88(3):437-43.
The effectiveness of intravenously administered immunoglobulin (Ig) therapy for prophylaxis of infection was
evaluated in high-risk preterm infants. Two hundred thirty-five premature newborns were randomly assigned, in a
double-blind controlled trial, to treatment and placebo groups. Thirty-five infants (29%) of the Ig group and 29
(25%) of the placebo group had one or more episodes of certain infection. Thirty infants (25%) of the Ig group and
18 (16%) of the placebo group had one or more episodes of probable infection. No significant differences were
observed in the incidence of certain or probable infection in treated and control infants. Nevertheless, among the
infants who had one or more certain or probable episodes of infection, more of them belonged to the Ig group
than to the placebo group. The possible deleterious effect of the administration of large amounts of polyspecific Ig
is discussed.
Ohlsson A, Lacy JB. Intravenous immunoglobulin for preventing infection in preterm and/or low-birth-weight
infants. Cochrane Database Syst Rev. 2004;(1)
BACKGROUND: Nosocomial infections continue to be a significant cause of morbidity and mortality among
preterm and/or low birth weight infants. Maternal transport of immunoglobulins to the fetus mainly occurs after 32
weeks gestation and endogenous synthesis does not begin until several months after birth. Administration of
intravenous immunoglobulin provides IgG that can bind to cell surface receptors, provide opsonic activity, activate
complement, promote antibody dependent cytotoxicity, and improve neutrophilic chemo luminescence.
Intravenous immunoglobulin thus has the potential of preventing or altering the course of nosocomial infections.
OBJECTIVES: To assess the effectiveness/safety of intravenous immunoglobulin (IVIG) administration
(compared to placebo or no intervention) to preterm (< 37 weeks gestational age at birth) and/or low birth weight
(LBW) (< 2500 g BW) infants in preventing nosocomial infections. SEARCH STRATEGY: MEDLINE, EMBASE,
and The Cochrane Library Databases were searched in September 2003 using the keywords: immunoglobulin
and infant-newborn and random allocation or controlled trial or randomized controlled trial (RCT). The reference
lists of identified RCTs and personal files were searched. No language restrictions were applied. SELECTION
CRITERIA: The criteria used to select studies for inclusion in this overview were: 1) Design: RCTs in which
administration of IVIG was compared to a control group that received a placebo or no intervention. 2) Population:
preterm (< 37 weeks gestational age) and/or LBW (<2500 g) infants. 3) Intervention: IVIG for the prevention of
bacterial/fungal infection during initial hospital stay (8 days or longer). (Studies that were primarily designed to
assess the effect of IVIG on humoral immune markers were excluded as were studies in which the follow-up
period was one week or less).4) At least one of the following outcomes was reported: sepsis, any serious
infection, death from all causes, death from infection, length of hospital stay, intraventricular hemorrhage (IVH),
necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD). DATA COLLECTION AND ANALYSIS: Two
reviewers independently abstracted information for each outcome reported in each study, and one researcher
(AO) checked for any discrepancies and pooled the results.Relative risk (RR) and Risk Difference (RD) with 95%
confidence intervals (CI) using the fixed effects model are reported. When a statistically significant RD was found
the number needed to treat (NNT) was also calculated with 95% CIs. The results include all accepted studies in
which the outcome of interest was reported. Statistically significant between study heterogeneity was reported.
The results of the inconsistency test (I squared) are also reported when statistically significant heterogeneity was
found. MAIN RESULTS: No new trials were identified in September 2003. Nineteen studies met inclusion criteria.
These included approximately 5,000 preterm and/or LBW infants and reported on at least one of the outcomes of
interest for this systematic review. When all studies were combined there was a statistically significant reduction
(p = 0.02) in sepsis, RR [0.85 (95% CI 0.74, 0.98)] and RD [-0.03 (95% CI 0.00, -0.05)], NNT 33. There was
statistically significant between-study heterogeneity (p = 0.02); I squared 54%. A statistically significant reduction
was found for any serious infection, one or more episodes, when all studies were combined [RR 0.82 (95% CI
0.74, 0.92); RD -0.04 (95% CI -0.02, -0.06,); NNT 25 (95% CI, 16.7, 50). There was statistically significant
between-study heterogeneity (p = 0.0006); I squared 50%. There were no statistically significant differences for
mortality from all causes, mortality from infection, incidence of NEC, BPD and IVH or length of hospital stay. No
major adverse effects of IVIG were reported in any of the studies. REVIEWER'
S CONCLUSIONS: IVIG
105
administration results in a 3% reduction in sepsis and a 4% reduction in any serious infection, one or more
episodes, but is not associated with reductions in other important outcomes: sepsis, NEC, IVH, or length of
hospital stay. Most importantly, IVIG administration does not have any significant effect on mortality from any
cause or from infections. Prophylactic use of IVIG is not associated with any short term serious side effects. From
a clinical perspective a 3-4% reduction in nosocomial infections without a reduction in mortality or other important
clinical outcomes is of marginal importance.The decision to use prophylactic IVIG will depend on the costs and
the values assigned to the clinical outcomes. There is no justification for further RCTs testing the efficacy of
previously studied IVIG preparations to reduce nosocomial infections in preterm and/or LBW infants. The results
of these meta-analyses should encourage basic scientists and clinicians to pursue other avenues to prevent
nosocomial infections.
G. Sandberg K, Fasth A, Berger A, Eibl M, Isacson K, Lischka A, Pollak A, Tessin I, Thiringer K. Preterm infants
with low immunoglobulin G levels have increased risk of neonatal sepsis but do not benefit from prophylactic
immunoglobulin J Pediatr. 2000 Nov;137(5):623-8.
OBJECTIVE: In a prospective, randomized, placebo-controlled, multicenter study, we evaluated the prevention of
neonatal infections with intravenous immunoglobulin G (IVIgG) prophylaxis for preterm infants (gestational age
<33 weeks) with umbilical cord blood IgG levels < or =4 g/L. STUDY DESIGN: Intravenous IgG or placebo
(albumin), 1 g/kg body weight, was given on days 0, 3, 7, 14, and 21 to 81 infants with umbilical cord blood IgG
levels < or =4 g/L: (1) IVIgG group, n = 40, mean (SD) gestational age 27.5 (2.2) weeks and birth weight 1.06
(0.39) kg; (2) placebo group, n = 41, mean (SD) gestational age 27.7 (2.5) weeks and birth weight 1.13 (0.38) kg.
Infants with umbilical cord blood IgG levels >4 g/L (n = 238) served as a separate comparison group. Neonatal
infections according to European Society of Pediatric Infectious Disease criteria were monitored until 28 days of
life. RESULTS: Infants with IgG levels < or =4 g/L at birth who received IVIgG had no significant reduction in
infectious episodes or mortality rate when compared with those given placebo. However, infants with a serum
concentration of IgG >4 g/L at birth had significantly fewer infectious episodes (culture-proven sepsis) than infants
with low serum concentrations of IgG (< or =4 g/L) when compared at the same gestational ages (26 to 29 weeks,
P <.003). CONCLUSIONS: Prophylactic immunotherapy with IVIgG did not improve the immune competence in
preterm infants with low serum IgG concentrations at birth. We speculate that a spontaneously high serum IgG
concentration at birth reflects placenta function and is an indicator of a more mature immune system capable of
protecting the preterm infant against severe neonatal infections.
Fanaroff AA, Korones SB, Wright LL, Wright EC, Poland RL, Bauer CB, Tyson JE, Philips JB 3rd, Edwards W,
Lucey JF. A controlled trial of intravenous immune globulin to reduce nosocomial infections in very-low-birthweight infants. National Institute of Child Health and Human Development Neonatal Research Network. N Engl J
Med. 1994 Apr 21;330(16):1107-13.
BACKGROUND. Nosocomial infections are a major cause of morbidity and mortality in premature infants. As a
rule, their low serum gamma globulin levels at birth subsequently decline to hypogammaglobulinemic values;
hence, prophylactic administration of intravenous immune globulin may reduce the rate of hospital-acquired
infections. METHODS. In this prospective, multicenter, two-phase controlled trial, 2416 infants were stratified
according to birth weight (501 to 1000 g and 1001 to 1500 g) and randomly assigned to an intravenous immune
globulin group (n = 1204) or a control group (n = 1212). Control infants were given placebo infusions during phase
1 of the study (n = 623) but were not given any infusions during phase 2 (n = 589). Infants weighing 501 to 1000 g
at birth were given 900 mg of immune globulin per kilogram of body weight, and infants weighing 1001 to 1500 g
at birth were given a dose of 700 mg per kilogram. The immune globulin infusions were repeated every 14 days
until the infants weighed 1800 g, were transferred to another center, died, or were sent home from the hospital.
RESULTS. Nosocomial infections of the blood, meninges, or urinary tract occurred in 439 of the 2416 infants
(18.2 percent): 208 (17.3 percent) in the immune globulin group and 231 (19.1 percent) in the control group
(relative risk, 0.91; 95 percent confidence interval, 0.77 to 1.08). Septicemia occurred in 15.5 percent of the
immune globulin recipients and 17.2 percent of the controls. During phase 1 the rate of nosocomial infections was
13.4 percent in the immune globulin group and 17.8 percent in the control group; the respective rates during
phase 2 were 21.0 percent and 20.4 percent. The predominant organisms included gram-positive cocci (53.0
percent), gram-negative bacilli (22.4 percent), and candida species (16.0 percent). Adverse reactions were rarely
observed during the infusions. Immune globulin therapy had no effect on respiratory distress syndrome,
bronchopulmonary dysplasia, intracranial hemorrhage, the duration of hospitalization, or mortality. The incidence
of necrotizing enterocolitis was 12.0 percent in the immune globulin group and 9.5 percent in the control group.
CONCLUSIONS. Prophylactic use of intravenous immune globulin failed to reduce the incidence of hospitalacquired infections in very-low-birth-weight infants.
106
ENDOBULINE®
GAMMAGARD®
KIOVIG®
OCTAGAM®
SANDOGLOBULINE®
SANDOGLOBULINE 120 mg/ml®
TEGELINE®
. Myosite à inclusions sans atteinte œsophagienne
. Encéphalomyélite aiguë disséminée
. Encéphalite auto-immune de Rasmussen
. Epilepsie de l’enfant : formes résistantes
. Polyneuropathie associée à une gammapathie monoclonale IgM anti-MAG
. Polyneuropathie associée à une gammapathie monoclonale non MAG
. Erythroblastopénie auto-immune
. Anémie hémolytique auto-immune
. Avortements précoces récidivants en dehors du syndrome des
antiphospholipides et des FIV
. Syndrome d’activation macrophagique (SAM) secondaire à une pathologie
infectieuse et maladie de Still compliquée de SAM
. Maladie de Still (adulte et enfant)
. Syndrome dégénératif secondaire aux histiocytoses langerhanciennes
. Syndrome de Lyell
. Dermatite atopique sévère
107
•
Myosite à inclusions sans atteinte œsophagienne
Les myosites à inclusions appartiennent au groupe des myosites (ou myopathies inflammatoires)
primitives, au même titre que les dermatomyosites et les polymyosites. Ces trois affections ont en
commun une atteinte inflammatoire des muscles striés.
Les essais cliniques évaluant l’effet des IgIV dans cette pathologie ont été réalisés sur de courtes
durées et de faibles effectifs. Les résultats sont inconstamment significatifs en fonction des échelles
d’évaluation utilisées. Il existerait une tendance à l’amélioration de la fonctionnalité des muscles et les
résultats seraient plutôt en faveur d’une amélioration de la déglutition.
Effet des IgIV dans les myosites à inclusion
Auteurs
Type d’étude
Posologie
Suivi
Résultats
Amélioration S de la fonction
IgIV :
- Temps de déglutition
2 g /kg (2x1 g /kg/j) 1 fois
mesuré sous
de déglutition dans le groupe
/mois pdt 3 mois
échographie
IgIV par rapport au placebo
Période
de
sevrage
Echelle
MRC (p < 0,05)
thérapeutique
d’au
(evaluation de la force
Amélioration NS de la
moins 1 mois
musculaire)
Puis permutation des
- Score de MVIC
fonctionnalité
traitements
Résultats NS
Dalakas Comparative
Prednisone + IgIV (2 g 4 mois
- Force musculaire
double-aveugle
(2001)
/kg
en
2
doses
- Echelle MRC
contre placebo
quotidiennes de 1 g
- Déglutition
Données
concernant
la
N = 36
/kg) : n = 19
déglutition
non
versus prednisone +
communiquées
placebo : n = 17
Comparative
Walter
IgIV :
1 an
- NSS ( évaluation par le - NSS : amélioration S des
double-aveugle
(2000)
2 g /kg 1 fois /mois pdt 6
patient de 14 activités scores dans chaque groupe
contre placebo
mois avec permutations
dont la déglutition)
entre score initial et score
cross-over
les 6 mois suivants
- Echelle MRC
post IgIV (gr1 de 24,4 à
N = 22
Groupe 1 : IgIV puis
30,6 ; gr2 de 30,5 à 33,1)
placebo
- MRC : NS
Groupe 2 : Placebo puis
IgIV
MRC : Medical Research Council MVIC : Maximum Voluntary Isomeric Contraction
NSS :Neuromuscular Symptom Score
Dalakas
(1997)
Comparative
double-aveugle
contre placebo
crosss-over
N = 19
Bibliographie
1. Dalakas MC, Sonies B, Dambrosia J, Sekul E, Cupler E, Sivakumar K.Treatment of inclusion-body myositis with IVIg: a
double-blind, placebo-controlled study. Neurology. 1997 Mar;48(3):712-6.
2. Dalakas MC, Koffman B, Fujii M, Spector S, Sivakumar K, Cupler E.A controlled study of intravenous immunoglobulin
combined with prednisone in the treatment of IBM. Neurology. 2001 Feb 13;56(3):323-7.
3. Walter MC, Lochmüller H, Toepfer M, Schlotter B, Reilich P, Schröder M, Müller-Felber W, Pongratz D. High-dose
immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study. J Neurol. 2000
Jan;247(1):22-8.
Résumés-abstracts
Dalakas MC, Sonies B, Dambrosia J, Sekul E, Cupler E, Sivakumar K. Treatment of inclusion-body myositis with
IVIg: a double-blind, placebo-controlled study. Neurology. 1997 Mar;48(3):712-6.
108
We randomized 19 patients with inclusion-body myositis (IBM) to a double-blind, placebo-controlled, crossover
study using monthly infusions of 2 g/kg intravenous immunoglobulin (IVIg) or placebo for 3 months. Patients
crossed over to the alternate treatment after a washout period. We evaluated responses at baseline and at the
end of each treatment period using expanded (0-10) MRC scales, the Maximum Voluntary Isometric Contraction
(MVIC) method, symptom and disability scores, and quantitative swallowing studies. We calculated the
differences in scores between IVIg and placebo from baseline to end of treatment. Of the 19 patients, 9 (mean
age, 61.2 years; mean disease duration, 5.6 years) were randomized to IVIg and 10 (mean age, 66.1 years; mean
disease duration, 7.4 years) to placebo. During IVIg the patients gained a mean of 4.2 (-16 to +39.8) MRC points,
and during placebo lost 2.7 (-10 to +8) points (p < 0.1). These gains were not significant. Similar results were
obtained with the MRC and MVIC scores when the patients crossed to the alternate treatment. Six patients had a
functionally important improvement by more than 10 MRC points that declined when crossed over to placebo.
Limb-by-limb analysis demonstrated that during IVIg the muscle strength in 39% of the lower extremity limbs
significantly increased compared with placebo (p < 0.05), while a simultaneous decrease in 28% of other limbs
was detected. The clinical importance of these minor gains is unclear. The duration of swallowing functions
measured in seconds with ultrasound improved statistically in the IVIg-randomized patients (p < 0.05) compared
with placebo. Although the study did not establish efficacy of IVIg, possibly because of the small sample size, the
drug induced functionally important improvement in 6 (28%) of the 19 patients. Whether the modest gains noted
in certain muscle groups justify the high cost of trying IVIg in IBM patients at a given stage of the disease remains
unclear.
Dalakas MC, Koffman B, Fujii M, Spector S, Sivakumar K, Cupler E. A controlled study of intravenous
immunoglobulin combined with prednisone in the treatment of IBM. Neurology. 2001 Feb 13;56(3):323-7.
OBJECTIVE: To investigate whether the combination of intravenous immunoglobulin (IVIg) with prednisone
improves muscle strength and alters endomysial inflammation in patients with sporadic inclusion body myositis (sIBM). BACKGROUND: In a previous controlled trial in s-IBM, IVIg did not significantly improve strength in spite of
modest benefits in some muscle groups. The possibility that prednisone may have a synergistic effect with IVIg
prompted another controlled trial. METHODS: Thirty-six patients with biopsy-proven IBM were randomized to
receive IVIg or placebo monthly for 3 months. Before infusions, all patients were started on high-dose prednisone
for 3 months. Primary outcome measures were differences in the 1) Quantitative Muscle Strength (QMT) testing;
and 2) modified Medical Research Council (MRC) scores, between the patients randomized to IVIg + prednisone
compared with those randomized to placebo + prednisone. Repeated open muscle biopsies were performed at
random in 24 patients to determine changes in the number of autoinvasive T cells and necrotic muscle fibers.
RESULTS: Nineteen patients were randomized to IVIg + prednisone and 17 to placebo + prednisone. No
significant change was noted in muscle strength, assessed by QMT and MRC, from baseline to the 2nd, 3rd, or
4th month after treatment between the two groups. The number of necrotic fibers was reduced in the IVIg
randomized group (p < 0.01), and the mean number of CD2+ cells was significantly decreased in both groups (p <
0.0001), denoting a steroid effect. CONCLUSION: IVIg combined with prednisone for a 3-month period was not
effective in IBM. Endomysial inflammation was significantly reduced after treatment, but the reduction was not of
clinical significance.
Walter MC, Lochmüller H, Toepfer M, Schlotter B, Reilich P, Schröder M, Müller-Felber W, Pongratz DHigh-dose
immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study. J Neurol.
2000 Jan;247(1):22-8.
Sporadic inclusion body myositis (s-IBM) is an acquired inflammatory muscle disease of unknown cause. In
general, s-IBM presents with slowly progressive, asymmetric weakness, and atrophy of skeletal muscle. There is
a mild transitory or nil responsiveness to standard immunosuppressive treatment. A controlled cross-over study of
22 s-IBM patients over 3 months showed a partial improvement in those treated with high-dose intravenous
immunoglobulin therapy (IVIG) versus placebo. The present study included 22 patients aged 32-75 years and with
a mean duration of disease of 5.2+/-3.6 years. They were randomized by a double-blind, placebo-controlled,
cross-over design to monthly infusions of 2 g/kg bodyweight IVIG or to placebo for 6 months each, followed by the
alternative treatment. After 6 and 12 months the response to treatment was evaluated, using a modified Medical
Research Council scale, Neuromuscular Symptom Score (NSS), the patient'
s own assessment of improvement,
arm outstretched time, and electromyography. No serious side effects were seen, in particular no viral infection
and no major cardiac or neurological complications. Overall there was no progression of the disease in 90% of
patients, unlike that which might have been expected in untreated patients. A mild and significant improvement
(11%) in clinical symptoms was found using NSS, but not with other test procedures. There was a trend to mild
improvement in treated patients when using other tests. Individual responses to treatment was heterogeneous.
The validity of this study may be reduced by mismatch of groups with regard to age at onset and variability in
disease expression. The findings of this study largely confirm those of a previous IVIG trial. Treatment with IVIG
may be mildly effective in s-IBM by preventing disease progression or inducing mild improvement. Long-term
studies are needed to evaluate further the benefit of IVIG therapy in s-IBM.
109
•
Encéphalomyélite aiguë disséminée
Egalement appelée encéphalite post-infectieuse, il s’agit d’une atteinte inflammatoire multifocale
touchant principalement la substance blanche du SNC (mécanisme auto-immun).
Les formes graves sont traitées en priorité par les échanges plasmatiques, les formes moins graves
ne sont pas traitées ou sont traitées par des corticoïdes.
La recherche bibliographique sur l’utilisation des IgIV dans cette pathologie ne trouve que des études
ouvertes réalisées sur des petits effectifs.
Effet des IgIV dans les encéphalomyélites aiguës disséminées (ADEM)
Auteurs
Shahar
(2002)
Sahlas
(2000)
Assa
(1999)
Type d’étude
Ouverte
N = 16
enfants
Posologie
IgIV :
2 g/kg sur 2 j
Critères
d’évaluation
Méthylprednisolone :
20-30 mg/kg sur 5 j
Résultats
10/16 : réponse à la méthylprednisolone IV
(patients ADEM)
1/ 16 avec sévère myélopathie : échec à la
corticothérapie orale, a reçu des IgIV :
récupération totale
6/16 : sévère myelopathie multifocale ont
récupéré en 1 sem après méthylprednisolone
IV puis
2/6 : + IgIV 1/2 réponse
3/6 : + IgIV : 2/3 : pas de réponse
N=2
. Methylprednisolone IV - Amélioration Cas n°1 : amélioration
+ IgIV : 30 g/j pdt 5j
fonctionnelle durable des symptômes
N =2
. Methylprednisolone : 1g
IV/j pdt 4 j + IgIV : 50 g/j
pdt 2 j
IgIV :
- Amélioration
2 g/kg sur 5 j
fonctionnelle
fonctionnelle
Cas n°2 : récupération de l’autonomie au
bout d’un mois
Cas n°1 : amélioration
symptômes à 6 mois
durable
des
Cas n °2 : idem cas n°1
Bibliographie
1. Shahar E, Andraus J, Savitzki D, Pilar G, Zelnik N. Outcome of severe encephalomyelitis in children: effect of high-dose
methylprednisolone and immunoglobulins. J Child Neurol. 2002 Nov;17(11):810-4
2. Sahlas DJ, Miller SP, Guerin M, Veilleux M, Francis G. Treatment of acute disseminated encephalomyelitis with intravenous
immunoglobulin.Neurology. 2000 Mar 28;54(6):1370-2.
3. Assa A, Watemberg N, Bujanover Y, Lerman-Sagie T. Demyelinative brainstem encephalitis responsive to intravenous
immunoglobulin therapy. Pediatrics. 1999 Aug;104(2 Pt 1):301-3.
4. Hahn JS, Siegler DJ, Enzmann D. Intravenous gammaglobulin therapy in recurrent acute disseminated encephalomyelitis.
Neurology. 1996 Apr;46(4):1173-4 : No abstract
5. Kleiman M, Brunquell P. Acute disseminated encephalomyelitis: response to intravenous immunoglobulin.
J Child Neurol. 1995 Nov;10(6):481-3.
Résumés-abstracts
Shahar E, Andraus J, Savitzki D, Pilar G, Zelnik N. Outcome of severe encephalomyelitis in children: effect of
high-dose methylprednisolone and immunoglobulins. J Child Neurol. 2002 Nov;17(11):810-4
110
Acute encephalomyelitis in children refers to an insult of cortical white matter leading to acute disseminated
encephalomyelitis, insult of the spinal cord leading to multifocal myelopathy, or a combined form of
encephalomyelitis. We report here the clinical presentations and outcome of 16 children with severe acute
encephalomyelitis analyzing the effect of high-dose methylprednisolone or intravenous immunoglobulins,
administered separately or in combination. Five children developed acute disseminated encephalomyelitis alone,
eight developed severe multifocal myelopathy accompanied in two of them by radiculoneuropathy, and three
developed the most severe form of combined encephalomyeloradiculoneuropathy. The indications for treatment
with either high-dose methylprednisolone, intravenous immunoglobulin, or a combination of the two were severe
acute disseminated encephalomyelitis, visual loss, or severe flaccid weakness accompanied by bladder and
bowel incontinence. Overall, 10 children had remarkably responded to high-dose methylprednisolone alone and
recovered within 10 days. One patient with severe myelopath, developing paraplegia, who failed oral
corticosteroids completely recovered following intravenous immunoglobulin. Of the isolated acute disseminated
encephalomyelitis group, all patients were initially treated with high-dose intravenous methylprednisolone and
recovered within 10 days, including visual remission in the child with severe optic neuritis. All six children with
solitary severe multifocal myelopathy were treated with high-dose methylprednisolone alone and recovered within
the first week. Two patients had severe myeloradiculoneuropathy and were therefore treated with combined highdose methylprednisolone and intravenous immunoglobulin: one remains paraplegic, whereas the second was
ventilated for 3 weeks and recovered after 2 months. The three children with the most severe form of
encephalomyeloradiculoneuropathy were treated with combined high-dose methylprednisolone and intravenous
immununoglobulin; two remain severely handicapped, of whom one is paraplegic, and the third unexpectedly
recovered within 3 months. Therefore, our experience indicates that either high-dose methylprednisolone or
intravenous immunoglobulin, given separately or combined, may be efficacious in severe debilitating pediatriconset acute encephalomyelitis. In children with the most severe form of encephalomyeloradiculoneuropathy, we
suggest initially administering high-dose methylprednisolone and intravenous immunoglobulin combined, given
the poorer outcome of our patients with combined severe central and peripheral demyelination.
Sahlas DJ, Miller SP, Guerin M, Veilleux M, Francis G. Treatment of acute disseminated encephalomyelitis with
intravenous immunoglobulin. Neurology. 2000 Mar 28;54(6):1370-2.
Acute disseminated encephalomyelitis (ADEM) is a presumed immune-mediated, demyelinating disease of the
CNS for which the standard treatment is high-dose steroids. We describe two patients with ADEM in whom
treatment with IV methylprednisolone coincided with deterioration in their clinical status. They were subsequently
treated with IV immunoglobulin and exhibited dramatic clinical improvement, with return to their previous level of
functioning.
Assa A, Watemberg N, Bujanover Y, Lerman-Sagie T. Demyelinative brainstem encephalitis responsive to
intravenous immunoglobulin therapy. Pediatrics. 1999 Aug;104(2 Pt 1):301-3.
We describe 2 patients with acute demyelinating brainstem encephalitis who were treated with intravenous
immunoglobulin (IVIG). Both patients improved rapidly, concomitant with the course of therapy. To the best of our
knowledge, these are the first reported cases of brainstem demyelinating lesions in children treated with IVIG. Our
experience suggests that IVIG should be considered as first-line treatment for similar cases.
111
•
Encéphalite auto-immune de Rasmussen
L'
encéphalite focale de Rasmussen, ou syndrome de Rasmussen, est une maladie rare, d'
évolution
chronique, d'
origine probablement auto-immune dégénérative et entrainant une atteinte neurologique
évoluant de façon péjorative avec des crises d'
épilepsie sévères et fréquentes, une hémiparésie puis
une hémiplégie et une perte de la parole.
On ne trouve dans la littérature que quelques études ouvertes, de faibles effectifs, peu convaincantes
et ne permettant pas d’évaluer le bénéfice/risque des IgIV dans cette pathologie.
Effet des IgIV dans les encéphalites auto-immunes, dont l’encéphalite de Rasmussen
Auteurs
Granata
(2003)
Type
d’étude
Ouverte
N = 15
Posologie
Suivi
IgIV : n = 11
1-27 ans
7/10 enfants : 2g/kg sur 25j/mois pdt 20 mois environ.
1 adulte de 23 ans reçoit
périodiquement
des
IgIV
depuis le début de sa maladie
Ouverte
N=2
Hart
(1994)
Ouverte
N = 19
Topçu
(1999)
Ouverte
N=6
Corticostéroïdes
Cyclophosphamide : pas d’effet
Cyclophosphamide
Chirurgie
IgIV :
0.4g/kg/j
pdt
traitement
de
0.4g/kg/mois
IgIV :
2/10 : ↓ fréquence des crises d’épilepsie
de 50%
6/11 : ↓ temporaire de la fréquence des
crises
3/9 : ont reçu le traitement dans les 6 mois
suivant le début de la maladie : meilleurs
résultats
Corticostéroïdes : n = 14
(Prednisone : 1mg/kg/j : n =
9/14)
(délai moyen entre début de la
maladie et administration de
corticostéroïdes : 27.3 mois)
Leach
(1999)
Résultats
Chirurgie : 11/13 : arrêt des crises
2/13 : ↓ fréquence des crises
5j
puis
maintien
IgIV : n = 9
Corticostéroïdes : n = 17
1 an
2/2 : amélioration avec ↓ des crises
d’épilepsie, ↓ des hémiparésies et
récupération des facultés intellectuelles
notamment de mémoire au bout de 4-5
cycles d’IgIV forte dose avec persistance
de l’effet lors de la phase de maintien
↓ fréquence des crises d’épilepsie sur un
court-terme : 8/9 et 10/17
Amélioration moindre des hémiparésies
Amélioration temporaire du contrôle des
crises : n = 3
Bibliographie
1. Granata T, Fusco L, Gobbi G, Freri E, Ragona F, Broggi G, Mantegazza R, Giordano L, Villani F, Capovilla G, Vigevano F,
Bernardina BD, Spreafico R, Antozzi C. Experience with immunomodulatory treatments in Rasmussen'
s encephalitis.
Neurology. 2003 Dec 23;61(12):1807-10
s encephalitis with long-term
2. Leach JP, Chadwick DW, Miles JB, Hart IK. Improvement in adult-onset Rasmussen'
immunomodulatory therapy.
Neurology. 1999 Mar 10;52(4):738-42
112
3. Hart YM, Cortez M, Andermann F, Hwang P, Fish DR, Dulac O, Silver K, Fejerman N, Cross H, Sherwin A. Medical treatment
of Rasmussen'
s syndrome (chronic encephalitis and epilepsy): effect of high-dose steroids or immunoglobulins in 19 patients.
Neurology.1994 Jun;44(6):1030-6
4. Topçu M, Turanli G, Aynaci FM, Yalnizoglu D, Saatçi I, Yigit A, Genç D, Söylemezoglu F, Bertan V, Akalin N. Rasmussen
encephalitis in childhood. Childs Nerv Syst. 1999 Aug;15(8):395-402;
Résumés-abstracts
Granata T, Fusco L, Gobbi G, Freri E, Ragona F, Broggi G, Mantegazza R, Giordano L, Villani F, Capovilla G,
Vigevano F, Bernardina BD, Spreafico R, Antozzi C. Experience with immunomodulatory treatments in
Rasmussen'
s encephalitis. Neurology. 2003 Dec 23;61(12):1807-10
The authors investigated immunomodulatory treatments in 15 patients with Rasmussen encephalitis (RE) (14 with
childhood and one with adolescent onset RE). Positive time-limited responses were obtained in 11 patients using
variable combinations of corticosteroids, apheresis, and high-dose IV immunoglobulins. Although surgical
exclusion of the affected hemisphere is the only treatment that halts disease progression, immunomodulation can
be considered when early surgery is not feasible, in late-onset patients with slower disease progression, and in
the few cases of bilateral disease.
Leach JP, Chadwick DW, Miles JB, Hart IK. Improvement in adult-onset Rasmussen'
s encephalitis with long-term
immunomodulatory therapy. Neurology. 1999 Mar 10;52(4):738-42
OBJECTIVE: To study the immediate and chronic effects of high-dose, long-term human i.v. immunoglobulin (h
i.v.Ig) therapy in two patients with advanced adult-onset Rasmussen'
s encephalitis (RE). BACKGROUND:
Despite advances in our understanding of the autoimmune pathogenesis of RE, medical options for chronic
treatment are limited. METHODS: In an open-label treatment trial, treatment started with monthly cycles of highdose h i.v.Ig (0.4 g/kg/d for 5 days) followed by maintenance therapy (0.4 g/kg 1 day each month) after the
patients' conditions began to improve. Outcome measures included clinical, psychological, functional, and
laboratory assessments before and at relevant intervals throughout 1 year of treatment. RESULTS: In both
patients, unrelenting pretreatment deterioration halted, and after this they displayed striking improvements in
seizure control, hemiparesis, and cognition that produced useful recovery of function. Improvements were
delayed until after 2 to 4 monthly cycles of high-dose h i.v.Ig and continued when patients switched to
maintenance treatment. Their recoveries were accompanied by increased cerebral perfusion on interictal SPECT
and suppression of inflammatory markers in CSF. CONCLUSIONS: h i.v.Ig can be a useful, possibly diseasemodifying, long-term therapy for adult-onset RE that should be considered before radical surgery is performed.
Because improvements can be delayed, we propose guidelines for intensive and prolonged trials of
immunomodulatory therapy in adults with this syndrome.
Hart YM, Cortez M, Andermann F, Hwang P, Fish DR, Dulac O, Silver K, Fejerman N, Cross H, Sherwin A
Medical treatment of Rasmussen'
s syndrome (chronic encephalitis and epilepsy): effect of high-dose steroids or
immunoglobulins in 19 patients. Neurology.1994 Jun;44(6):1030-6
We treated 19 patients with Rasmussen'
s syndrome (chronic encephalitis and epilepsy)--a rare progressive
disorder of unknown etiology causing focal epilepsy, hemiparesis, and intellectual deterioration--with intravenous
immunoglobulins, high-dose steroids, or both, to control seizures and improve the end point of the disease. Ten of
17 patients receiving steroids, and eight of nine patients receiving immunoglobulins, had some reduction of
seizure frequency in the short term. Improvement in hemiparesis was slight. The effect of these drugs in
ameliorating the end point of the disease in the long term remains unknown, and further multicenter studies with
standardized protocols are warranted.
Topçu M, Turanli G, Aynaci FM, Yalnizoglu D, Saatçi I, Yigit A, Genç D, Söylemezoglu F, Bertan V, Akalin
N.Rasmussen encephalitis in childhood. Childs Nerv Syst. 1999 Aug;15(8):395-402;
Six patients admitted to the Department of Pediatric Neurology at Hacettepe University Children'
s Hospital
between 1992 and 1997 with a clinical diagnosis of Rasmussen encephalitis received surgical treatment for their
intractable epilepsy. MRI, SPECT and WADA tests were performed in patients with an epileptic focus
demonstrated on routine or long-term video EEG monitoring. Viral studies using the PCR methodology were
performed in cases with histopathological evidence of Rasmussen encephalitis. The ages of these patients
ranged between 7 and 16 years, and the mean age at onset of seizures was 7.1+/-2.2 years. In four patients
113
seizures presented as epilepsia partialis continua and were refractory to anticonvulsive drug therapy. In three
cases intravenous immunoglobulin therapy yielded temporary and partial improvement in seizure control. The
mean presurgical follow-up duration was 2.04+1.74 years, and early surgical intervention for epilepsy was
performed in one case. The surgical approach selected for the treatment of epilepsy was resective surgery with
electrocorticography. The mean postoperative follow-up duration was 32.3+17.2 months. Seizures were fully
controlled in one patient, in whom surgery was performed 3 months after the seizures first started. Early surgical
intervention may provide histopathological evidence for diagnosis as well as effective seizure control.
114
•
Epilepsie de l’enfant : formes résistantes
L’effet des IgIV dans les épilepsies réfractaires de l’enfant, y compris le syndrome de Landau-Kleffner,
le syndrome de West et le syndrome de Lennox-Gastaut, n’a été évalué qu’au cours d’études
ouvertes de faibles effectifs et pour la plupart relativement anciennes.
Ce type d’évaluation devrait faire l'
objet d'
un PHRC mais la méthodologie est extrêmement complexe
en raison de l'
hétérogénéité de ces patients et de leur rareté dans chaque groupe.
Effet des IgIV dans les formes résistantes d’épilepsie chez l’enfant
Auteurs
Type d’étude
Posologie
Suivi
Critères
Résultats
d’évaluation
0.15 à - Fréquence des - ↓ fréquence des crises d’épilepsie : 52%
12
crises
- Amélioration EEG : 45%
mois
- EEG
- Rémission complète des crises : 23%
- Amélioration du comportement : 63%
Baziel
(1994)
Revue de 24 études IgIV :
non contrôlées
0.3 à 6.8g/kg
Billiau
(2007)
Ouverte
IgIV :
N = 13 enfants d’âge 0.4 g/kg pdt
moyen : 6.9 ans
4j /3 sem
- Fréquence des ↓ fréquence des crises de 50 % : n=7
crises
- EEG
↓ fréquence des crises de 25-50% : n=4
Turkay
(1996)
Ouverte
N=6
- Fréquence des
crises
- EEG
- Fréquence des
crises
- EEG
- Fréquence des
crises
- EEG
Fonction
cognitive
IgIV :
0.2g/kg/3sem
Revue de 29 études IgIV
non contrôlées
N = 373
Gross-Tsur Ouverte
IgIV :
N =9
(1993)
0.2g/kg
les 15 j
Duse
(1996)
Etzoni
(1991)
Fois
(1990)
Echenne
(1991)
Ouverte
N =8
26
tous mois
IgIV :
0.2g/kg
3x
/sem toutes
les 3 sem
Ouverte
IgIV :
N = 31
0.4g/kg puis
10
doses
max tous les
15 j –3 sem
Ouverte
IgIV
N = 23
0,4 g/kg pdt 5
. n = 19 syndrome de j toutes les 6
West
sem
. n = 4 patients plus
âgés avec des crises Puis 1g/kg/j
d’épilepsie
ayant pdt 2 j toutes
précédées
le les 3 sem pdt
syndrome de Lennox- 6 mois
Gastaut
EEG : pas de modifications
Amélioration totale : n=4
Amélioration partielle : n=2
Bonne réponse : n=174
Rémission complète : n= 4 (pdt 9 mois :
n=1 et pdt 22-26 mois : n=3)
Réponse partielle avec plus de 50% de ↓
de la fréquence des crises d’épilepsie : n=3
Absence de réponse : n=2
- Fréquence des Amélioration clinique et EEG : n=4
crises
Réponse partielle : n=1
- EEG
Absence de réponse : n=3
- Fréquence des Fréquence des crises : ↓ transitoire : n=12
crises
- EEG
Rémission pdt 30 mois : n= 1
- Etat clinique
- EEG
Absence d’amélioration : n=15
Amélioration transitoire
clinique : n=3
EEG
et
Normalisation complète : n=5
Bibliographie
115
état
1. Baziel GM, van Engelen BG, Renier WO, Weemaes CM, Gabreels FJ, Meinardi H. Immunoglobulin treatment in epilepsy, a
review of the literature. Epilepsy Res. 1994 Dec;19(3):181-90.
2. Billiau AD, Witters P, Ceulemans B, Kasran A, Wouters C, Lagae L. Epilepsia. Intravenous immunoglobulins in refractory
childhood-onset epilepsy: effects on seizure frequency, EEG activity, and cerebrospinal fluid cytokine profile. 2007
Sep;48(9):1739-49.
3. Duse M, Notarangelo LD, Tiberti S, Menegati E, Plebani A, Ugazio AG. Intravenous immune globulin in the treatment of
intractable childhood epilepsy. Clin Exp Immunol. 1996 May;104 Suppl 1:71-6.
4. Türkay S, Baskin E, Dener S, Gültekin A, Tanzer F, Sekreter E. Immune globulin treatment in intractable epilepsy of
childhood. Turk J Pediatr. 1996 Jul-Sep;38(3):301-5.
5. Gross-Tsur V, Shalev RS, Kazir E, Engelhard D, Amir N.Intravenous high-dose gammaglobulins for intractable childhood
epilepsy..Acta Neurol Scand. 1993 Sep;88(3):204-9.
6. Etzioni A, Jaffe M, Pollack S, Zelnik N, Benderly A, Tal Y. High dose intravenous gamma-globulin in intractable epilepsy of
childhood. Eur J Pediatr. 1991 Jul;150(9):681-3
7. Fois A, Vascotto M. Use of intravenous immunoglobulins in drug-resistant epilepsy.Childs Nerv Syst. 1990 Nov;6(7):400-5.
8. Villani F, Avanzini G. The use of immunoglobulins in the treatment of human epilepsy. Neurol Sci. 2002 Apr;23
Suppl 1:S33-7.
9. Arias M, Dapena D, Arias-Rivas S, Sesar A, Vázquez F, Prieto A, Suárez-Peñaranda JM. Rasmussen encephalitis in the
sixth decade: magnetic resonance image evolution and immunoglobulin response.
s syndrome. Curr Opin Neurol. 1996 Apr;9(2):75-7
10. Dulac O. Rasmussen'
11. Mikati MA, Shamseddine AN. Management of Landau-Kleffner syndrome. Paediatr Drugs. 2005;7(6):377-89.
12. Echenne B, Dulac O, Parayre-Chanez MJ, Chiron C, Taillebois L, Cognot C, Andary M, Clot J, Baldy-Moulinier M. Treatment
of infantile spasms with intravenous gamma-globulins. Brain Dev. 1991 Sep;13(5):313-9.
13. Illum N, Taudorf K, Heilmann C, Smith T, Wulff K, Mansa B, Platz P. Intravenous immunoglobulin: a single-blind trial in
children with Lennox-Gastaut syndrome. Neuropediatrics. 1990 May;21(2):87-90.
Résumés-abstracts
Baziel GM, van Engelen BG, Renier WO, Weemaes CM, Gabreels FJ, Meinardi H. Immunoglobulin treatment in
epilepsy, a review of the literature. Epilepsy Res. 1994 Dec;19(3):181-90.
The purpose of this study is to ascertain possible efficacy and to understand possible mechanisms of action of
intramuscular or intravenous immunoglobulin (IVIg) in the treatment of intractable epilepsy, through a review of all
identifiable articles on this topic. In 24 studies, none with a placebo controlled design, 368 patients with epilepsy
receiving IVIg were identified. Patients'ages ranged from < 1 to 35 years, mean 7.3 years. Female/male ratio was
0.6. All patients were reported to suffer from intractable epilepsy. The average percentage of patients with an
IgG2 deficiency was 25%. The total dose of IVIg varied between 0.3 and 6.8 g/kg for a period of 0.15 to 12
months. Whenever reported, adverse effects of IVIg were minimal. None of the studies reported the need of
cessation of IVIg administration due to adverse effects. On the average, the mean clinical seizure reduction and
the mean EEG improvement were 52% and 45%, respectively. On the average the percentage of patients with
complete seizure remission and the percentage of patients with behavioral improvement were 23% and 63%,
respectively. Cumulative meta-analysis of the identified articles is not possible due to the lack of controlled
studies, the heterogeneity of the available studies, and the possible publication bias of unpublished negative data.
Given these pitfalls, this literature study nevertheless allows some conclusions: (i) There is no formal proof of
efficacy of IVIg treatment in epilepsy, and the present review underscores the need of controlled clinical trials
before firm conclusions concerning efficacy can be drawn. The uncontrolled clinical observations discussed in this
'
state-of-the-art'review generate suggestive evidence at best. They suggest that IVIg might be effective in some
patients with intractable epilepsy, and may be considered as a safe add-on medication in various types of
idiopathic and symptomatic intractable epilepsy. (ii) Review of the literature did not help in explaining intractable
epilepsy or the mechanism of action of IVIg, but did permit some inferences that could serve to design future
clinical and experimental approaches to IVIg administration in epilepsy.
Billiau AD, Witters P, Ceulemans B, Kasran A, Wouters C, Lagae L. Epilepsia. 2007 Sep;48(9):1739-49.
Intravenous immunoglobulins in refractory childhood-onset epilepsy: effects on seizure frequency, EEG activity,
and cerebrospinal fluid cytokine profile.
PURPOSE: Several studies have reported favorable effects of intravenous immunoglobulins (IVIG) in refractory
epilepsy. Evidence substantiating an immunomodulatory action is scarce. In an open-label study, we
prospectively investigated the effect of IVIG on clinical, EEG and serum/CSF immunological parameters in
patients with refractory childhood-onset epilepsy. METHODS: Thirteen patients (median age 6.9 years; range 1.625.8) with refractory seizures despite 3-4 antiepileptic drug regimens were given IVIG (Sandoglobulin, ZLBBehring, add-on, 4 x 400 mg/kg/3 weeks). Seizure frequency, 24-h video-EEG, and CSF/serum immunological
parameters and cytokine profiles (IL-6/IL-8/IL-12/IL-10) were documented before and after completion of the
116
course. RESULTS: Seizure frequency was reduced by > or = 50% in four, and by 25%-50% in three patients. In
contrast, variation in automatically recorded spike counts (1-h-wake and -sleep) did not correlate with clinical
improvement. Serum immunological parameters showed variable deviations in eight patients (e.g., IgG(2)
deficiency) and CSF immunoblotting showed oligoclonal bands in two patients. Blood-brain barrier permeability
was normal in 12 patients. IL-6 and IL-8 were clearly detectable in CSF of all patients; the levels were significantly
higher than those in plasma but remained unaffected by IVIG treatment. CONCLUSIONS: Despite unchanged
EEG spike counts, substantial reductions in seizure frequency occurred in 7 of 13 patients, suggesting that IVIG
hinder progression of central epileptic activity into clinical seizures. Intrathecal presence of IL-8 and IL-6 was
documented in all patients, but was unaffected by IVIG, suggesting that their production is directly related to
electrical seizure activity and that IVIG may act through interference with immune pathways downstream to IL-6
and IL-8.
Türkay S, Baskin E, Dener S, Gültekin A, Tanzer F, Sekreter E. Immune globulin treatment in intractable epilepsy
of childhood. Turk J Pediatr. 1996 Jul-Sep;38(3):301-5.
Six children suffering from epilepsy refractory to conventional anti-convulsive therapy were treated with high-dose
intravenous immune globulin (IVIG) (200 mg/kg three times per week, repeated after three weeks). In four
children clinical and EEG findings markedly improved, while a partial response was noted in the other cases.
These results suggest that high-dose intravenous immune globulin may have a beneficial effect in the treatment
of intractable epilepsy.
Duse M, Notarangelo LD, Tiberti S, Menegati E, Plebani A, Ugazio AG.Intravenous immune globulin in the
treatment of intractable childhood epilepsy. Clin Exp Immunol. 1996 May;104 Suppl 1:71-6.
Many clinical and experimental data strongly support the role of immune mechanisms in the pathogenesis of
childhood epilepsy. Following Pechadre'
s first observations with intramuscular immune globulin (IMIG),
intravenous immune globulin (IVIG) has been employed in some forms of intractable childhood epilepsy (ICE),
mainly in West syndrome (WS) and Lennox Gastaut syndrome (LGS), with good results. So far, 373 children
suffering from ICE have been treated in 29 studies and 174 have responded favourably. Although these studies
are heterogeneous and controls are lacking, most authors report similar responsiveness ranging from 30% to
50%. Several mechanisms have been suggested to account for the efficacy of IVIG in ICE including antiviral
effect, substitutive therapy in patients with concomitant humoral immunodeficiency, idiotype-anti-idiotype
interaction or a neuromodulant effect. To better define the real efficacy of IVIG in ICE in paediatric patients, a
randomized, multicenter, double-blind clinical trial was started in 1993, including only patients suffering from WS
and LGS. To date, only one double-blind trial had been carried out (with both adult and paediatric patients); it
showed a clear trend in favour of IVIG treatment but lacked statistical significance, perhaps because of the small
and heterogeneous sample. Controlled multicentre studies on well-defined populations are needed and patients
with WS and LGS are probably the best candidates.
Gross-Tsur V, Shalev RS, Kazir E, Engelhard D, Amir N. Intravenous high-dose gammaglobulins for intractable
childhood epilepsy. Acta Neurol Scand. 1993 Sep;88(3):204-9.
Immunological mechanisms have been implicated in the pathogenesis of epileptic seizures in some patients and
in experimental animal models of epilepsy. A beneficial effect of high dose intravenous gammaglobulin (IVIG) has
been demonstrated for some children with intractable epilepsy. In this study we treated 9 children ages 1.1-9.2
years (mean 5.0 years) with intractable epilepsy not responsive to conventional antiepileptic drugs (AEDs) and
steroid therapy. Eight children had Lennox-Gastaut syndrome and 1 had complex partial seizures with secondary
generalization. Each child received 3 doses of IVIG (200 mg/kg of polyvalent immunoglobulin) on Days 1, 15 and
36. Concomitant AEDs were not changed. Four children had complete remission, 3 had partial response with a
more than 50% reduction in seizure frequency and 2 had no response. Onset of response varied from immediate
to 7 months after the last injection. No toxicity was noted. Duration of remission was 9 months in 1 case. The
other 3 cases have remained in remission to date with a follow up period of 22-26 months. We conclude that IVIG
is a safe therapy which appears to be effective in some children with intractable seizures. Children with shorter
duration of their seizure disorder (< 1 year) and relatively preserved cognitive function (IQ > 70) appear to have a
more favorable response. Larger scale controlled trials are needed to determine the optimal timing and dosage,
as well as to identify specific subgroups which may benefit most from IVIG treatment.
Etzioni A, Jaffe M, Pollack S, Zelnik N, Benderly A, Tal Y. High dose intravenous gamma-globulin in intractable
epilepsy of childhood. Eur J Pediatr. 1991 Jul;150(9):681-3
Eight children aged between 1.3 and 13 years suffering from epilepsy refractory to conventional anticonvulsive
therapy were treated with high dose intravenous gamma globulin (200 mg/kg, 3 times per week, repeated after 3
117
weeks). Immunological studies after therapy showed normal results. In four children, clinical and EEG findings
markedly improved. In one other case a partial response was noted. No improvement was observed in the
remaining three cases. We confirm that although the mechanism is still obscure, high doses of i.v. gammaglobulin
may have a beneficial effect in a significant number of children with intractable epilepsy.
Fois A, Vascotto M. Use of intravenous immunoglobulins in drug-resistant epilepsy. Childs Nerv Syst. 1990
Nov;6(7):400-5.
Among the 257 pediatric patients examined, 104 were classified as having drug-resistant epilepsy (DRE). In all of
them genetic, metabolic, chromosomal and infectious causes were investigated, and brain imaging with computed
tomography scans and nuclear magnetic resonance were obtained. Since treatment with gammaglobulins (GGs)
has been reported to be useful in pediatric cases of epilepsy, informed consent for GGs treatment was obtained in
43 patients with DRE. The etiology or evidence of brain lesions was identified in 16 of them. In 31 of these
patients, neither conventional drug treatment, nor a trial with adrenocorticotropic hormone was successful. Intact
monomeric GGs, 400 mg/kg, were given intravenously. A second dose was given after 15 days and, thereafter,
every 21 days for a maximum of ten injections (protocol A), or every 2nd day for a maximum of five doses
(protocol B). In every patient, the type of epilepsy was identified according to the classification of the International
League Against Epilepsy. The frequency of seizures was recorded for a period beginning at least 6 months before
the administration of GGs. Immunological evaluation was also performed before and after the treatment with GGs.
A transient decrease of the seizure frequency was noted in 12 subjects. In another patient with infantile idiopathic
myoclonic epilepsy, seizures disappeared for 30 months. In 1 case a persistent 80% reduction in the number of
seizures was observed. A persistent disappearance of seizures was noted in a subject with complex partial
seizures (CPS) that followed an idiopathic infantile spasm syndrome.
Villani F, Avanzini G.The use of immunoglobulins in the treatment of human epilepsy. Neurol Sci. 2002 Apr;23
Suppl 1:S33-7.
The use of immunoglobulin (IVIg) in intractable epilepsy is one of its oldest applications in medicine, starting from
the empirical observation of its beneficial effect on seizures. Immune system dysfunction may play a role in
epilepsy by triggering, maintaining or, unexpectedly, improving intractable seizures. Several laboratory and
clinical investigations are in favor of an immunological basis for different forms of experimental and human
epilepsies. A wide range of immune abnormalities have been reported, suggesting the existence of different
subtypes of epileptic syndromes with different abnormalities of the immune system. In this view, IVIg with its
broad immunomodulatory mechanism of action could be effective in different forms of immune-dysregulated
intractable epilepsies. Non-immunological mechanisms of action have been also suggested, based either on
human epilepsy data or on animal experimental data. The possible anticonvulsant properties and the ability of
IVIg to interfere with the final common pathway of seizures at a cellular level, with a significant increase in seizure
threshold, have been demonstrated in different experimental epilepsy model. Although IVIg may represent a
valuable resource in some drug-refractory epilepsies and its effectiveness has important pathogenetic
implications, controlled studies with the systematic monitoring of immunological markers are needed to define
Mikati MA, Shamseddine AN.Management of Landau-Kleffner syndrome. Paediatr Drugs. 2005;7(6):377-89.
Landau-Kleffner syndrome (LKS) is an acquired epileptic aphasia disorder in which children, usually 3-8 years of
age who have developed age-appropriate speech, experience language regression with verbal auditory agnosia,
abnormal epileptiform activity, behavioral disturbances, and sometimes overt seizures. There are no controlled
clinical trials investigating the therapeutic options for LKS. Only open-label data are available. Early diagnosis and
initiation of prompt medical treatment appear to be important to achieving better long-term prognosis. Several
antiepileptic drugs have been reported to be beneficial in treating this syndrome. These include valproic acid
(valproate sodium), diazepam, ethosuximide, clobazam, and clonazepam. Reports on the efficacy of lamotrigine,
sultiame, felbamate, nicardipine, vigabatrin, levetiracetam, vagal nerve stimulation, and a ketogenic diet are few
and more experience is needed. Carbamazepine and possibly phenobarbital and phenytoin have been reported
to occasionally exacerbate the syndrome. As initial therapy, valproic acid or diazepam is often empirically chosen.
Subsequently, other antiepileptic drugs, corticosteroids, or intravenous immunoglobulin (IVIG) therapy are often
used. Corticosteroid therapy should probably not be delayed more than 1-2 months after the initial diagnosis.
Various corticosteroid regimens including oral prednisone and, recently, high doses of intravenous pulse
corticosteroids, as well as corticotropin (adrenocorticotropic hormone) have been reported to be effective in LKS.
Oral corticosteroids are used more often and usually need to be maintained for a long period of time to prevent
relapses. The use of IVIG has been associated with an initial dramatic response in only a few patients. In our
experience, a long-term worthwhile improvement has been noted in only 2 of 11 patients. These two patients had
an immediate response to IVIG initially and after relapses before eventually achieving a long-term sustained
remission. Surgical treatment by multiple subpial transection, which is reserved for patients who have not
118
responded to multiple medical therapies, has been followed in selected cases by a marked improvement in
language skills and behavior. However, a widely accepted consensus about suitable candidates for this surgery
and about its efficacy is still lacking. Speech therapy, including sign language, and a number of classroom and
behavioral interventions are helpful in managing LKS, and should be used in all patients.
Echenne B, Dulac O, Parayre-Chanez MJ, Chiron C, Taillebois L, Cognot C, Andary M, Clot J, Baldy-Moulinier M.
Treatment of infantile spasms with intravenous gamma-globulins. Brain Dev. 1991 Sep;13(5):313-9.
In a prospective study, 23 children with infantile spasms received intravenous gammaglobulins in high doses. 19
patients present a West syndrome. 4 older patients were included in the study because infantile spasms had
preceded their Lennox-Gastaut syndrome. None of the patients had recently undergone corticosteroid therapy.
No effect was observed in 15 patients, while transitory clinical and/or electroencephalographic improvement was
noted in 3. Complete normalization was obtained in the remaining 5 patients, of whom 4 had severe brain lesions.
No correlation existed between the therapeutic results and immunological abnormalities, a deficiency in IgG
subclasses in particular. On the whole, the therapeutic results were disappointing. But the existence of some
cases in which spectacular electroencephalographic and/or clinical improvement was obtained leads us to
suggest that IV gamma-globulins be used as auxiliary treatment in infantile spasms.
Illum N, Taudorf K, Heilmann C, Smith T, Wulff K, Mansa B, Platz P. Intravenous immunoglobulin: a single-blind
trial in children with Lennox-Gastaut syndrome. Neuropediatrics. 1990 May;21(2):87-90.
The antiepileptic effect of intravenous immunoglobulin (Sandoglobulin, Sandoz) was investigated in LennoxGastaut syndrome by an add-on, placebo-controlled, single-blind trial. Ten patients, aged 4-14 years, with
insufficient response to conventional anticonvulsive therapy received placebo and Sandoglobulin 400 mg/kg two
times each with an interval of two weeks. The washout period was four weeks and the total observation period 14
weeks, during which parents daily registered number and type of seizures. EEG, in vitro lymphocyte
transformation tests and concentrations of immunoglobulins including IgG subclasses were evaluated before and
after active treatment. Two children showed an immediate reduction in their high-frequency and invariable seizure
activity from 42% to 100% and a less abnormal EEG. In addition, general well-being and intellectual performance
was improved. The strongest response was observed in one child with a concomitant finding of a low level of
IgG2, the only abnormal immunologic test in this study. The remaining 8 children, who had either a high or a low
but variable seizure frequency showed no immediate change as EEG and their general condition was unaffected.
We conclude that intravenous immunoglobulin had an immediate and pronounced effect on break-through seizure
activity and a simultaneous neurophysiologic effect in 20% of our patients with Lennox-Gastaut syndrome. The
effect was not confined to patients with immunologic abnormalities.
119
•
Polyneuropathie associée à une gammapathie monoclonale IgM antiMAG (Glycoprotéine associée à la myéline)
Les polyneuropathies dysimmunitaires chroniques sont rares et leur mécanisme physiopathologique
est encore largement méconnu. Des critères cliniques, électrophysiologiques et le cas échéant
immunologiques et neuropathologiques permettent d'
individualiser 3 groupes : les polyradiculonévrites
chroniques idiopathiques inflammatoires, les neuropathies motrices multifocales avec blocs de
conduction persistants et les polyneuropathies associées à une gammapathie monoclonale.
Une revue Cochrane de 2006 a identifié dans la littérature 5 essais randomisés contrôlés ayant inclus un
total de 97 patients traités avec IgIV, INF-alpha ou échanges plasmatiques. Aucun de ces traitements n’a
montré d’effet significatif. Les IgIV pourraient avoir un effet bénéfique à court-terme.
Effet des IgIV dans les polyneuropathies associées à une gammapathie monoclonale IgM anti-MAG
Auteurs
Lunn
(2006)
Type d’étude
Cochrane
5 essais randomisés
contrôlés avec N = 97
patients ayant été
traités avec IgIV, INFalpha ou échanges
plasmatiques
- Echelle d’évaluation de l’incapacité
d’origine neurologique
Ou score modifié de Rankin12 mois
après la randomisation
- Temps de marche sur 10 m
- Paramètres électrophysiologiques à
6 et 12 mois
- Taux de paraprotéine IgM
- Taux d’AC anti-myéline à 6 mois
Résultats
Effet NS pour
d’évaluation.
tous
les
critères
Les IgIV ont montré une amélioration
du score modifié de Rankin à 2
semaines et une amélioration du
temps de marche sur 10 m à 4
semaines
Aucun effet
rapporté
indésirable
n’a
été
Résumés-abstracts
Lunn MP, Nobile-Orazio E. Immunotherapy for IgM anti-myelin-associated glycoprotein paraprotein-associated
peripheral neuropathies. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD002827.
BACKGROUND: Serum monoclonal anti-myelin associated glycoprotein antibodies may be pathogenic in some
people with IgM paraprotein and demyelinating neuropathy. Immunotherapies aimed at reducing the level of these
antibodies might be expected to be beneficial. OBJECTIVES: To examine the efficacy of any form of
immunotherapy in reducing disability and impairment resulting from IgM anti-myelin associated glycoprotein
paraprotein-associated demyelinating peripheral neuropathy. SEARCH STRATEGY: We searched the Cochrane
Neuromuscular Disease Group Register (March 2005), MEDLINE (January 1966 to March 2005) and EMBASE
(January 1980 to March 2005) for controlled trials. We also checked bibliographies and contacted authors and
experts in the field. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials of
participants of any age treated with any type of immunotherapy for anti-myelin-associated glycoprotein antibody
associated demyelinating peripheral neuropathy with monoclonal gammopathy of undetermined significance of
any severity. Our primary outcome measure was change in the Neuropathy Impairment Scale or Modified Rankin
Scale at six months after randomisation Secondary outcome measures were: Neuropathy Impairment Scale or
the Modified Rankin Score at 12 months after randomisation; ten-metre walk time, subjective clinical scores and
electrophysiological parameters at six and 12 months after randomisation; IgM paraprotein levels and anti-myelin
associated glycoprotein antibody titres at six months after randomisation and adverse effects of treatments. DATA
COLLECTION AND ANALYSIS: We identified eight possible trials. Of these, five randomised controlled trials
were included after discussion between the authors. One author extracted and the other checked the data. No
missing data could be obtained from trial authors. MAIN RESULTS: The five eligible trials (97 participants) tested
intravenous immunoglobulin, interferon-alpha or plasma exchange. Only two, of intravenous immunoglobulin, had
comparable interventions and outcomes but both were short-term. There were no significant benefits of the
treatments used in the outcomes predefined for this review, but not all the predefined outcomes were used in
every included trial. Intravenous immunoglobulin showed benefits in terms of improvement in Modified Rankin
Scale at two weeks and 10-metre walk time at four weeks. Serious adverse effects of intravenous immunoglobulin
are known to occur from observational studies but none were encountered in these trials. AUTHORS'
CONCLUSIONS: There is inadequate reliable evidence from trials of immunotherapies in anti-myelin associated
glycoprotein paraproteinaemic neuropathy to recommend any particular immunotherapy treatment. Intravenous
120
immunoglobulin is relatively safe and may produce some short-term benefit. Large well-designed randomised
trials of at least six to 12 months duration are required to assess existing or novel therapies.
Chassande B, Léger JM. Neurological manifestations of monoclonal gammopathies. Rev Prat. 1993 Feb
1;43(3):314-6.
The spectrum of peripheral neuropathy associated with monoclonal gammapathy is wide: peripheral neuropathy
associated with IgM monoclonal gammapathy, in which serum antibody activity has been demonstrated against
MAG (myelin-associated-glycoprotein) and SGPG, mainly presents as a chronic demyelinating sensory
polyneuropathy, with predominant tremor and ataxia. Polyneuropathy reported in association with multiple
myeloma or MGUS (monoclonal gammapathy of undetermined significance) IgG and IgA are more heterogenous:
mainly axonal, mixed or sometimes demyelinating as in POEMS syndrome. The treatment of these
polyneuropathies is evaluated in trials in progression using corticosteroids, plasma exchanges and IgIV
(polyvalent immunoglobulins).
121
•
Polyneuropathie associée à une gammapathie non MAG
L’insuffisance des données ne permet pas d’évaluer le bénéfice-risque des IgIV dans cette situation.
Une revue Cochrane de 2007 n’a recensé qu’un seul essai randomisé portant sur 18 patients ayant
une neuropathie paraprotéinémique IgG et IgA traitée par des échanges plasmatiques. Les autres
études étaient ouvertes et concernaient l’usage de traitements tels que les échanges plasmatiques,
l’association cyclophosphamide et la prednisolone, ou l’association IgIV et corticostéroïdes. Les
auteurs de la revue concluent que les données sont insuffisantes pour le traitement de ces situations.
Résumés-abstracts
Allen D, Lunn MP, Niermeijer J, Nobile-Orazio E. Treatment for IgG and IgA paraproteinaemic neuropathy.
Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005376.
BACKGROUND: Paraproteinaemic neuropathy refers to those neuropathies associated with a monoclonal
gammopathy or paraprotein. Typically it presents with a chronic predominantly sensory, symmetrical neuropathy,
similar to chronic inflammatory demyelinating polyradiculoneuropathy but with relatively more sensory
involvement, both clinically and neurophysiologically. The optimal treatment for IgG and IgA monoclonal
gammopathy of uncertain significance neuropathies is not known. OBJECTIVES: The objective of this review is to
examine the efficacy of any treatment for IgG or IgA paraproteinaemic peripheral neuropathy. SEARCH
STRATEGY: We performed searches of the Cochrane Neuromuscular Disease Group Trials register (May 2005),
MEDLINE (from January 1966 to May 2005), EMBASE (from January 1980 to May 2005). We also checked
bibliographies for controlled trials of treatments for IgG or IgA paraproteinaemic peripheral neuropathy.
SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials using any treatment for
IgG or IgA paraproteinaemic peripheral neuropathy. People with IgM paraproteins were excluded. We excluded
participants where the monoclonal gammopathy was considered secondary to an underlying disorder. We
included participants of any age with a diagnosis of monoclonal gammopathy of uncertain significance with a
paraprotein of the IgG or IgA class and a neuropathy. Included participants were not required to fulfil specific
electrophysiological diagnostic criteria. DATA COLLECTION AND ANALYSIS: The full texts of potentially relevant
studies were obtained and assessed and independent data extraction was performed by three authors. Additional
data and clarification were received from one author. MAIN RESULTS: We identified only one randomised
controlled trial with 18 participants which fulfilled the predetermined inclusion criteria. Four other trials were
identified but these were not randomised controlled trials. The included trial revealed a modest short-term benefit
of plasma exchange in IgG or IgA paraproteinaemic neuropathy, over a short follow-up period, when compared to
sham plasma exchange. AUTHORS'CONCLUSIONS: The evidence from randomised controlled trials for the
treatment of IgG or IgA paraproteinaemic neuropathy is currently inadequate. More randomised controlled trials of
treatments are required. These should have adequate follow-up periods and contain larger numbers of
participants, perhaps through multicentre collaboration, considering the relative infrequency of this condition.
Observational or open trial data provide limited support for the use of treatments such as plasma exchange,
cyclophosphamide combined with prednisolone, intravenous immunoglobulin and corticosteroids. These show
potential therapeutic promise but the potential benefits must be weighed against adverse effects. Their optimal
use and the long-term benefits need to be considered and validated with well-designed randomised controlled
trials.
122
•
Erythroblastopénie auto-immune
L’érythroblastopénie auto-immune est une maladie rare définie par la disparition de la lignée
érythroblastique dans la moelle osseuse, sans anomalie des autres lignées. Sa traduction clinique est
une anémie normochrome normocytaire d'
aggravation progressive avec réticulocytopénie profonde,
sans hémorragie, hémolyse ou carence.
Il n’y a pas de données suffisantes pour évaluer le bénéfice/risque des IgIV dans cette pathologie.
Effet des IgIV dans les érythroblastopénies autoimmunes
Auteurs
Type d’étude
Charles
(1996)
Ouverte
IgIV :
N = 37
?
4/37 ont reçu
des IgIV
Clauvel
(1983)
N=4
Ballester
(1992)
N=3
Posologie
IgIV :
0.4 g/kg/j pdt 5 j
n=2
(Sandoglobuline®)
n=2
(Veinoglobuline®)
IgIV :
0.4 g/kg/j pdt 5 j
Suivi
3 ans
Critères
d’évaluation
Amélioration
de
l’état clinique et des
constantes
biologiques
Taux
de
réticulocytes
Taux
d’érythroblastes
Concentration d’[Hb]
Résultats
Sur les 4 patients traités par IgIV : 4
décès
. 1décès (IM) au bout de 9 mois
. 1 CR sur 2 ans puis rechute 1 an
après, Leucémie LGL
. 1 décès par BPCO
. 1 lymphome à 2 ans et décès
2/4 (Sandoglobuline®) :
↑ réticulocytes : 10 %
↑ érythroblastes : 30-40 %
↑ [Hb] : 12-14 g/dL
1/2 : rechute puis 2ème cure d’IgIV
(Veinoglobuline®) et échec.
de 1/3 : échec
2/3 : réticulocytose modérée suivie par
une ↑ stable de [Hb]
Taux
réticulocytes
Taux
d’érythroblastes
Concentration d’[Hb]
IM : infarctus du myocarde
CR : complète rémission
LGL : large granular lymphocytic
BPCO : broncho-pneumopathie chronique obstructive
Bibliographie
1. Charles RJ, Sabo KM, Kidd PG, Abkowitz JL.The pathophysiology of pure red cell aplasia: implications for therapy. Blood.
1996 Jun 1;87(11):4831-8.
2. Clauvel JP, Vainchenker W, Herrera A, Dellagi K, Vinci G, Tabilio A, Lacombe C.Treatment of pure red cell aplasia by high
dose intravenous immunoglobulins. Br J Haematol. 1983 Oct;55(2):380-2.
3. Ballester OF, Saba HI, Moscinski LC, Nelson R, Foulis P. Pure red cell aplasia: treatment with intravenous immunoglobulin
concentrate. Semin Hematol. 1992 Jul;29(3 Suppl 2):106-8.
Résumés-abstracts
Charles RJ, Sabo KM, Kidd PG, Abkowitz JL. The pathophysiology of pure red cell aplasia: implications for
therapy. Blood. 1996 Jun 1;87(11):4831-8.
123
To determine the utility of marrow culture in defining the natural history and therapeutic response of pure red cell
aplasia we have studied 37 patients. Patients were evaluated at the University of Washington before specific
therapies (n = 21) or at the time of treatment failure in = 16). Evaluation included a medical and drug exposure
history, a physical examination, a chest x-ray or computed tomography to rule out thymoma, lymphocyte
immunophenotype studies, anti-nuclear antibody and rheumatoid factor determinations, marrow cytogenetics, and
marrow progenitor cell cultures. Retrospective Southern analyses to detect human parvovirus B19 was performed
in the 27 patients for whom sera was stored. Clinical follow-up was obtained to document therapeutic responses.
Normal burst forming unit-erythroid (BFU-E) growth (>30 bursts/10(5) marrow mononuclear cells [MMNC]) in
culture proved an outstanding predictor of clinical response, as 27 of 29 individuals with normal frequencies of
erythroid bursts in culture responded to immunomodulating therapies (sensitivity 96%, specificity 78%, predictive
value 93%, P = .0001 with two-tailed chi square analysis). Overall, 28 patients responded to either
immunomodulating therapies or drug withdrawal. Twenty-four patients obtained a normal hematocrit (complete
response [CR] and 4 additional patients became transfusion independent (partial response). Although responding
patients often required several therapies, 20 of 24 (83%) patients who obtained a CR have sustained a normal
hematocrit without maintenance therapy at the time of last follow-up (median 5 years). In contrast, of 8 patients
with poor in vitro BFU-E growth (<6 bursts/10(5) MMNC), 7 failed to respond to any therapy and all died (median
survival time 17 months). Our data suggest that in individuals, from whom BFU-E mature appropriately in culture,
immunosuppressive drugs should be used sequentially until a CR is obtained and a durable remission is the
expected outcome.
124
•
Anémie hémolytique auto-immune
L’anémie hémolytique auto-immune est la plus fréquente des anémies hémolytiques. Les hématies
sont détruites par des auto-Ac anti-érythrocytaires spécifiques dirigés contre des déterminants
antigéniques des groupes sanguins érythrocytaires.
Il existe deux types d'
anémies hémolytiques auto-immunes : celles à auto-anticorps chauds et celles à
auto-anticorps froids, selon que la température optimale d'
activité des anticorps est de 37 °C ou 4 °C.
Cette distinction est importante, car le traitement varie d'
une forme à l'
autre.
- Les auto-anticorps chauds touchent surtout les adultes et provoquent une anémie hémolytique
chronique, parfois sévère. Elles représentent 80 % des anémies hémolytiques auto-immunes. Dans la
moitié des cas, elles peuvent être déclenchées par certains médicaments (alpha-méthyldopa, L-dopa)
ou certaines maladies (tumeur ovarienne, syndrome lymphoprolifératif, etc.).
- Les auto-anticorps froids sont associés à des épisodes aigus de destruction de globules rouges
causés par le froid. Dans 30 % des cas, il s’agit d’une réaction auto-immune secondaire à une
infection virale ou un mycoplasme.
Les données publiées sont insuffisantes pour établir le bénéfice/risque du traitement des AHAI par les
IgIV, notamment chez les adultes.
Effet des IgIV dans les anémies hémolytiques auto-immunes
Auteur
Blouin
(2005)
Besa
(1988)
Majer
(1988)
Type d’étude
Posologie
Critères
d’évaluation
Rétrospective
. Corticoïdes : 35/36 1 mois Taux d’[Hb] :
N = 36 enfants avec . IgIV : 32/36
à
22 . RC : taux
un
syndrome
de . Imunosuppres
ans
d’[HB]
<
Evans : PTI + AHAI
seurs : 14/36
11g/dl
. Splénectomie :
. RP : taux
. AHAI (1er épisode) :
9/36
d’[Hb] entre
n =10 enfants
. AC monoclonal
8 et 11 g/dl
. PTAI (1er épisode) :
anti -CD 20 : 6/36
. réfractaires :
n = 14
pas
de
. AHAI + PTI :
réponse
n = 12
Ouverte
IgIV :
4 ans
Hématocrite
N=7
0.4g/kg/j : 5 doses
stabilisé pdt 3
AHAI associée à un puis tous les 3-4
sem par une
syndrome
sem
dose d’IgIV
lymphoprolifératif
Ouverte
IgIV :
Plaquettes
N=2
0.5g/kg/j pdt 5 j
[Hb]
AHAI
Argiolu Ouverte
IgIV
(1990) N = 4
3/ 4 : 2 g/kg
AHAI + thalassémie 1/ 4 : 2.5-5 g/kg
majeure
Flores Ouverte
Etude pilote:
(1993) N = 73
-0,5 g /kg /j pdt 5-7 j
-ou 1 g/kg /j pdt 5-7 j
Une
étude
pilote
multicentrique
Etudes publiées :
N = 37 (32 adultes + 5 0,4 à 2 g /kg /j pdt 2enfants)
5j (en majorité 0,4
ou 0,5 g /kg /j pdt 5j)
Résultats combinés à
ceux d’études publiées
N = 36 (30 adultes + 6
enfants)
Bussel N = 4
Ttt d’attaque :
(1986) Age au moment du 1 g /kg pdt 5 j (ou 7 j
Suivi
Consommatio
n
en
composants
du sang
Réponse de
type I : ↑ [Hb]
2 g /100 ml
dans les 10 j
suivant
le
début du ttt
Réponse de
type II : idem
type
I
+
obtention
d’[Hb] 10 g
/100 ml
[Hb]
Résultats
Enfants vivants : 33/36
Les enfants ayant un faible taux
sérique d’Ig sont plus résistants aux
traitements par corticoïdes et IgIV (p =
0.03)
IgIV + corticostéroïdes :
↑ plus rapide de Ht
6/7 n’ont pas eu d’épisode d’AHAI
entre 6 mois et 4 ans
1 / 2 : AHAI + PTI :
↑ plaquettes mais pas [Hb]
1/2 :
AHAI
+
lymphoprolifératif :
↑ rapide de [Hb]
synd
Normalisation de la consommation en
composants du sang
-Taux global de réponse : 39,7 % (29
/73)
-Réponse de type I : 40 ,3 % (25 /62)
-Réponse de type II : 14,8 % (9 /61)
-Taux de réponse enfants 54,5 %) et
adultes (37 %) NS
-Persistance de l’↑ d’[Hb]
3 sem
dans la plupart des cas
- variables corrélées (p < 0,005) à la
réponse aux Ig : existence d’1
hépatomégalie et taux bas d’[Hb] (6-7
g /100ml) avant ttt
Réponse persistante dans 2 cas.
Réponse transitoire dans 1 cas.
125
Auteur
Type d’étude
diagnostic :
- patient : 1 6 mois
- patient 2 : 2,5 ans
- patient 3 : 27 ans
- patient 4 : 1 an.
Posologie
patient 3)
Critères
d’évaluation
Ttt d’entretien :
1 g /kg
=
4
patients 0,2 à 0,4 g /j pdt 5 j
Mitchel N
l
résistants
aux
(1987) corticoïdes
Age : 20 à 59 ans
Wonde N = 1
?
rgem
AHAI
mixte
(2006) compliquant un LED
Hilgart
ner
(1987)
Suivi
N=4
1 g /kg pdt 5 à 7 j
< 2 ans au moment du
diagnostic
Réponse :
↑
ou
stabilisation
d’[Hb]
-↓
↓ [Hb] et
LDH
- ↑ durée de
vie des GR
(méthode
51
Cr)
Patient Augmentation
1:
2 d’[Hb]
ans
après
fin
traitem
ent
Résultats
Echec dans 1 cas.
Patient 1 : A J8 ↑ [Hb] de 7,8 à 9,1 g
/100 ml. Après diminution des
corticoïdes puis arrêt et ttt d’entretien
IgIV 2x/sem pdt 3 mois : [Hb] = 12 g
/100 ml.
Rechute après environ 3 mois. TT
d’IgIV seules (4 cures) : ↑ [Hb] de 8,5
à 12,5. 3 cures supplémentaires sur 1
mois. 6 mois après arrêt : [Hb] > 12 g
/100 ml.
Patient 2 : Après ttt d’attaque + 1 cure
supplémentaire : [Hb] inchangé à 7 g
/100 ml. Puis chute [Hb] à 5,5 10 j.
Reprise ttt d’attaque + ttt d’entretien 2
fois /sem : réponse rapide. A 18 mois
après fin tt : [Hb] > 12 g /100 ml.
Patient 3 : ↑ [Hb] de 4,7 à 7,4 après
ttt d’attaque puis chute à 4,7. Reprise
4 g /kg IgIV sur 3 j + augmentation
corticoïdes : [Hb] à 6,9. Chute [Hb] de
nouveau (à 4,8) malgré 2 g /kg IgIV.
Patient 4 : aucune ↑ d’[Hb] après ttt
d’attaque pdt 5 j + 4 cures
supplémentaires 1j /2.
Réponse chez 3 patients sur 4,
temporaire dans 2 cas :
Patient 1 : ↑ [Hb] de 5 à 9,5 5 j après
IgIV permettant une splénectomie
sans transfusion.
Patient 2 : ↑ progressive d’[Hb].
Rémission durant 2 ans.
Patient 3 : [Hb] maintenue pdt les 5 j
d’IgIV. Reprise de l’hémolyse à l’arrêt
du ttt.
Persistance de l’hémolyse malgré de
fortes doses de corticoïdes. Chute de
l’[Hb] de 11,1 g /100 ml après
transfusion à 6,4 30j après.
Injection d’IgIV a permis d’éviter la
splénectomie. Stabilisation du taux
d’[Hb] puis remontée à 13 g /100 ml.
Réponse chez 3 patients sur 4, dont 2
réponses persistantes permettant
l’arrêt des corticoïdes.
Patient 1 : ttt d’attaque (après
absence de réponse aux corticoïdes et
faibles doses d’IgIV) : stabilisation
[Hb]. Rechute traitée par 1 cure
mensuelle d’IgIV pdt 3 mois. Deux ans
après fin ttt : [Hb] = 12,5 g /100 ml
Patient 2 : 3ème épisode d’anémie
traitée par IgIV (car effets indésirables
majeurs des corticoïdes). Stabilisation
[Hb] pdt 10 j. Puis diminution [Hb]
après 2 sem. Réponse rapide après
2ème cure d’IgIV + tt d’entretien à 1-2 g
/kg /sem pdt 2 sem.
Patient 3 : pas de réponse après
corticoïdes et splenectomie. Après
IgIV, ↑ [Hb] de 4,7 à 7 g /100ml et du
% de réticulocytes de 2 à 10. Nouvelle
cure d’IgIV après chute du % de
réticulocytes : réponse idem. Arrêt du
126
Auteur
Richm
ond
(1987)
Type d’étude
N=1
Posologie
Suivi
1ère cure : 0,4 g /kg /j
pdt 5j
ème
cure : 1 g /kg /j
2
pdt 5j
ème
3
cure :
Hb = hémoglobine
LED = lupus erythémateux disséminé
Critères
d’évaluation
Taux d’[Hb]
Résultats
traitement après rechute d’hépatite
chronique.
-Stabilisation d’[Hb] durant les 5 1ers j
de ttt. Puis chute.
-Stabilisation d’[Hb] pdt la 2ème cure
puis ↑ avec un max 2 j après fin 2ème
cure. Puis chute rapide d’[Hb].
-Pas de réponse pdt la 3ème cure avec
diminution progressive de l’[Hb] pdt tt
malgré ↓ des doses à 0,4 g /kg.
-↑ [Hb] dans les 72h suivant l’arrêt du
ttt
IRA : insuffisance rénale aiguë
AHAI : anémie hémolytique autoimmune
ttt = traitement
Bibliographie
1. Flores G, Cunningham-Rundles C, Newland AC, Bussel JB. Efficacy of intravenous immunoglobulin in the treatment of
autoimmune hemolytic anemia: results in 73 patients. Am J Hematol. 1993 Dec;44(4):237-42.
2. Bussel JB, Cunningham-Rundles C, Abraham C. Intravenous treatment of autoimmune hemolytic anemia with very high
dose gammaglobulin. Vox Sang. 1986;51(4):264-9.
3. Mitchell CA, Van der Weyden MB, Firkin BG. High dose intravenous gammaglobulin in Coombs positive hemolytic anemia.
Aust N Z J Med. 1987 Jun;17(3):290-4.
4. Hilgartner MW, Bussel J.Use of intravenous gamma globulin for the treatment of autoimmune neutropenia of childhood and
autoimmune hemolytic anemia. Am J Med. 1987 Oct 23;83(4A):25-9
5. Richmond GW, Ray I, Korenblitt A. Initial stabilization preceding enhanced hemolysis in autoimmune hemolytic anemia
treated with intravenous gammaglobulin. J Pediatr. 1987 Jun;110(6):917-9 : No abstarct available
6. King KE. Review: pharmacologic treatment of warm autoimmune hemolytic anemia.Immunohematol. 2007;23(3):120-9. No
abstract available
7. Macintyre EA, Linch DC, Macey MG, Newland AC. Successful response to intravenous immunoglobulin in autoimmune
haemolytic anaemia. Br J Haematol. 1985 Jun;60(2):387-8. No abstract available
8. Oda H, Honda A, Sugita K, Nakamura A, Nakajima H. High-dose intravenous intact IgG infusion in refractory autoimmune
hemolytic anemia (Evans syndrome). J Pediatr. 1985 Nov;107(5):744-6. No abstract available.
9. Blouin P, Auvrignon A, Pagnier A, Thuret I, Antoni G, Bader-Meunier B, Le Deist F, Chastagner P, Aladjidi N, Pellier I,
Bertrand Y, Behar C, Landmann-Parker J, Leverger G, Perel Y. Evans'syndrome: a retrospective study from the ship (French
Society of Pediatric Hematology and Immunology) (36 cases). Arch Pediatr. 2005 Nov;12(11):1600-7.
10. Besa EC. Rapid transient reversal of anemia and long-term effects of maintenance intravenous immunoglobulin for
autoimmune hemolytic anemia in patients with lymphoproliferative disorders. Am J Med. 1988 Apr;84(4):691-8
11. Bolis S, Marozzi A, Rossini F, Casaroli I, Pogliani EM, Corneo G. High dose intravenous immunoglobulin (IVIgG) in Evans'
syndrome.Allergol Immunopathol (Madr). 1991 Sep-Oct;19(5):186
12. Majer RV, Hyde RD. High-dose intravenous immunoglobulin in the treatment of autoimmune haemolytic anaemia.
Clin Lab Haematol. 1988;10(4):391-5.
13. Salama A, Mahn I, Neuzner J, Graubner M, Mueller-Eckhardt C. IgG therapy in autoimmune haemolytic anaemia of warm
type. Blut. 1984 Jun;48(6):391-2.
Résumés-abstracts
Flores G, Cunningham-Rundles C, Newland AC, Bussel JB. Efficacy of intravenous immunoglobulin in the
treatment of autoimmune hemolytic anemia: results in 73 patients. Am J Hematol. 1993 Dec;44(4):237-42.
To determine whether warm-antibody autoimmune hemolytic anemia (AIHA) responds to treatment with
intravenous gammaglobulin (IVGG), we conducted separate pilot studies at three institutions enrolling a total of 37
patients. We combined these results with a review of 36 cases of AIHA treated with IVGG reported in the
literature. Sixteen clinical variables were examined to determine associations with response to IVGG. Overall, 29
of 73 patients (39.7%) responded to IVGG therapy. Two variables were strongly related to a good response to
IVIG: the presence of hepatomegaly (with and without splenomegaly) and a low pre-treatment hemoglobin. A
127
trend towards a better response was observed in the 11 children. Overall, IVGG provided acute benefit in only 1/3
of patients and therefore cannot be recommended as standard therapy for AIHA. It may, however, be useful as
adjunctive treatment in selected cases, such as in those with a pre-treatment hemoglobin < 6-7 gm/dl or those
with hepatomegaly, and in clinical settings where the toxicity of other treatments may be an important
consideration.
Bussel JB, Cunningham-Rundles C, Abraham C. Intravenous treatment of autoimmune hemolytic anemia with
very high dose gammaglobulin. Vox Sang. 1986;51(4):264-9.
Autoimmune hemolytic anemia (AIHA) has been considered to be unresponsive to intravenous gammaglobulin
(IVGG) at the doses that are effective in immune thrombocytopenic purpura and autoimmune neutropenia (usually
2 g/kg total dose). This study reports the use of a higher dose (5 g/kg total dose over 5 days) in four severe cases
of AIHA which resulted in a sustained remission in two patients, a transient response in the third, and a failure in
the forth patient. These data suggest that larger quantities of IVGG may be needed in this disease, possibly
because the reticuloendothelial system appears to be enlarged in AIHA patients.
Mitchell CA, Van der Weyden MB, Firkin BG.High dose intravenous gammaglobulin in Coombs positive hemolytic
anemia. Aust N Z J Med. 1987 Jun;17(3):290-4.
Four patients with warm type autoimmune hemolytic anemia who failed to respond to steroid therapy received
high dose intravenous gammaglobulin (0.2-0.4 g/kg daily) for five days. In one patient hemolysis occurred in
association with non-Hodgkin'
s lymphoma and in the others the cause of the hemolysis was not established; two
patients had prior splenectomy. A response to gammaglobulin therapy, demonstrable by a rise in or stabilisation
of hemoglobin levels, a decrease in elevated serum bilirubin and lactate dehydrogenase levels, or prolongation of
a shortened red cell (51Cr) survival, was observed in three patients. In two of these patients the effect of
gammaglobulin therapy was temporary but allowed for splenectomy to proceed in one patient, without blood
transfusion. The third patient continued to improve after cessation of gammaglobulin treatment. These findings
suggest that high dose intravenous gammaglobulin may temporarily ameliorate hemolysis in some individuals
with warm type immune hemolytic anemia, and may be a useful adjunct to steroids immediately before
splenectomy.
Hilgartner MW, Bussel J. Use of intravenous gamma globulin for the treatment of autoimmune neutropenia of
childhood and autoimmune hemolytic anemia. Am J Med. 1987 Oct 23;83(4A):25-9.
Intravenous gamma globulin (IVIG) was used to treat autoimmune neutropenia of childhood and autoimmune
hemolytic anemia, two autoimmune disorders not previously treated with this modality. Six children younger than
two years of age, who presented with severe infections and persistent absolute neutrophil counts (300/mm3),
were treated with 1 g of gamma globulin per kilo body weight until counts reached more than 1,000/mm3. The
average response occurred with a dose of 3.0 g/kg within five to seven days and lasted an average of 14 days
before counts decreased to baseline levels. Four patients with autoimmune hemolytic anemia were also treated
with IVIG, 1 g/kg for five to seven days (average dose of 5 g/kg), for severe Coombs'
-positive hemolytic anemia.
Response of the hemolytic anemia to IVIG was excellent in one patient and good in two patients. No response
occurred in the fourth patient. Response was slower in these patients than in patients treated for immune
thrombocytopenic purpura (ITP). The average total amount of gamma globulin required for a response is
markedly different: 1 g/kg for ITP, 3.0 g/kg for autoimmune neutropenia, and 5 g/kg for hemolytic anemia.
Possible mechanisms of action include blockade of reticuloendothelial system Fc receptors, suppression of
autoantibody production, and/or interference in the binding of autoantibodies to target cells.
Blouin P, Auvrignon A, Pagnier A, Thuret I, Antoni G, Bader-Meunier B, Le Deist F, Chastagner P, Aladjidi N,
Pellier I, Bertrand Y, Behar C, Landmann-Parker J, Leverger G, Perel Y.Evans'syndrome: a retrospective study
from the ship (French Society of Pediatric Hematology and Immunology) (36 cases) Arch Pediatr. 2005
Nov;12(11):1600-7.
Evans'Syndrome (ES) is defined as the combination of immune thrombocytopenia (ITP) and autoimmune
haemolytic anemia (AIHA), in the absence of any known underlying etiology. Pathophysiology, epidemiology and
outcome remain unclear. POPULATION: Thirty-six children (20 male, 16 female), who were diagnosed in the
SHIP french centres (Société d'
hématologie et d'
immunologie pédiatrique) between 1990 and 2002 with ES, were
included in this retrospective study. RESULTS: Median age at diagnosis was 4 years. In 21 children, ES occurred
in the setting of consanguinity, family history of autoimmune/inflammatory disease, associated autoimmune
disorder or immunoregulatory abnormalities (serum imunoglobulins, peripheral blood lymphocytes subsets, low
level of the C3-C4 complement components, nuclear antibodies). Several successive treatments were used in this
serie (median: 3, range: 0-10) including corticosteroid therapy (35/36), intravenous immunoglobulins (32/36),
128
immunosuppressive agents (14/36), splenectomy (9/36) and anti CD 20 monoclonal antibodies (6/36). Patients
with a low level of serum immunoglobulins were more often non-responders to corticosteroidtherapy/intravenous
immunoglobulins and required more frequently further therapy (P=0.03). Three patients died (intracranial
bleeding, N=2, Guillain-Barre syndrome; N=1). CONCLUSION: ES was a severe, life-threatening disease,
requiring aggressive immunosuppressive therapy in as many as half the patients. Our forthcoming study aims to
(i) describe homogeneously-studied and prospectively-analysed cohort of childhood ES, (ii) separate ES from
specific immune deficiency (especially fas gene mutations), generalised autoimmune/inflammatory disorders and
genetic diseases, (iii) identify well-defined ES subsets, (iv) establish prognostic factors and optimal treatment
within these subsets.
Besa ECRapid transient reversal of anemia and long-term effects of maintenance intravenous immunoglobulin for
autoimmune hemolytic anemia in patients with lymphoproliferative disorders. . Am J Med. 1988 Apr;84(4):691-8
Seven patients with autoimmune hemolytic anemia (AIHA) associated with an underlying lymphoproliferative
disorder were treated with intravenous immunoglobulin. Five patients with chronic lymphocytic leukemia, a patient
with Hodgkin'
s lymphoma with severe AIHA associated with a "warm" IgG antibody, and a patient with nonHodgkin'
s lymphoma with an IgM "cold" antibody were treated with intravenous immunoglobulin G (0.4 g/kg) daily
for five doses followed by maintenance therapy every 21 to 28 days if evidence of recurrence was noted. Two
additional patients with refractory chronic lymphocytic leukemia and hypogammaglobulinemia were given
maintenance therapy with intravenous immunoglobulin G every 21 days for previously recurrent AIHA and
infections. Hematocrit levels of patients with AIHA stabilized followed by a gradual improvement at 21 days after
intravenous immunoglobulin G infusion without steroids. Treatment with steroids and intravenous immunoglobulin
G resulted in faster and higher increments in hematocrit levels in these patients. Other patients who had partial
responses to steroids showed further improvement in their hematocrit levels by the addition of intravenous
immunoglobulin G. Another patient with a cold agglutinin disease was refractory to intravenous immunoglobulin G
therapy. Five patients with chronic lymphocytic leukemia and acute AIHA and two patients with previous
recurrences of AIHA required maintenance intravenous immunoglobulin G every 21 days. All seven patients
except one did not have any episodes of AIHA from six months to as long as four years while receiving the threeweek intravenous immunoglobulin G therapy. These observations indicate a role for intravenous immunoglobulin
G in the management of IgG-mediated but not IgM-associated autoimmune hemolysis in immunocompromised
patients with lymphoproliferative diseases.
Argiolu F, Diana G, Arnone M, Batzella MG, Piras P, Cao A.High-dose intravenous immunoglobulin in the
management of autoimmune hemolytic anemia complicating thalassemia major. Acta Haematol. 1990;83(2):65-8.
Patients with thalassemia major due to red blood cell autoantibodies may develop an increase in transfusional
blood consumption. In this study we report the results of treatment with high intravenous immunoglobulin (Ig) in 4
patients who developed an increase in blood consumption related to the presence of autoantibodies of defined or
undefined specificities. Three patients showed a normalization of the blood consumption. No adverse effects were
detected. These results indicate that high-dose intravenous Ig therapy is indicated in patients with thalassemia
major manifesting an increase in blood consumption following the development of red cell autoantibodies.
Majer RV, Hyde RD. High-dose intravenous immunoglobulin in the treatment of autoimmune haemolytic anaemia.
Clin Lab Haematol. 1988;10(4):391-5.
Conventional doses of intravenous immunoglobulin (i.v. Ig) (0.4 g/kg/day for 5 days) commonly produce a
remission in immune thrombocytopenia (ITP) but have only rarely been successful in autoimmune haemolytic
anaemia (AIHA). There are a few reports of higher doses of i.v. Ig being more effective in AIHA. We have treated
two patients with AIHA with high-dose i.v. Ig (0.5 g/kg/day for 5 days). In one patient with an associated ITP a
prompt rise in platelet count but no change in Hb concentration occurred. The second patient with AIHA
associated with chronic lymphatic leukaemia showed a prompt response, with a rise in Hb concentration and fall
in plasma bilirubin. The poor response to i.v. Ig seen in AIHA may be related to the expansion of the reticuloendothelial system seen in AIHA but not ITP. Clearance of antibody-coated red cells and platelets may occur at
different rates and/or sites in the reticulo-endothelial system and this may account for the differential response
seen in case 1. Higher doses of i.v. Ig, in the range 0.5-1 g/kg/day for 5 days, are required in AIHA, particularly if
significant splenomegaly is present, and may be effective in refractory cases.
Salama A, Mahn I, Neuzner J, Graubner M, Mueller-Eckhardt C. IgG therapy in autoimmune haemolytic anaemia
of warm type. Blut. 1984 Jun;48(6):391-2.
129
Three patients with autoimmune haemolytic anaemia of warm type were treated with high doses of intravenous
immunoglobulin (Sandoglobulin). The therapy was ineffective in all three cases. The possible reasons for this
therapeutic failure are discussed.
130
•
Avortements précoces récidivants en dehors du syndrome des
antiphospholipides et des FIV
Les fausses couches spontanées peuvent être primaires (sans enfant vivant déjà né) ou secondaires
(avec enfant vivant déjà né). Elles sont précoces si la mort embryonnaire intervient avant la douzième
semaine d'
aménorrhée (cas le plus fréquent), au-delà on parle de fausses couches spontanées
tardives, puis de mort fœtale intra-utérine. On parle de maladie abortive (ou fausses couches
spontanées à répétitions) après trois accidents spontanés successifs chez la même femme même en
l'
absence de changement de procréateur
Cas général
On dispose d’une méta-analyse Cochrane de bonne qualité qui concerne 7 essais contre placebo
ayant inclus 303 patientes et ne suggère aucune efficacité des IgIV dans la prévention secondaire des
avortements précoces récidivants (OR=0.98 [0.61, 1.58]), bien que l’intervalle de confiance soit
compatible avec une efficacité. Les autres études sont soit présentes dans la méta-analyse, soit non
randomisées.
Après FIV
Une méta-analyse de 3 essais montre une augmentation significative du nombre de naissance par
rapport au placebo lorsqu’on prend comme unité statistique la patiente. Cependant, le résultat devient
moins convainquant lorsqu’on tient compte du nombre d’embryons transplantés.
Effet des IgIV dans les avortements précoces récidivants
Auteurs
Type d’étude
Posologie
Résultats
Porter
(2006)
Cochrane
20 essais
IgIV
% de bébés vivants : NS par rapport aux
groupes contrôles
Hutton
(2006)
Revue de 8 essais :
N = 442
IgIV
Daya
(1998)
Méta-analyse :
IgIV
4 essais randomisés : IgIV versus
placebo
Perino
(1997)
N = 46
Femmes ayant eu au moins 3
fausses-couches (causes autoimmunes exclues)
N = 34 femmes ayant eu des
fausses-couches
après
une
naissance ou une fausse-couche
au bout du 2ème trimestre de
grossesse
% de naissance : NS versus placebo chez les
femmes ayant eu des fausses-couches
récidivantes primaires
% de naissance : S chez des femmes ayant eu
des fausses-couches secondaires
% de succès de grossesse :
. 2 études : NS
. 2 études : S mais en excluant les faussescouches avec une cause évidente
% de grossesses : NS
. IgIV : 68%
. Pla : 79%
Christian
sen
(1995)
Christian
sen
(2002)
N = 58
au moins 4 fausses-couches
Carp
(2001)
Rétrospective
Comparative
N = 76
IgIV :
25 g/j pdt 2j :
n = 22 à partir
S5-7 de grossesse
puis une dose à S8
IgIV :
35 g pdt 2 sem (S5S6) puis 25 g de S7
à S26 et 30 g de
S28 à S34
% de naissance : NS
. IgIV : 52.9%
. Pla : 29.4%
Dans le sous-groupe de femmes avec des
fausses-couches secondaires (n = 24) : NS
. IgIV : 64.2%
. Pla : 20%
IgIV :
% de naissance :
n = 29
- IgIV : 50%
0.8 g/kg jusqu’à S20 - Pla : 23 % : NS
de grossesse puis
1g/kg de S20 à S26 Si on considère uniquement les femmes ayant
eu des fausses-couches secondaires : S
. IgIV : n = 58%
. Pla : n = 24 %
IgIV :
% de naissance :
0.4g/kg pdt la phase 49% versus 31% chez des contrôles :
folliculaire
131
Auteurs
Type d’étude
Posologie
Résultats
> 5 fausses-couches dues à une
immunisation
des
leucocytes
paternels ou exprimant des AC
anti-complément paternel
Groupe contrôle :
n = 74 femmes idem (base de
données)
Bibliographie
1. Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for recurrent miscarriage.Cochrane Database Syst Rev. 2006 Apr
19;(2):CD000112
2. Hutton B, Sharma R, Fergusson D, Tinmouth A, Hebert P, Jamieson J, Walker M. Use of intravenous immunoglobulin for
treatment of recurrent miscarriage: a systematic review. BJOG. 2007 Feb;114(2):134-42.
3. Daya S, Gunby J, Clark DA. Intravenous immunoglobulin therapy for recurrent spontaneous abortion: a meta-analysis.
Am J Reprod Immunol. 1998 Feb;39(2):69-76.
4. Christiansen OB, Mathiesen O, Husth M, Rasmussen KL, Ingerslev HJ, Lauritsen JG, Grunnet N. Placebo-controlled trial of
treatment of unexplained secondary recurrent spontaneous abortions and recurrent late spontaneous abortions with i.v.
immunoglobulin. Hum Reprod. 1995 Oct;10(10):2690-5
5. Perino A, Vassiliadis A, Vucetich A, Colacurci N, Menato G, Cignitti M, Semprini AE. Short-term therapy for recurrent abortion
using intravenous immunoglobulins: results of a double-blind placebo-controlled Italian study.
Hum Reprod. 1997 Nov;12(11):2388-92
6. Carp HJ, Toder V, Gazit E, Ahiron R, Torchinski A, Mashiach S, Shoenfeld Y. Further experience with intravenous
immunoglobulin in women with recurrent miscarriage and a poor prognosis. Am J Reprod Immunol. 2001 Oct;46(4):268-73.
Résumés-abstracts
Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev.
2006 Apr 19;(2):CD000112
BACKGROUND: Because immunological aberrations might be the cause of miscarriage in some women, several
immunotherapies have been used to treat women with otherwise unexplained recurrent pregnancy loss.
OBJECTIVES: The objective of this review was to assess the effects of any immunotherapy, including paternal
leukocyte immunization and intravenous immune globulin on the live birth rate in women with previous
unexplained recurrent miscarriages. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth
Group Trials Register (December 2005), the Cochrane Central Register of Controlled Trials (The Cochrane
Library 2004, Issue 3), MEDLINE (1966 to September 2004) and EMBASE (1980 to September 2004).
SELECTION CRITERIA: Randomized trials of immunotherapies used to treat women with three or more prior
miscarriages and no more than one live birth after, in whom all recognised non-immunologic causes of recurrent
miscarriage had been ruled out and no simultaneous treatment was given. DATA COLLECTION AND ANALYSIS:
The review author and the two co-authors independently extracted data and assessed study quality for all studies
considered for this review. MAIN RESULTS: Twenty trials of high quality were included. The various forms of
immunotherapy did not show significant differences between treatment and control groups in terms of subsequent
live births: paternal cell immunization (12 trials, 641 women), Peto odds ratio (Peto OR) 1.23, 95% confidence
interval (CI) 0.89 to 1.70; third party donor cell immunization (three trials, 156 women), Peto OR 1.39, 95% CI
0.68 to 2.82; trophoblast membrane infusion (one trial, 37 women), Peto OR 0.40, 95% CI 0.11 to 1.45;
intravenous immune globulin, Peto OR 0.98, 95% CI 0.61 to 1.58. AUTHORS'CONCLUSIONS: Paternal cell
immunization, third party donor leukocytes, trophoblast membranes, and intravenous immune globulin provide no
significant beneficial effect over placebo in improving the live birth rate.
132
Hutton B, Sharma R, Fergusson D, Tinmouth A, Hebert P, Jamieson J, Walker M. Use of intravenous
immunoglobulin for treatment of recurrent miscarriage: a systematic reviewBJOG. 2007 Feb;114(2):134-42.
BACKGROUND: Intravenous immunoglobulin (IVIG) is a fractionated blood product whose off-label use for
treating a variety of conditions, including spontaneous recurrent miscarriage, has continued to grow in recent
years. Its high costs and short supply necessitate improved guidance on its appropriate applications.
OBJECTIVE: We conducted a systematic review of randomised controlled trials evaluating IVIG for treatment of
spontaneous recurrent miscarriage. SEARCH STRATEGY: A systematic search strategy was applied to Medline
(1966 to June 2005) and the Cochrane Register of Controlled Trials (June 2005). SELECTION CRITERIA: We
included all randomised controlled trials comparing all dosages of IVIG to placebo or an active control. DATA
COLLECTION AND ANALYSIS: Two investigators independently extracted data using a standardised data
collection form. Measures of effect were derived for each trial independently, and studies were pooled based on
clinical and methodologic appropriateness. MAIN RESULTS: We identified eight trials involving 442 women that
evaluated IVIG therapy used to treat recurrent miscarriage. Overall, IVIG did not significantly increase the odds
ratio (OR) of live birth when compared with placebo for treatment of recurrent miscarriage (OR 1.28, 95% CI 0.782.10). There was, however, a significant increase in live births following IVIG use in women with secondary
recurrent miscarriage (OR 2.71, 95% CI 1.09-6.73), while those with primary miscarriage did not experience the
same benefit (OR 0.66, 95% CI 0.35-1.26). AUTHOR'
S CONCLUSIONS: IVIG increased the rates of live birth in
secondary recurrent miscarriage, but there was insufficient evidence for its use in primary recurrent miscarriage.
Daya S, Gunby J, Clark DA. Intravenous immunoglobulin therapy for recurrent spontaneous abortion: a metaanalysis. Am J Reprod Immunol. 1998 Feb;39(2):69-76.
PROBLEM: Published randomized trials of the use of intravenous immunoglobulins (IVIG) as a treatment for
recurrent spontaneous abortion (RSA) have produced conflicting results. The purpose of this study was to
conduct a systematic review of the current evidence to evaluate the effectiveness of IVIG for RSA. METHOD OF
STUDY: After a thorough search of the literature, four randomized, double-blind trials comparing IVIG with
placebo for treatment of RSA were included in the meta-analysis. Live birth rates for each treatment group were
extracted, and the overall odds ratio (OR) and absolute treatment effect for IVIG were calculated. RESULTS: Two
of the trials showed an increase in successful pregnancy outcome with IVIG treatment and two did not. The
overall OR was 1.48 (95% CI, 0.84-2.60) in favor of IVIG, with an absolute treatment effect of 10.1% (95% CI, 4.8-24.6). Excluding pregnancy failures with an obvious cause produced statistically significant results, but this
approach may be subject to bias. CONCLUSION: This meta-analysis suggests that IVIG may have a role in the
treatment of recurrent abortion, but as yet no conclusive evidence is available.
Christiansen OB, Mathiesen O, Husth M, Rasmussen KL, Ingerslev HJ, Lauritsen JG, Grunnet N.Placebocontrolled trial of treatment of unexplained secondary recurrent spontaneous abortions and recurrent late
spontaneous abortions with i.v. immunoglobulin. Hum Reprod. 1995 Oct;10(10):2690-5
The aim of this trial was to investigate whether infusions of i.v. immunoglobulins (Ig) to women with secondary
recurrent spontaneous abortions and recurrent second trimester spontaneous abortions can increase the rate of
successful pregnancy. In a prospective, double-blind, placebo-controlled trial, infusions of i.v. Ig (Nordimmun) or
placebo were given during pregnancy to 34 women with a history of either unexplained recurrent spontaneous
abortion subsequent to a birth or including at least one second trimester miscarriage. The success rate was
52.9% in the i.v. Ig group compared with 29.4% in the placebo group (not significantly different, therapeutic gain
23.5%, 95% confidence interval -8.6 to 55.7%). No changes in autoantibody concentrations or major lymphocyte
subsets were induced by i.v. Ig treatment. In conclusion, an expected 55% therapeutic gain of i.v. Ig in recurrent
spontaneous abortion could not be confirmed using the treatment regimen tested. However, to determine whether
the trend of therapeutic gain of i.v. Ig in these women may be statistically significant, a larger trial is in progress.
Christiansen OB, Pedersen B, Rosgaard A, Husth M. A randomized, double-blind, placebo-controlled trial of
intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women
with secondary recurrent miscarriage. Hum Reprod. 2002 Mar;17(3):809-16
BACKGROUND: Previous trials of intravenous immunoglobulin (IvIg) treatment of women with recurrent
miscarriage (RM) have provided diverging results. This may be due to different inclusion criteria and suboptimal
treatment protocols in some trials. METHODS: According to a computer-generated list, 58 women with at least
four unexplained miscarriages were randomly assigned to receive infusions of high doses of IvIg or placebo
starting as soon as the pregnancy test was positive. RESULTS: In the intention-to-treat analysis, a 45% live birth
rate was found in both allocation groups. In patients with secondary RM, 50% in the treatment group and 23% in
the placebo group had successful pregnancies (P = not significant). When data from the present and a previous
placebo-controlled trial of the same treatment were combined, 15/26 (58%) of the patients with secondary RM in
the treatment group versus 6/26 (24%) in the placebo group had successful outcomes (P < 0.02). Only 7% of the
karyotyped abortuses were abnormal. CONCLUSIONS: IvIg may improve pregnancy outcome in patients with
133
secondary RM. A new placebo-controlled trial focusing on this subgroup should be conducted to confirm the
results.
Perino A, Vassiliadis A, Vucetich A, Colacurci N, Menato G, Cignitti M, Semprini AEShort-term therapy for
recurrent abortion using intravenous immunoglobulins: results of a double-blind placebo-controlled Italian study. .
Hum Reprod. 1997 Nov;12(11):2388-92
It is still unclear whether i.v. immunoglobulins (Ig) can facilitate the reproductive prognosis of women who have
suffered recurrent pregnancy loss. We report the results of a multicentre placebo-controlled study on the effect of
Ig administration on pregnancy outcome in 46 women who had suffered at least three recurrent miscarriages. All
were screened to exclude chromosomal or Müllerian abnormalities, the presence of antinuclear antibodies, lupus
anticoagulant (LA) or elevated titres of anticardiolipin antibodies which may have revealed an underlying
autoimmune problem. To avoid a selection bias towards ongoing pregnancies, i.v. Ig or placebo were
administered between weeks 5 and 7 of gestation for 2 consecutive days as soon as each woman knew she was
pregnant and before embryonic heart activity could be detected. A further infusion was administered at week 8
when ultrasonography confirmed an ongoing embryonic development. In all, 68% of the women who received Ig
went to term versus 79% of those who received a placebo (not significant), with no significant differences in the
pregnancy course or the perinatal outcome. These results suggest either that women with recurrent miscarriages
who have no recognized cause of pregnancy loss have a good reproductive prognosis without any treatment or
that the emotional care associated with the administration of a placebo can indirectly facilitate the progression of
pregnancy.
Carp HJ, Toder V, Gazit E, Ahiron R, Torchinski A, Mashiach S, Shoenfeld Y. Further experience with intravenous
immunoglobulin in women with recurrent miscarriage and a poor prognosis. Am J Reprod Immunol. 2001
Oct;46(4):268-73.
PROBLEM: Women with three or more unexplained miscarriages have a 60% chance of a subsequent live birth.
Intravenous immunoglobulin (IVIG) has not been conclusively shown to improve this prognosis. This study
assessed the effect of IVIG in patients expected to have a poor outcome if untreated, i.e. women with five or more
abortions, who have aborted after paternal leukocyte immunization or who continue to abort despite expressing
anti-paternal complement dependent antibody. METHODS: Seventy-six women received IVIG in a dose of 400
mg/kg body weight, in one day (total 30-45 g) in the follicular phase of a cycle in which pregnancy was planned. A
booster dose was administered when pregnancy was diagnosed. Their results were compared to an untreated
control group of 74 women. RESULTS: Thirty-five (49%) pregnancies in treated women have resulted in live
births or passed their previous stages of abortion compared to 23 (31%) in control patients (P = 0.04).
CONCLUSIONS: These figures indicate that IVIG may prevent further miscarriages in this poor prognosis
population. These figures are especially significant considering the doubt concerning the efficacy of IVIG in
patients with three miscarriages and therefore a relatively good prognosis.
134
•
Syndrome d’activation macrophagique (SAM) secondaire à une
pathologie infectieuse et maladie de Still compliquée de SAM.
Le SAM est classé dans les désordres histiocytaires qui comprennent les maladies du macrophage.
Deux groupes de SAM sont individualisés : les SAM primaires ou génétiquement déterminés, rares
chez l’adulte dont le plus fréquent est la lymphohistiocytose hémophagocytaire familiale et les SAM
secondaires ou acquis concernant les enfants et les adultes compliquant de nombreuses pathologies :
infections, néoplasies, maladies inflammatoires ou auto-immunes systémiques ou médicaments. Le
SAM qu’il soit familial ou acquis est la résultante d’une réponse immune hautement stimulée mais
inefficace, mettant parfois en jeu le pronostic vital si elle n’est pas freinée par un traitement approprié.
Les traitements de référence sont la corticothérapie et la ciclosporine.
Pour évaluer l’effet des IgIV dans cette pathologie, on ne dispose que de quelques petites études non
contrôlées. Les situations cliniques étaient extrêmement hétérogène, de même que la prise en charge.
Les succès du traitement IgIV sont de fréquence insuffisante pour suggérer une efficacité.
Il est noté la grande difficulté de monter une étude randomisée chez l’adulte.
Effet des IgIV dans le syndrome d’activation macrophagique
Auteurs
Veerakul
(2002)
Ningsanond
(2000)
Emmenegger
(2001)
Asci
(2006)
Type d’étude
Posologie
Suivi
Ouverte
N = 52 enfants dont IgIV
15 ont un SAM
secondaire à une
infection
Ouverte
10 ans
N = 50 enfants âgés IgIV :
de 2 mois à 14 ans.
N =8
- 0.5 g/kg/j pdt 5 j (4/8)
-2 g/kg pdt 1 j (4/8)
Ouverte
N = 20
IgIV :
adultes avec un taux
de 0.4g/kg/j pdt 1j à
de ferritine > 10 000
1g/Kg/j pdt 3 j
µg/L
Rétrospective
>30 M
N=13
IgIV + Antibiotique
Critères
d’évaluation
Nombre de décès
Nombre
survivants
Rétrospective
SAM II
IgIV :
N=17 dont 9 de
causes infectieuse
1.6 g/kg 1 à 2 cures de 1
à6j
1/ 15 décès
de 15/50 : 30%
Décès dans les 3 semaines
après traitement
Amélioration et
15/20 : amélioration partielle
↓ taux sérique de ou retardée avec ↓
ferritine
taux sérique de ferritine
5/20 : pas d’amélioration
- Gpe sans IgIV :
. guérisons : 2
. décès : 2 patients résistants
aux ttt antibio et dont l’HHS
est liée à une inf (tuberculose
& CMV)
Gpe IgIV : n = 6
âge : 38.6 +/- 10 ans
HHS + greffe rénale
Larroche
(2000)
Résultats
-Signes cliniques
+ corticoides
- Gpe avec IgIV :
. guérison : 4/6
- Efficacité des IgIV > dans
les
SAM
d’étiologie
infectieuse (78% vs 37.5% ;
NS)
- Efficacité des IgIV pour les
SAM
toutes
causes
confondues : 59 %
+ antiviraux
Chen
(1995)
Rétrospective
N=17
EBV ou HHV-6
8 mois - Paramètres
à 2ans hépatiques et
2/3
hématologiques
Fièvre
. N = 9 : IgIV seules :
400 mg/kg / j pdt 5 j ou
1g/kg/j pdt 2 j
IgIV et/ou etoposide
- IgIV seules :
2/9 : RC
5/9 : RP
2/9 : pas de réponse
- IgIV + Etoposide :
5/ 7 décès (gpe IgIV puis
etoposide)
+ 2 /3 décès (grpe IgIV +
135
Auteurs
Type d’étude
Posologie
. N = 15 : etoposide
7/15 :
IgIV
puis
etoposide ;
Suivi
Critères
d’évaluation
Résultats
etoposide)
survie de 8 patients dont 2
RC avec Etoposide seule
3/15 : IgIV + Etoposide
Stephan
(2001)
Rétrospective
N = 24
Echec : 4/4
IgIV :
N=4
Bibliographie
1. Veerakul G, Sanpakit K, Tanphaichitr VS, Mahasandana C, Jirarattanasopa N. Secondary hemophagocytic
lymphohistiocytosis in children: an analysis of etiology and outcome. J Med Assoc Thai. 2002 Aug;85 Suppl 2:S530-41.
2. Ningsanond V. Infection associated hemophagocytic syndrome: a report of 50 children. J Med Assoc Thai. 2000
Oct;83(10):1141-9
3. Emmenegger U, Frey U, Reimers A, Fux C, Semela D, Cottagnoud P, Spaeth PJ, Neftel KA. Hyperferritinemia as indicator for
intravenous immunoglobulin treatment in reactive macrophage activation syndromes.
Am J Hematol. 2001 Sep;68(1):4-10.
4.. Asci G, Toz H, Ozkahya M, Cagirgan S, Duman S, Sezis S, Ok E. HIGH-DOSE IMMUNOGLOBULIN THERAPY IN RENAL transplant
recipients with hemophagocytic histiocytic syndrome. J Nephrol. 2006 May-Jun;19(3):322-6.
5. Larroche C, Bruneel F, André MH, Bader-Meunier B, Baruchel A, Tribout B, Genereau T, Zunic P; Comité d'
Evaluation et de
Diffusion des Innovation Technologiques (CEDIT). Intravenously administered gamma-globulins in reactive hemaphagocytic
syndrome. Multicenter study to assess their importance, by the immunoglobulins group of experts of CEDIT of the AP-HP Ann
Med Interne (Paris). 2000 Nov;151(7):533-539.
6. Stéphan JL, Koné-Paut I, Galambrun C, Mouy R, Bader-Meunier B, Prieur AM. Reactive haemophagocytic syndrome in
children with inflammatory disorders. A retrospective study of 24 patients. Rheumatology (Oxford). 2001 Nov;40(11):1285-92.
7. Chen RL, Lin KH, Lin DT, Su IJ, Huang LM, Lee PI, Hseih KH, Lin KS, Lee CY. Immunomodulation treatment for childhood
virus-associated haemophagocytic lymphohistiocytosis. Br J Haematol. 1995 Feb;89(2):282-90
8. Emmenegger U, Reimers A, Frey U, Fux Ch, Bihl F, Semela D, Cottagnoud P, Cerny A, Spaeth PJ, Neftel KA. Reactive
macrophage activation syndrome: a simple screening strategy and its potential in early treatment initiation. Swiss Med Wkly.
2002 May 4;132(17-18):230-6.
Résumés-abstracts
Veerakul G, Sanpakit K, Tanphaichitr VS, Mahasandana C, Jirarattanasopa N.Secondary hemophagocytic
lymphohistiocytosis in children: an analysis of etiology and outcome. J Med Assoc Thai. 2002 Aug;85 Suppl
2:S530-41.
Fifty-two pediatric patients were diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH) at the
Department of Pediatrics, Siriraj Hospital between 1989 and 1998. Of these, 15 were infection-associated (IAHS),
25 were malignancy-associated (MAHS) and 12 were idiopathic HLH. Causative organisms for IAHS were
Salmonella (3), Staphylococcus (2), enterobactor (2), dengue virus (3), malaria (2) and one each of Ebstein Barr
virus (EBV), Serratia marcesens and Penicillium maneffei. Unlike those reported in adults and in the Western
literature, 47 of 52 children in the present series were immunocompetent hosts. In addition, the proportion of
MAHS was higher than expected (48.1%). Twenty-two of 25 MAHS presented with hemophagocytic syndrome
and were subsequently found to have malignant diseases. Sixty per cent of MAHS (15 cases) were associated
with non-Hodgkin'
s lymphoma (NHL), mainly T-cell. Other malignancies included acute leukemias (7) MDS (1),
Langerhans cell histiocytosis (1) and histiocytic sarcoma (1). Treatment approaches were specific therapy for
individuals with known causes. Supportive treatment with blood components transfusions, steroid, intravenous
immunoglobulins (IVIG), and chemotherapeutic agents, mainly vinblastine and etoposides, were used in indicated
cases. Of the 52 cases, 15 (28.8%) had a fatal outcome during the acute phase, and other 4 died of their
subsequent malignant diseases. There was a statistically significant association between poorer prognosis and
patients'age < 3 years (p= 0.004) or MAHS (p=0.005). Conclusion: Secondary HLH is not uncommon in Thai
136
children who are immunocompetent. Malignancies, particulary NHL, are highly suspicious especially for cases not
responsive to conventional therapy. Poor prognostic factors are age less than 3 years and MAHS.
137
Ningsanond V. Infection associated hemophagocytic syndrome: a report of 50 children. J Med Assoc Thai. 2000
Oct;83(10):1141-9.
Fifty children were diagnosed with infection associated hemophagocytic syndrome (IAHS) over the 10 year period
from January 1988 through December 1997 at Queen Sirikit National Institute of Child Health, Thailand. Their
ages ranged from 2 months to 14 years (mean 4.14 years). There was no difference in sex. Bacterial,
mycobacterial, viral, fungal and protozoa were the associated infections in some of these patients. Supportive
with specific therapy for the underlying disease was administered aggressively in all patients. Intravenous
immuneglobulin (IVIG) was given in 8 patients. Thirty-five patients (70%) died, mostly as a result of coagulopathy
with multiple organ failure and opportunistic infections. Two patients developed acute lymphoblastic leukemia 25
days and 3 months after recovering from IAHS.
Emmenegger U, Frey U, Reimers A, Fux C, Semela D, Cottagnoud P, Spaeth PJ, Neftel KA. Hyperferritinemia as
indicator for intravenous immunoglobulin treatment in reactive macrophage activation syndromes. Am J Hematol.
2001 Sep;68(1):4-10.
The underlying mechanisms of reactive macrophage activation syndromes (rMAS) are not understood in detail,
and there is no specific treatment. This observational study was prompted by intravenous immunoglobulin (IVIG),
dramatically halting two distinct rMAS episodes in the same patient. We evaluated the potential benefits of IVIG
administration in treating fulminant rMAS and the usefulness of monitoring serum ferritin levels as an indication for
emergency treatment with IVIG. Ten females and 10 males experiencing 22 episodes of rMAS were recruited on
the basis of serum ferritin levels >or=10,000 microg/l and/or direct evidence of haemophagocytosis in 11 intensive
care units in secondary and tertiary care hospitals in Switzerland between October 1993 and May 2000. In
individual patients, serially measured ferritin was closely related to disease activity. Abrupt increases of up to
>100,000 microg/l could be observed within hours. Rapid and profound beneficial effects of emergency IVIG
treatment were seen in 12 episodes of rMAS accompanied by a prompt decrease of serum ferritin. IVIG produced
partial or delayed improvements in 5 patients. No apparent effects were seen in 5 patients. IVIG was only
successful if started early during the ferritin run-up to peak values. In conclusion, IVIG is effective in at least a
subgroup of adult rMAS when started at the beginning of the macrophage activation process. The monitoring of
serum ferritin levels might be helpful in detecting macrophage activation in order to commence IVIG treatment
early enough.
Asci G, Toz H, Ozkahya M, Cagirgan S, Duman S, Sezis S, Ok E. High-dose immunoglobulin therapy in renal
transplant recipients with hemophagocytic histiocytic syndrome. J Nephrol. 2006 May-Jun;19(3):322-6.
BACKGROUND: Hemophagocytic histiocytic syndrome (HHS) generally occurs in immunocompromised patients
and often has a rapidly fatal course. HHS may be cured by treatment of the underlying disorder, especially when it
is triggered by an infection. If no cause has been found, no therapy is known and outcome is poor. The aim of this
study was to investigate the clinical course and response to intravenous immunoglobulin treatment in renal
transplant patients diagnosed with HHS. METHODS: Thirteen patients who were diagnosed with HHS between
1995 and 2003 were retrospectively assessed. The mean age of HHS patients was 38.6 +/- 10 years (5 women, 8
men). RESULTS: Median time to onset of symptoms after renal transplantation was 15.1 +/- 12.1 months (range
0.5-30 months). The first 2 patients in whom no etiologic factor was found were seen before 1998 and died due to
multiorgan failure. HHS was related to an infectious etiology in 6 of 13 patients: tuberculosis (n=3),
cytomegalovirus (CMV) infection (n=2), Escherichia coli (E. coli)-associated septicemia (n=1), but HHS was cured
by antimicrobial therapy in only 2 of them (1 with tuberculosis, the other with E. coli-associated septicemia). After
June 1998, high-dose immunoglobulin (IVIg) therapy was used in 6 patients. HHS was related to an infectious
etiology in 2 patients unresponsive to antimicrobial treatment, and of unknown etiology in 4 patients. All of them
completely recovered. Before 1998, 2 patients unresponsive to antimicrobial therapy (1 with tuberculosis, the
other with CMV) died. They were not given IVIg. CONCLUSIONS: We concluded that when HHS does not
respond to treatment of the underlying infection, or is of unknown etiology in immunocompromised patients, highdose IVIg therapy should be administered.
Larroche C, Bruneel F, André MH, Bader-Meunier B, Baruchel A, Tribout B, Genereau T, Zunic P; Comité
d'
Evaluation et de Diffusion des Innovation Technologiques (CEDIT)Intravenously administered gamma-globulins
in reactive hemaphagocytic syndrome. Multicenter study to assess their importance, by the immunoglobulins
group of experts of CEDIT of the AP-HP . Ann Med Interne (Paris). 2000 Nov;151(7):533-539.
Reactive hemophagocytic syndrome is characterized by systemic proliferation and activation of benign
hemophagocytic cells of the monocyte-macrophage lineage. Treatment should be directed to the etiology, but
successful treatment with high-dose gamma-globulin has been reported, especially in viral-associated
hemophagocytic syndrome. We report 17 patients, of which 9 had infection-associated hemophagocytic
syndrome, all treated with high-dose gamma-globulin. High-dose gamma-globulins appear to be more effective in
138
infection-associated hemophagocytic syndrome, with a mean dose of 1.6gm/kg for one or two cycles. A
multicentric randomized study is required to evaluate high-dose gamma-globulin in the treatment of reactive
hemophagocytic syndrome.
Chen RL, Lin KH, Lin DT, Su IJ, Huang LM, Lee PI, Hseih KH, Lin KS, Lee CY. Immunomodulation treatment for
childhood virus-associated haemophagocytic lymphohistiocytosis. Br J Haematol. 1995 Feb;89(2):282-90.
The Epstein-Barr virus (EBV), or human herpesvirus-6 (HHV-6) associated haemophagocytic lymphohistiocytosis,
has been found prevalent in Taiwan; it affects previously healthy children and is always fatal when treated only
supportively. Recognition of the underlying pathogenesis for this disease prompted adoption of an
immunomodulatory regimen of intravenous immunoglobulin (IVIG) and/or etoposide on 17 such patients treated
between 1990 and 1993. Remarkable improvement in patients'prognoses was demonstrated. Eight patients are
still alive with a median follow-up of 1 year and 2 months post-treatment. Both IVIG and etoposide had positive
immunomodulation effects such as alleviation of fever and normalization of haematological and hepatic
parameters. Sustained complete response was obtained in two of nine cases of EBV-associated diseases treated
with IVIG only. EBV transcripts became undetectable after etoposide and/or IVIG treatment without antiviral
agents. Etoposide given by split-doses schedule appeared to be superior to conventional three-consecutive-days
schedule for both remission induction and disease-free survival. Our preliminary trial apparently provides a
promising improvement in the treatment of this previously fatal disease. IVIG or etoposide is effective in reversing
the process of lymphohistiocytic dysregulation resulting from virus infection of immune cells in this syndrome and
probably helps hosts to control active virus replication in certain cases, through immunomodulation.
Stéphan JL, Koné-Paut I, Galambrun C, Mouy R, Bader-Meunier B, Prieur AM.Reactive haemophagocytic
syndrome in children with inflammatory disorders. A retrospective study of 24 patients. Rheumatology (Oxford).
2001 Nov;40(11):1285-92.
BACKGROUND: The reactive haemophagocytic syndrome (RHS) is a little-known life-threatening complication of
rheumatic diseases in children. It reflects the extreme vulnerability of these patients, especially those with
systemic-onset juvenile chronic arthritis (JCA). This immunohaematological process may be triggered by events
such as herpes virus infection and non-steroidal anti-inflammatory drug therapy. Treatment has not been
standardized. METHODS: We characterized this unusual disorder and determined its incidence by carrying out a
retrospective study of patients identified over a 10-yr period in French paediatric units. RESULTS: Twenty-four
cases (nine males, 15 females) were studied. Eighteen had typical systemic-onset JCA, two had polyarthritis, two
had lupus and two had unclassifiable disorders. Clinical features at diagnosis included high spiking fever (24
patients), enlargement of the liver and spleen (14), haemorrhagic diathesis (six), pulmonary involvement (12) and
neurological abnormalities (coma or seizures) (12). RHS was the first manifestation of systemic disease in three
cases. Admission to intensive care was required in ten cases. Hypofibrinogenaemia, elevated liver enzymes and
hypertriglyceridaemia were found consistently. Phagocytic histiocytes were found in 14 of 17 bone marrow
smears. RHS was presumed to have been precipitated by infection in 11 cases (four Epstein-Barr virus, three
varicella-zoster virus, one parvovirus B19, one Coxsackie virus, one Salmonella, one Pneumocystis carinii) and
by the introduction of medication in three cases (Salazopyrin plus methotrexate; morniflumate; aspirin).
Macrophage activation was indicated by high levels of monokines in the serum of two patients. Twenty patients
had only one episode, three had an early relapse and one patient had two relapses. The treatment regimen was
tailored to each child as the clinical course was variable. There was no response to intravenous immunoglobulins,
which were used in four cases. Intravenous steroids at doses ranging from conventional to pulse
methylprednisolone induced remission in 15 of 21 episodes when used alone as the first-line treatment.
Cyclosporin A was consistently and rapidly effective, both when used as second-line therapy in all seven of the
episodes in which steroids failed and in all five patients who received it as their first-line treatment. This supports
a central role of T lymphocytes in the haemophagocytic syndrome. Two patients died. One patient with lupus died
of congestive fulminant heart failure after 4 days, despite treatment with intravenous steroids and
immunoglobulins, and one patient with systemic-onset JCA died from multiorgan failure despite aggressive
therapy with pulsed steroids and etoposide. CONCLUSIONS: RHS may be a more common complication of
systemic disease in childhood than previously thought. This life-threatening complication should be diagnosed
promptly, as it calls for the immediate withdrawal of potentially triggering medications, anti-infective therapy when
relevant, and urgent immunosuppressive treatment, measures that are very often effective. Cyclosporin A may be
the drug of choice.
Emmenegger U, Reimers A, Frey U, Fux Ch, Bihl F, Semela D, Cottagnoud P, Cerny A, Spaeth PJ, Neftel KA.
Reactive macrophage activation syndrome: a simple screening strategy and its potential in early treatment
initiation. Swiss Med Wkly. 2002 May 4;132(17-18):230-6.
QUESTIONS UNDER STUDY: starting treatment of reactive macrophage activation syndromes as early as
possible (rMAS, haemophagocytic lymphohistiocytosis), e.g., with intravenous immunoglobulins (IVIG), seems to
139
be essential for optimal outcome. However, there is no diagnostic gold standard which reliably indicates need for
early treatment. We used a simple screening strategy consisting of serum ferritin measurements and/or
morphological assessment of haemophagocytosis and compared the studied patient population with published
series. METHODS: Retrospective analysis of clinical and laboratory data of 57 patients experiencing 60 episodes
of rMAS. RESULTS: Screening by serum ferritin measurements and/or morphological assessment of
haemophagocytosis of patients presenting with a systemic inflammatory response syndrome (SIRS) indicates that
rMAS might be considerably more frequent than stated in the literature. Serum ferritin exceeded >10,000 microg/L
in 91% rMAS episodes. Although the patient population studied was otherwise similar in most aspects to the
published rMAS series, the fact that 40% of patients fulfilled the criteria for Still'
s disease (SD) as the disorder
underlying rMAS is remarkable and questions the distinct nature of the two diseases. IVIG responders and nonresponders did not differ regarding their initial characteristics with exception to the timepoint of IVIG
administration, confirming the importance of early treatment initiation. Malignancy-associated rMAS however, has
a poor prognosis and seems to be refractory to manipulation with IVIG in most instances, even when responding
initially. CONCLUSIONS: rMAS has to be considered in patients with a SIRS- or SD-like clinical presentation.
Hyperferritinaemia >or=10,000 microg/l seems to be a good marker for defining patients with or at risk for
developing rMAS and should be completed with a morphological assessment of haemophagocytosis. The
perception of acute SD and rMAS as two distinct entities has to be questioned at least in a subgroup of patients.
140
•
Maladie de Still
La maladie de Still de l’adulte ou débutant à l’âge adulte est un rhumatisme inflammatoire rare,
caractérisé principalement par des pics de fièvre au cours desquels surviennent des éruptions
cutanées accompagnées ou non de douleurs articulaires. Des maux de gorge y sont souvent
associés. La maladie de Still survient le plus souvent chez l’enfant (arthrite chronique juvénile). Il est
probable que la forme apparaissant à l’âge adulte soit une réactivation de la forme juvénile.
Il est difficile d’estimer le nombre de personnes atteintes de cette maladie puisque les manifestations
cliniques peuvent être très variables et les épisodes peu fréquents. La prévalence est d’un peu plus
de 1/100000 adulte. La fréquence est plus grande entre 16 ans et 35 ans avec une légère
prédominance pour les femmes.
Les études trouvées dans la littérature sont anciennes. Chez l’enfant, les 2 seules études
comparatives versus placebo publiées ne mettent pas en évidence d’effet des IgIV dans cette
pathologie. Aucune étude comparative n’a été publiée chez l’adulte.
Effet des IgIV dans la maladie de Still de l’enfant (Arthrite Chronique Juvénile)
Posologie
Suivi
Critères
Résultats
d’évaluation
ère
IgIV:
Giannini Ouverte en 1
4 ans
. Etat clinique Phase 1 :
partie
et - Phase 1 ouverte :
(1996)
- Amélioration clinique : 19/25
comparative
- Arrêt de traitement : 3
1, 5 à 2 g/kg (max : 100
double
aveugle g) 2x/mois pdt les 2
- Non-répondeurs : 3
versus placebo en premiers
mois
puis
ème
2
partie
- Phase 2 : échecs :
1x/mois pdt 6 mois
Phase 1 : N = 25
IgIV : 2/10
enfants de 2 à 23 - Phase 2 en double
Pla : 5/9
ans
aveugle à partir du 3ème
Phase 2 : N = 19 mois : IgIV 1xmois pdt 4
Evolution de la maladie à 4 ans :
NS
répondant au critère mois ou placebo
« amélioration
clinique
importante »
IgIV :
Silverma Comparative
1an
. Etat clinique - Amélioration clinique : NS
double-aveugle
nn
1,5 g/kg (n =14)
. Efficacité
. IgIV : 50%
versus placebo
(1994)
ou placebo (n= 15)
. Activité de . Pla : 27%
N= 31 enfants avec toutes les 2 semaines
- Activité de la maladie : NS
la maladie
- Efficacité : NS
arthrite
juvénile pdt 2 mois puis tous les
réfractaire
mois pdt 4 mois
. IgIV : 4/14 échecs
. Pla : 8/15 échecs
Rétrospective
IgIV :
Uziel
- Nombre de Après 6 mois de traitement :
N= 25
(1996)
1g/kg/j pdt 2j pdt 2 ans
jours
de . 20/25 : ↓ de 50% d’au moins un
Enfants avec arthrite 1.5g/kg/ en une seule
fièvre
des critères d’évaluation
juvénile
fois
toutes
les
2
- Dose de . 5 non répondeurs
semaines pdt 5 M et
prednisone
toutes les 4 semaines
Nombre Après dernière visite :
pdt 6 M puis les doses
d’articulations .11/ 20 répondeurs (rémission)
d’IgIV sont espacées.
actives
. 3/20 : amélioration clinique mais
maladie de Still encore active
. 6/20 : non répondeurs
Ouverte
IgIV :
Prieur
7,5
- Paramètres . 2 décès longtemps après arrêt
N = 16
(1990)
300-400 mg/kg pdt 5 j ans
d’inflammatio de la corticothérapie
Enfants avec arthrite puis 1x/2 sem puis 1x/4
n
Gpe I :
juvénile
sem (1ère année) et 1x/6- Etat clinique . amélioration clinique : 6/8
8 sem (2ème année) puis
. rechute après la fin du ttt: 1/8
1x/8 sem….
Gpe II :
Gpe I : > 1 an de ttt par
. amélioration clinique : 4/ 6
. amélioration S des paramètres
IgIV (1à 5 ans)
Gpe II : ttt par IgIV de
d’inflammation dans la majorité
court terme : 1 à 10 M
des cas
IgIV :
Silverma Ouverte
> 1 an - Etat clinique . Amélioration clinique S : 5/8
N= 8
nn
1mg/kg/j pdt 2j
- dose de . Arrêt corticoïdes : 3/8
141
Auteurs
Type d’étude
Posologie
(1990)
Enfants avec arthrite pdt 6 M pour 6/8 patients
juvénile réfractaire et 10 et 13 M pour 2
aux traitements de patients
ère
ème
1 et de 2
ligne
et/ou les corticoïdes
Tt : traitement
Suivi
Critères
d’évaluation
stéroïdes
- Paramètres
biologiques
Résultats
. ↓ des corticoïdes de 50 % : 3/ 8
. Amélioration des paramètres
biologiques : 7/8
Effet des IgIV dans la maladie de Still de l’adulte
Auteurs
Type d’étude
Vignes
(1998)
Ouverte
N=7
Age moyen : 37.9 ans
Permal
(1995)
Ouverte
N= 7
Mahmud
(1999)
N=1
Femme de 34 ans
Kuek
(2007)
N=1
Homme de 18 ans
Maladie de Still +
myocardite
fulminante
réfractaire aux AINS
Bennett
(2004)
N=1
Homme de 32 ans
Maladie de Still +
péricardite réfractaire
N=1
Femme de 28 ans
enceinte
Liozon
(1999)
Kulke
(1996)
N=1
Femme de 18 ans
Diamond
(1997)
N=1
Homme de 22 ans
Maladie de Still + syndr
urémique hémolytique +
microangiopathie
thrombotique
Réfractaire
aux
corticoïdes
et
plasmaphérèse
Posologie
Critères
d’évaluation
IgIV :
Caractéristiques
2 g/kg pendant 2 à 5 j cliniques
et
toutes les 4 semaines. biologiques
4 à 5 cycles
IgIV :
Rémission
1g/kg/j pdt 2 j
clinique
1 à 8 cures
Résultats
5/7 : répondeurs après 4 à 6 doses
d’IgIV
ème
1 rechute après 5
dose
2 non –répondeurs
Rémission clinique : 7/7
Rechute : 3/7 au bout de 90 j
Rémission se poursuit chez 4/7
pendant 2 à 24 mois (13 mois en
moyenne)
IgIV :
. Etat clinique
2ème jour post IgIV : amélioration de
0.4 mg/kg/j pdt 5 j +
. Paramètres de l’état clinique et des paramètres
Dose de maintien de l’inflammation
: d’inflammation.
prednisolone : 5 mg/j
ESR,
CRP, Maintien de l’état et des paramètres
ferritine
pdt 9 mois
IgIV :
.Paramètres
Maintien de l’état clinique et des
0.4 g/kg/j pdt 6 j
d’inflammation
paramètres
d’inflammation et
Puis étanercept 25 mg . Etat clinique
cardiaques
2x/sem + méthotrexate .
Fonction
20
mg/sem
et cardiaque
prednisolone 5 mg/j
IgIV :
.
Paramètres Amélioration de l’état clinique
0.4g/kg/j pdt 5j
d’inflammations
Puis mycophenolate . Etat clinique
mofetil 0.5g/j;
.Fonction rénale
ème
IgIV :
semaine
.Etat clinique
Amélioration à la 25
1g/kg/j pdt 2j
2ème dose à la 31ème semaine puis
.paramètres
+ 3g:j de salicylates
d’inflammation
rechute 5 mois post-partum
À la 22ème semaine
. Tolérance
Bonne tolérance
2ème cure d’IGIV à la
31ème semaine
IgIV :
. Etat clinique
. Amélioration de l’état clinique
20 g pdt 3 j (9 mois .
paramètres . Amélioration des paramètres
après le début des biologiques
et biologiques et d’inflammation
symptômes)
d’inflammation
IgIV :
. Etat clinique
Après la 2ème dose :
1mg/kg/j pdt 3j
.
paramètres - Arrêt des plasmaphérèses
Puis 1mg/kg toutes les d’inflammation et - ↓ dose des glucocorticoïdes de
2 semaines pdt 1 mois biologiques
120 à 30 mg/j
et 1x/mois pdt 2 mois
Bibliographie
142
Maladie de Still chez l’enfant
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polyarticular juvenile rheumatoid arthritis: a phase I/II study. J Rheumatol. 1996 May;23(5):919-24. Comment in: J Rheumatol.
1997 Mar;24(3):608; author reply 609-10.
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immunoglobulin in the treatment of systemic juvenile rheumatoid arthritis: a randomized placebo controlled trial. Pediatric
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systemic juvenile rheumatoid arthritis.. Arthritis Rheum. 1990 Jul;33(7):1015-22
Maladie de Still chez l’adulte
1. Vignes S, Wechsler B, Amoura Z, Papo T, Francès C, Huong DL, Veyssier P, Godeau P, Piette JC.Intravenous
immunoglobulin in adult Still'
s disease refractory to non-steroidal anti-inflammatory drugs. Clin Exp Rheumatol. 1998 MayJun;16(3):295-8
2. Permal S, Wechsler B, Cabane J, Perrot S, Blum L, Imbert JC.Treatment of Still disease in adults with intravenous
immunoglobulins. Rev Med Interne. 1995;16(4):250-4.
3. Mahmud T, Hughes GR. Intravenous immunoglobulin in the treatment of refractory adult Still'
s diseaseJ Rheumatol. 1999
Sep;26(9):2067-8.
4. Kuek A, Weerakoon A, Ahmed K, Ostör AJ. Adult-onset Still'
s disease and myocarditis: successful treatment with intravenous
immunoglobulin and maintenance of remission with etanercept. Rheumatology (Oxford). 2007
Jun;46(6):1043-4.
5. Bennett AN, Peterson P, Sangle S, Hangartner R, Abbs IC, Hughes GR, D'
Cruz DP. Adult onset Still'
s disease and collapsing
glomerulopathy: successful treatment with intravenous immunoglobulins and mycophenolate mofetil. Rheumatology (Oxford).
2004 Jun;43(6):795-9.
6. Liozon E, Ly K, Aubard Y, Vidal E. Intravenous immunoglobulins for adult Still'
s disease and pregnancy. Rheumatology
(Oxford).. 1999 Oct;38(10):1024-5.
7. Kulke R, Koeppel M, Hey D.Treatment of adult Still'
s disease with intravenous immunoglobulin. Lancet. 1996 Feb
3;347(8997):337.
8. Diamond JR. Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) complicating adult Still'
s disease:
remission induced with intravenous immunoglobulin G. J Nephrol. 1997 Sep-Oct;10(5):253-7.
Résumés-abstracts : maladie de Still chez l’enfant
Giannini EH, Lovell DJ, Silverman ED, Sundel RP, Tague BL, Ruperto N.Intravenous immunoglobulin in the
treatment of polyarticular juvenile rheumatoid arthritis: a phase I/II study. J Rheumatol. 1996 May;23(5):919-24.
Comment in: J Rheumatol. 1997 Mar;24(3):608; author reply 609-10.
OBJECTIVE. To obtain preliminary information about the safety and efficacy of intravenous immune globulin
(IVIG: Iveegam, Immuno AG, Vienna) in the treatment of polyarticular juvenile rheumatoid arthritis (poly-JRA)
resistant to other forms therapy. METHODS. We used a multicentered, phase I/II blinded-withdrawal design with
stratified entry. All patients began by receiving open infusions of IVIG at a dose between 1.5 and 2.0 g/kg/infusion
(100 g maximum) bimonthly for the first 2 months, then monthly for up to 6 months. Beginning at Month 3, those
who met the criteria for "clinically important improvement" were randomized to receive monthly infusions for 4
months of either placebo or IVIG in a double blind (DB) phase. Patients were permitted nonsteroidal
antiinflammatory drugs, slow acting antirheumatic drugs, and low dose (< 10 mg/day) prednisone at constant
doses. An "early escape" provision in the DB allowed those who showed "clinically important worsening" to again
receive IVIG (if taking placebo) or a higher dose of IVIG (if taking the lower dose of IVIG). RESULTS. Efficacy.
Twenty-five children entered the trial and 19 (76%) met the criteria for "clinically important improvement" during
the open phase (OP) and entered the DB. Three patients completed the OP but failed to meet the criteria for
response, and 3 patients dropped out of the OP, none of whom showed benefit from IVIG. Treatment effect sizes
produced by IVIG were moderate to large for all variables in the OP. Patients who continued IVIG in the DB
continued to show improvement over that achieved in the OP. Those given placebo showed a rapid loss of
efficacy, suggesting IVIG has a limited duration of effect after discontinuation. Safety. No patient developed
serious or unexpected adverse side effects in the open or DB phases, and none dropped out of the study due to
toxicity or side effects. CONCLUSION. Substantial clinical improvement from IVIG is produced in about three-
143
fourths of patients with poly-JRA during open administration, but the duration of the beneficial effect is short after
discontinuation. Those with disease < 3 years'duration may be more likely to respond than those who have had
their disease for > 5 years. Short term safety is excellent.
Silverman ED, Cawkwell GD, Lovell DJ, Laxer RM, Lehman TJ, Passo MH, Zemel LS, Giannini EH. Intravenous
immunoglobulin in the treatment of systemic juvenile rheumatoid arthritis: a randomized placebo controlled trial.
Pediatric Rheumatology Collaborative Study Group. J Rheumatol. 1994 Dec;21(12):2353-8.
OBJECTIVE. To assess the efficacy and safety of intravenous immunoglobulin (IVIG) in juvenile rheumatoid
arthritis (JRA). METHODS. Thirty-one children with active, refractory, systemic JRA were randomized into a
multicentered, double blinded, placebo controlled trial. Patients received infusions of 1.5 g/kg of IVIG or placebo
(0.1% albumin) every 2 weeks for 2 months, then monthly for 4 months (total: up to 9 infusions over 6 months).
Twenty-nine of the 31 patients were included in the efficacy subset. RESULTS. Fourteen patients discontinued
prematurely from study, 7 in each treatment group. A higher proportion of patients in the IVIG group improved (50
vs 27%) as assessed by the physician'
s global assessment. However, the sample size was small and this
difference was not statistically significant. IVIG was not more effective than placebo in reducing the number of
days with fever or other systemic manifestations. Changes from baseline in the joint count, hemoglobin, albumin,
platelet count, and erythrocyte sedimentation rate did not differ between treatment groups. CONCLUSION. Our
results suggest that high dose IVIG has limited clinical utility in systemic JRA. However, this trial failed to enroll
adequate numbers of patients to permit valid statistical intergroup comparisons, and the results must be
considered nondefinitive.
Uziel Y, Laxer RM, Schneider R, Silverman ED. Intravenous immunoglobulin therapy in systemic onset juvenile
rheumatoid arthritis: a followup study. J Rheumatol. 1996 May;23(5):910-8.
OBJECTIVE. To report the short and longterm effect of intravenous immunoglobulin (IVIG) in patients with
systemic onset juvenile rheumatoid arthritis (SOJRA). METHODS. A retrospective chart review of 27 patients with
SOJRA treated with IVIG and followed for 37.1 +/- 18.2 months was undertaken. Indications for treatment were
fever, arthritis, or steroid dependency. RESULTS. We treated 27 patients with SOJRA with IVIG monthly for 3-54
months. Six months after IVIG therapy, 20 patients had a least a 50% decrease in at least one of the following:
the number of days of fever; prednisone dose; or the number of active joints. Five patients failed to respond to
IVIG, and 2 dropped out after 3 and 4 months. At last followup visit (mean 37.6 +/- 18 months), 11 of the initial 20
responder group patients were in remission, while 3 had significantly improved but still had active arthritis, and 6
were now unresponsive. Of the initial 5 patients in the nonresponder group, 4 had nonresponsive arthritis and 1
had improved at last followup. Three patients in the responder group subsequently developed other diseases.
CONCLUSION. The main benefit of IVIG therapy to most of our patients was a significant improvement in the
systemic features, with resolution of fever and a significant reduction in the steroid dose. The efficacy of IVIG in
altering the course of arthritis was less predictable. We suggest that IVIG has a role in the management of
SOJRA, but it should be limited to patients with severe SOJRA in whom prolonged unresponsiveness to standard
therapy is present.
Oppermann J, Möbius D.Therapeutical and immunological effects of methylprednisolone pulse therapy in
comparison with intravenous immunoglobulin. Treatment in patients with juvenile chronic arthritis. Acta Univ Carol
[Med] (Praha). 1994;40(1-4):117-21
Twenty patients with polyarticular or systemic subtypes of juvenile chronic arthritis were primary treated with
either Methylprednisolone (MP) pulses (group I) or i.v. Immunoglobulin (IG) (group II) in combination with
Methotrexat and low dosages of Glucocorticosteroids. Clinical effects of treatment were rapid and excellent in
both groups and also the regression of inflammatory activity. MP-pulses and also IG-treatment decrease
significant the respective part of lymphocytes and T-cells. Significant is also the decrease of CD4 and CD8 cells
and the normalization of the CD4/CD8 ratio in both groups. Different are the effects on B-cells and NK-cells
between the two groups. Whereas MP-pulses decrease the number of B-cells. IG-treatment leads to high
increase. The number of NK-cells increases after each single MP-pulse and decreases significant after IGinfusions.
Prieur AM, Adleff A, Debre M, Boulate P, Griscelli C. High dose immunoglobulin therapy in severe juvenile chronic
arthritis: long-term follow-up in 16 patients. Clin Exp Rheumatol. 1990 Nov-Dec;8(6):603-8
Sixteen children with severe juvenile chronic arthritis received high dose intravenous immunoglobulin (IVGG).
Extra-articular symptoms improved to some degree in 6 of ten patients. A decrease in the number of active joints
occurred in 7 patients of the 11 who received more than ten months of IVGG. Hemoglobin levels increased, the
ESR and platelet counts decreased and the IgG levels diminished in most of the patients who received long term
treatment. The treatment was totally ineffective in three children who had very severe disease. Two children had
144
respectively a vasculitic rash and urticaria thought to be side effects of the treatment. One had proteinuria. This
last might have been due to other therapeutic agents given. Although clinical and biological benefits occurred in
some, the state of the patients who had short term (m = 2-3 months) or long term (m = 2-7 years) therapy was not
different at the last visit.
Silverman ED, Laxer RM, Greenwald M, Gelfand E, Shore A, Stein LD, Roifman CM.Intravenous gamma globulin
therapy in systemic juvenile rheumatoid arthritis. Arthritis Rheum. 1990 Jul;33(7):1015-22
Intravenous (IV) gamma globulin has been successfully used as replacement therapy for antibody-deficient
patients and, more recently, in the treatment of autoimmune diseases such as idiopathic thrombocytopenic
purpura, myasthenia gravis, and Kawasaki disease. In view of the successful treatment of these diseases, we
initiated a pilot study of the effect of IV gamma globulin in systemic juvenile rheumatoid arthritis (JRA). Eight
patients with active systemic JRA that was unresponsive to first-line agents, second-line agents, and/or
corticosteroids received this therapy monthly for 6 months. Outcome measures included changes in articular and
extraarticular features, steroid dosage, and laboratory parameters. Following IV gamma globulin therapy, there
was significant improvement in arthritis and/or morning stiffness in 5 of 8 patients, while extraarticular features
significantly improved in 7 of 8 patients. At study entry, 6 of 8 patients were receiving prednisone; at study end,
prednisone was discontinued in 3 patients and decreased by more than 50% in the other 3. Overall, there was an
80% reduction in the prednisone dosage. Initially, all patients had anemia, low levels of serum albumin, and an
elevated erythrocyte sedimentation rate, while a thrombocytosis was seen in 7 of 8 patients. Serum IgG was
initially elevated in 6 patients. IV gamma globulin therapy resulted in a significant increase in hemoglobin and
albumin levels and a significant decrease in the mean serum IgG level, platelet count, and erythrocyte
sedimentation rate. In only 1 patient did IV gamma globulin fail to significantly improve the clinical or laboratory
features of the disease. We suggest that this therapy may be beneficial in the treatment of systemic JRA.
Résumés-abstracts : maladie de Still chez l’adulte
Vignes S, Wechsler B, Amoura Z, Papo T, Francès C, Huong DL, Veyssier P, Godeau P, Piette JC.Intravenous
immunoglobulin in adult Still'
s disease refractory to non-steroidal anti-inflammatory drugs. Clin Exp Rheumatol.
1998 May-Jun;16(3):295-8
OBJECTIVE: Adult onset Still'
s disease (AOSD) is a systemic disorder with an uncertain outcome at the time of
diagnosis. The clinical response to nonsteroidal antiinflammatory drugs (NSAIDs) is often unsatisfactory in adult
patients. Chronic use of steroids is frequently required, but may result in severe side effects. We report the results
of an uncontrolled, unblinded trial of intravenous immunoglobulin (IVIG) in 7 patients with AOSD. METHODS:
Seven consecutive patients unresponsive or poorly responsive to NSAIDs were enrolled. None of them had
received steroids previously. AOSD was defined by the Yamaguchi criteria (J Rheumatol 1992; 19: 424). IVIG
were administered every 4 weeks. NSAIDs were initially maintained. A positive response was defined by the
disappearance of fever and arthritis within 2 weeks after the first IVIG infusion. RESULTS: Two patients failed to
respond. Five patients initially considered to be good responders were given a total of 4 to 6 IVIG infusions. One
of them relapsed at the time of the fourth IVIG infusion. The four others had a favourable clinical and biological
course. At the time of evaluation 3 patients were symptom-free and off therapy, while one was still receiving low
dose NSAIDs. CONCLUSION: This short, uncontrolled, unblinded study suggests that IVIG might represent a
potential alternative to classical steroid therapy in patients with AOSD refractory to NSAIDs. These preliminary
results need to be confirmed, however, in a double-blind randomized study.
Permal S, Wechsler B, Cabane J, Perrot S, Blum L, Imbert JC.Treatment of Still disease in adults with
intravenous immunoglobulins. Rev Med Interne. 1995;16(4):250-4.
In most cases, the treatment of adult'
s Still disease presents difficulties, in view of its undesirable side-effects. For
this reason, we made an open trial of the effects of high-dose intravenous immunoglobulins (IVIg), a therapy with
low iatrogen risk, and whose effectiveness in the treatment of other multisystemic diseases has been
acknowledged. Seven patients suffering from adult Still'
s disease were given between one and eight IVIg
infusions with a dose of 1 g/kg/day for two consecutive days. All seven responded positively, with clinical
improvement. It lasted between 1 and 90 days in three patients, who subsequently relapsed; it has been
continuing for an average of 13 months (2 to 24 months) in the other four patients. There were no clinical features
making it possible to distinguish, after the trial, the patients who responded positively to intravenous
immunoglobulins. This data, which needs to be confirmed with a controlled trial, provides hope of improved
therapy for the one half of patients suffering from adult Still'
s disease who respond positively to intravenous
immunoglobulins.
145
Bennett AN, Peterson P, Sangle S, Hangartner R, Abbs IC, Hughes GR, D'
Cruz DP. Adult onset Still'
s disease
and collapsing glomerulopathy: successful treatment with intravenous immunoglobulins and mycophenolate
mofetil. Rheumatology (Oxford). 2004 Jun;43(6):795-9.
In this Grand Round we present a 32-yr-old African man who became severely ill after a 5-month history of weight
loss, pyrexia, arthralgia, sweats and rash. He went on to develop pericarditis, pericardial effusion with tamponade,
hepatomegaly with abnormal liver function tests, lymphadenopathy, massive proteinuria and required ventilatory,
circulatory and renal support. The differential diagnosis was adult onset Still'
s disease, systemic lupus
erythematosus (SLE), infection and lymphoma. Primary infection and lymphoma were excluded and he was
treated, with dramatic success, with intravenous immunoglobulins (i.v.IG). Subsequent renal biopsy excluded SLE
but confirmed collapsing glomerulopathy. The proteinuria improved dramatically following treatment with
mycophenolate mofetil. We discuss some of the difficult diagnostic and management issues raised by this patient
and the different uses and mechanisms of action of i.v.IG.
G. Diamond JR. Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) complicating adult
Still'
s disease: remission induced with intravenous immunoglobulin J Nephrol. 1997 Sep-Oct;10(5):253-7.
Coexistence of hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) and adult Still'
s
disease is extremely rare. We describe the case history of a 22-year-old young man who presented with evidence
of a thrombotic microangiopathy complicated by dialysis-dependent renal failure, encephalopathy, and an
ischemic retinopathy. The most important and novel feature of this case was the dramatic and sustained clinical
remission of the TMA induced by intravenous immunoglobulin (IVIg) after failure of plasmapheresis and
glucocorticoids to d
146
•
Syndrome dégénératif secondaire aux histiocytoses langerhanciennes
Le syndrome dégénératif du SNC est une complication rare très invalidante et chronique des
histiocytoses langerhansiennes. Cela représente environ 30 cas/an en France.
Il existe un registre des patients pédiatriques et adultes dans le centre de référence du Dr Donadieu
(Hôpital Trousseau-Paris).
Auteurs
Type d’étude
Posologie
Imashuku
(2007)
Ouverte
N=5 enfants
Age= 0.3 à 4.8 ans
LCH + atteinte cérébrale
4/5 : diabète insipide
3/5 : ataxie cérébelleuse
IgIV
19-38
250-400 mg/kg/dose mois
1 x/mois pdt 2 ans
puis tous les 2 mois
+
stéroïdes
+/vinblastine +/- 6Mercaptopurine +/Methothrexate
N=1
Age= 18 ans
LCH + atteinte cérébrale
IgIV
3 x 400 mg/kg/dose
pendant
5
j
consécutifs
+
immunosuppresseurs
Kalpinsky
(2005)
Suivi
Critères
d’évaluation
IRM cérébral
IRM cérébral
Résultats
- N=4 (23 à 34 doses) :
. état clinique stable
. pas de progression des
signes neurologiques
- N=1 (2 doses) :
. aggravation de l’atteinte
neurologique et incapacité à
marcher à 7.7 ans
- Amélioration de l’état général
. ↑ l’expression orale
. ↑ dysphagie
. ↑ mémoire
LCH : Histiocytose langerhansienne acquise
Bibliographie
1. Imashuku S, Okazaki NA, Nakayama M, Fujita N, Fukuyama T, Koike K, Minato T, Kobayashi R, Morimoto
A.Treatment of neurodegenerative CNS disease in langerhans cell histiocytosis with a combination of intravenous
immunoglobulin and chemotherapy. Pediatr Blood Cancer. 2008 Feb;50(2):308-11.
2. Kalpinsky C., Hoffmann C, Toren A. Intravenous IG treatment of neurodegenerative LCH. At the 21 st annual
meeting of histiocyte Society. 21st Annual Meeting Of The Histiocyte Society, September 25-27, 2005 Vancouver,
Canada. Pediatric Blood & Cancer Volume 46, Issue 3 , Pages 392 – 405, 2006 2005, abstract p35
Résumés-abstracts
Imashuku S, Okazaki NA, Nakayama M, Fujita N, Fukuyama T, Koike K, Minato T, Kobayashi R, Morimoto A.
Treatment of neurodegenerative CNS disease in langerhans cell histiocytosis with a combination of intravenous
immunoglobulin and chemotherapy. Pediatr Blood Cancer. 2008 Feb;50(2):308-11.
BACKGROUND: In rare cases, patients with Langerhans cell histiocytosis (LCH) develop neurodegenerative CNS
disease (ND-CNS-LCH). Management of ND-CNS-LCH has not been established. METHODS: We treated five
pediatric patients with a combination of intravenous immunoglobulin (IVIG) and chemotherapy (steroid +/vinblastine +/- 6-mercaptopurine +/- methotrexate). Prior to the therapy, three of the five patients had cerebellar
ataxia while the remaining two had abnormal MRI findings without apparent neurological deficits. IVIG was given
monthly or twice monthly at the dosage of 250-400 mg/kg/dose. RESULTS: The four patients administered more
than 23 doses of IVIG and chemotherapy remained in a stable condition and did not show significant progression
signs in neurological deficits or brain MRI findings during the 30-month follow-up period (median; range: 19+ to
38+) following the initiation of therapy for ND-CNS-LCH. CONCLUSION: The IVIG-containing treatment may be
147
promising for ND-CNS-LCH; however, its effectiveness remains to be further tested in more patients as well as in
a randomized trial.
148
•
Syndrome de Lyell
Le syndrome de Lyell est une épidermolyse nécrosante suraiguë grave causée le plus souvent chez
l'
adulte, par une intoxication médicamenteuse. Les principaux médicaments inducteurs sont :
- les sulfamides antibactériens,
- les anticonvulsivants,
- les pyrazolés,
- les AINS.
Le délai entre la prise médicamenteuse et l'
apparition de la réaction est compris entre 7 et 21 jours.
Le pronostic est sévère avec une mortalité de près de 20 à 30% si des troubles hémodynamiques ou
des surinfections s'
installent. Bien que la guérison puisse s'
effectuer en un mois environ, les séquelles
laissées peuvent être graves, surtout au niveau des yeux.
Chez les plus jeunes, le syndrome de Lyell infantile concerne une épidermolyse staphylococcique
aiguë qui réalise un tableau clinique similaire à ce qui est décrit chez l’adulte.
Le traitement doit se faire en unité de soins intensifs spécialisés ou en centre de brûlés :
• apport d'
électrolyte et de macromolécules
• prévention des infections
• soins locaux cutanés et des muqueuses
Certaines études sont en faveur de l’utilisation des IgIV (immunoglobulines par voie IV) : Tan, Prins,
Trent, Lissia, Campione, avec une diminution de la mortalité. D’autres études sont plutôt en défaveur
de leur utilisation : la méta-analyse de Rougeau, les études rétrospectives de Yip, Schort et l’étude
prospective de Brown comparative par rapport à un groupe contrôle historique.
L’insuffisance des données n’a pas permis d’évaluer le bénéfice/risque des immunoglobulines dans le
syndrome de Lyell. L’analyse des publications ne montre pas d’études contrôlées versus placebo (pas
éthique) ou versus un traitement de référence. Il s’agit d’études soit rétrospectives, soit prospectives
non comparatives comportant en moyenne de 10 à 20 patients.
Effet des IgIV dans le syndrome de Lyell
Auteur
Type d’étude
Posologie
Tan
(2005)
Rétrospective
N = 12
patients
.n=8
patients avec
toxic
epidermal
necrosis
(TEN)
.n=4
patients avec
StevensJohnson
syndrometoxic (SJS)
Prospective
ouverte
N = 34
. n = 9 (SJS)
. n = 5 (SJSTEN)
. n = 20 (TEN)
Bachot
(2003)
Suivi
Résultats
Immunoglob
ulines IgIV :
2g/kg
- temps moyen de
réponse post IgIV
- temps
d’hospitalisation
- taux de survie
- Temps moyen de réponse : 3.6+/1.9 jours
- durée d’hospitalisation : 20.4+/-8
jours
- taux de survie : 91.6%
IgIV :
2g/kg sur 2
jours
- proportion de surface
corporelle
« détachable » avant et
après traitement
- mortalité
- détachement épidermique . . . avant
traitement : 19% +/-16%
après traitement : 32% +/-26% avec
une progression pour 22 cas sur 34
- score prédictif de décès : 8.2
morts : 24%
Décès : 11 : 32% avec IC 95 : 17%51% (+ fréquemment chez les
patients âgés avec une insuffisance
149
rénale)
Pas d’effet des IVIg sur la progression
du détachement ou sur la vitesse de
réépidermalisation.
Prins
(2003)
Rétrospective IgIV :
N = 48 patients 2.7g/kg en
TEN
moyenne
sur une
moyenne de
2.3 jours
Trent
(2003)
Rétrospective
N = 16
patients TEN
IgIV :
n = 15
patients :
1g/kg/jour
n=1
patient :
0.4g/kg
SCORTEN : système
de prédiction de la
mortalité
Lissia
(2005)
Rétrospective
N=5
patients avec
TEN sévère
IgIV et
plasmaphérèse
SMR
Campio
ne
(2003)
Ouverte
N =10
patients TEN
AlMutairi
(2004)
Ouverte
N = 12
patients
TEN
Tristani
-Firouzi
(2002)
Ouverte
N = 8 patients
TEN
Stella
(2001)
Ouverte
N = 9 patients
TEN
Viard
(1998)
Ouverte
IgIV
N = 10 patients
TEN
Yip
(2005)
Rétrospective IgIV :
N = 28 patients 2g/kg sur 2
TEN
jours
n
=
10
patients traités
n = 18 patients
non traités
IgIV :
0.4
g/kg
/jour
pendant 5
jours
consécutifs
IgIV :
0.5-1
avec g/kg/jour
pendant 4-5
jours
IgIV :
0.05-0.1
mg/kg/jour
45
jours
- temps de réponse au
traitement
- % de réponse
- taux de survie
SCORTEN
- temps de réponse : 2.3 jours en
moyenne
- 90 % de répondeurs
-taux de survie : 88 %
Conclusion : traiter le plus tôt
possible avec une dose de 3g/kg sur
3 jours consécutifs
- 1 décès alors que 5.81 décès
étaient attendus.
- Ce taux de mortalité est comparée
au ratio de mortalité standard
(SMR) : SMR = 0.17 IC 95% (0.00.96) : 83 % des patients TEN traités
par IVIg avaient moins de probabilité
de mourir que ceux non traités.
- Taux de mortalité : 20%
- Taux de mortalité attendu : 66%
- SMR : 0.3 IC95% (0.0-0.96)
correspondant à 70 % de réduction
de mortalité
- Taux de mortalité prévu : 35 %
- Après traitement : taux de
mortalité : 10 %
5 ans
-temps d’arrêt de la
progression de la TEN
- temps de cicatrisation
complet
- durée d’hospitalisation
- Temps moyen d’arrêt de la
progression de la maladie : 2.83
jours
- complète réépithélialisation : 7.33
jours en moyenne
- durée d’hospitalisation moyenne :
12.5 jours
Pas de décès et tous les patients ont
répondu au traitement
3 ans
- Temps d’arrêt de la
progression des lésions
- Complète
réépithélialisation
- Nombre de patients
répondeurs
- Temps de réponse
moyen
-temps de complète
cicatrisation
- temps de progression des lésions :
2.1 jours
- Complète réépithélialisation : 8.1
jours
- Taux de mortalité : 0%
- 8 patients ont cicatrisé et 1 décès
- Temps de réponse moyen : 4.8
jours
- Temps de complète cicatrisation :
12 jours
- Issue favorable et la progression de
la maladie est rapidement stoppée
Pas d’amélioration des complications
oculaires des patients traités par
IVIg.
150
Shortt
(2004)
Rétrospective
N = 32
patients TEN
n = 16 patients
traités
n = 16 patients
contrôles
Faye
(2005)
Méta-analyse
Rétrospective
N
=
156
patients
Ouverte
N = 45
. n = 21
contrôles
historiques
. n = 24 patients
TEN
Brown
(2004)
IgIV :
0.7+/- 0.2
g/kg/jour sur
4+/- 1 jour
- temps d’arrêt de la
progression
progression
des
lésions
- taux de mortalité
Taux de mortalité
SCORTEN
Durée d’hospitalisation
- progression des lésions : 13%
(groupe traité) versus 27 % groupe
contrôle
- arrêt de la progression des lésions :
47 % GP traité versus 18 % GP
contrôle NS
- temps d’arrêt de la progression des
lésions : NS
- Taux de mortalité : NS
Taux de mortalité : 20.5 %
Sur 5 séries de patients traités :
. taux de mortalité prévue : 30%
. taux de mortalité réel : 27 %
Pas de différence significative entre
les 2 groupes pour le taux de
mortalité, SCORTEN équivalent
Pas de bénéfice du traitement par
IVIg
Durée d’hospitalisation plus longue
chez les patients traités
Bibliographie
1-Tan AW, Thong BY, Yip LW, Chng HH, Ng SK. High-dose intravenous immunoglobulins in the treatment of toxic epidermal
necrolysis : an Asian series J Dermatol. 2005 Jan;32(1):1-6.
2- Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobin treatment for Stevens-Johnson syndrome and toxic epidermal
necrolysis : a prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol. 2003
Jan;139(1):33-6.
3- Prins C, Kerdel FA, Padilla RS, Hunziker T, Chimenti S, Viard I, Mauri DN, Flynn K, Trent J, Margolis DJ, Saurat JH, French
LE; Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobins : multicenter retrospective analysis of 48
consecutive cases. Arch Dermatol. 2003 Jan;139(1):26-32
4-Lissia M, Figus A, Rubino C. Intravenous immunoglobulins and plasmapheresis combined treatment in patients with severe
toxic epidermal necrolysis: preliminary report. Br J Plast Surg. 2005 Jun;58(4):504-10
5- Campione E, Marulli GC, Carrozzo AM, Chimenti MS, Costanzo A, Bianchi L. High-dose intravenous immunoglobulin for
severe drug reactions: efficacy in toxic epidermal necrolysis. Acta Derm Venereol. 2003;83(6):430-2
6- Al-Mutairi N, Arun J, Osama NE, Amr Z, Mazen AS, Ibtesam el-A, Nazeha el-B. Prospective, non comparative open study
from Kuwait of the role of intravenous immunoglobulin in the treatment of toxic epidermal necrolysis. Int J Dermatol. 2004
Nov;43(11):847-51
7-Tristani-Firouzi P, Petersen MJ, Saffle JR, Morris SE, Zone JJ. Treatment of toxic epidermal necrolysis with intravenous
immunoglobulin in children. J Am Acad Dermatol. 2002 Oct;47(4):548-52
8-Tristani-Firouzi P, Petersen MJ, Saffle JR, Morris SE, Zone JJ. Treatment of toxic epidermal necrolysis with intravenous
immunoglobulin in children.J Am Acad Dermatol. 2002 Oct;47(4):548-52
9- Mangla K, Rastogi S, Goyal P, Solanki RB, Rawal RC. Efficacy of low dose intravenous immunoglobulins in children with
toxic epidermal necrolysis : an open uncontrolled study. Indian J Dermatol Venereol Leprol. 2005 Nov-Dec;71(6):398-400
10-Stella M, Cassano P, Bollero D, Clemente A, Giorio G. Toxic epidermal necrolysis treated with intravenous high-dose
immunoglobulins : our experience. Dermatology. 2001;203(1):45-9
11-Viard I, Wehrli P, Bullani R, Schneider P, Holler N, Salomon D, Hunziker T, Saurat JH, Tschopp J, French LE. Inhibition of
toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science. 1998 Oct 16;282(5388):
490-3
12-Yip LW, Thong BY, Tan AW, Khin LW, Chng HH, Heng WJ. High-dose intravenous immunoglobulin in the treatment of toxic
epidermal necrolysis : a study of ocular benefits. Eye. 2005 Aug;19(8):846-53
13-Shortt R, Gomez M, Mittman N, Cartotto R. Intravenous immunoglobulin does not improve outcome in toxic epidermal
necrolysis. J Burn Care Rehabil. 2004 May-Jun;25(3):246-55
14-Brown KM, Silver GM, Halerz M, Walaszek P, Sandroni A, Gamelli RL. Toxic epidermal necrolysis : does immunoglobulin
make a difference ?J Burn Care Rehabil. 2004 Jan-Feb;25(1):81-8
15-Faye O, Roujeau JC. Treatment of epidermal necrolysis with high-dose intravenous immunoglobulins (IVIg):
Clinical experience to date: Drugs. 2005;65(15):2085-90
151
Résumés-abstracts
Intravenous immunoglobin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis : a
prospective noncomparative study showing no benefit on mortality or progression. Bachot N, Revuz J, Roujeau
JC. Arch Dermatol. 2003 Jan;139(1):33-6.
BACKGROUND: It has been proposed that Fas-Fas ligand interaction was responsible for the apoptosis of
epidermal cells in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) and that high doses of
intravenous immunoglobulin (IVIG) could help patients by blocking the apoptosis. OBJECTIVE: To study the
effects of IVIG on SJS and TEN. DESIGN: Prospective open trial. SETTING: Referral center of a university
hospital. PATIENTS: Thirty-four consecutive patients admitted for SJS (n = 9), SJS-TEN (n = 5), or TEN (n = 20)
a mean of 4.3 days after onset. INTERVENTION: A dose of 2 g/kg of IVIG was administered within 2 days (half
doses or full doses over a longer period for patients with low creatinine clearance). MAIN OUTCOME
MEASURES: Detached plus detachable proportions of the total body surface area measured before and after
treatment and predicted death rate estimated on admission with a validated prognostic score. RESULTS:
Epidermal detachment involved a mean +/- SD 19% +/- 16% of the total body surface area on admission and 32%
+/- 26% after IVIG treatment (progression in 22 of 34 cases, including most patients referred early). The
prognostic score predicted 8.2 deaths (24%); 11 were observed (32%; 95% confidence interval, 17%-51%). Most
deaths occurred in elderly patients who had initially impaired renal function. CONCLUSIONS: The confidence
interval of the observed death rate excludes a dramatic decrease in mortality. No measurable effect was observed
on the progression of detachment or on the speed of reepidermalization. These results do not support the routine
use of IVIG treatment for patients with SJS or TEN, especially in cases of impaired renal function.
Prospective, non comparative open study from Kuwait of the role of intravenous immunoglobulin in the treatment
of toxic epidermal necrolysis. Al-Mutairi N, Arun J, Osama NE, Amr Z, Mazen AS, Ibtesam el-A, Nazeha el-B. Int J
Dermatol. 2004 Nov;43(11):847-51
BACKGROUND: High-dose intravenous immunoglobulin (IVIG) is emerging as a promising new therapy for
treating the rare but potentially fatal drug reaction toxic epidermal necrolysis (TEN). Experimental in vitro studies
support that IVIG can block the Fas-FasL-mediated apoptosis in TEN. METHODS: Twelve consecutive patients
(7M, 5F) with TEN admitted over a 5-year period from January 1998 to December 2002 were treated with a dose
of 0.5-1.0 g/kg/d of IVIG for 4-5 days along with standard care protocol. Clinical outcome in terms of average
duration to arrest the progression, complete healing, hospital stay, side-effects and complications were
determined to find the efficacy of IVIG treatment. RESULTS: Average age was 27.16 years (7-50 years). There
were four children (2M, 2F) aged 7-12 years. One patient had an underlying malignancy. No patient had HIV
infection. The average total body surface area involvement was 57.5% (30-90%). An IVIG infusion was started, on
average, 1.58 days (1-3 days) after admission. All patients responded well to the treatment. There was no
mortality. The disease progression was arrested in a mean of 2.83 days (1-5 days). Time taken for complete
healing (re-epithelialization) was 7.33 days (5-13 days). The average duration of hospital stay was 12.5 days (721 days). No side-effects of the IVIG treatment were observed in these patients. The drugs triggering TEN in
these patients were phenytoin (four patients), followed by penicillin (three), cotrimoxazole (two), phenobarbital
and furosemide (one patient each), respectively. In one patient, the offending drug could not be ascertained.
CONCLUSION: Our experience of treating 12 patients with TEN using IVIG, in Kuwait, confirms that it is a safe
and effective treatment for these patients.
Treatment of toxic epidermal necrolysis with intravenous immunoglobulin in children. Tristani-Firouzi P, Petersen
MJ, Saffle JR, Morris SE, Zone JJ. J Am Acad Dermatol. 2002 Oct;47(4):548-52
BACKGROUND: Toxic epidermal necrolysis (TEN) is an acute illness characterized by rapid onset of skin
necrosis and high mortality. Standard treatment is primarily aimed at supportive care in a burn unit setting.
OBJECTIVE: We evaluated the outcome of 8 pediatric patients treated for TEN with intravenous immunoglobulin
(IVIg) over a 3-year period. METHODS: We performed a retrospective analysis of pediatric patients with a
diagnosis of TEN between 1999 and 2001, obtained from a computerized database. RESULTS: Mean body
surface involvement of 8 patients treated with IVIg was 67%. The average length of hospitalization was 13.6 days,
with an average delay in treatment of 3.2 days. The average time to arrest in progression of lesions was 2.1 days
and to complete re-epithelialization, 8.1 days. The mortality rate was 0%. The majority of complications were
infectious. CONCLUSION: IVIg is a safe and effective treatment for TEN in the pediatric population. Randomized
trials are needed to further evaluate the efficacy of IVIg compared with other modalities.
Toxic epidermal necrolysis treated with intravenous high-dose immunoglobulins : our experience. Stella M,
Cassano P, Bollero D, Clemente A, Giorio G. Dermatology. 2001;203(1):45-9
152
BACKGROUND: Toxic epidermal necrolysis (TEN) is a rare severe acute exfoliative drug-induced skin disorder
which has recently been ascribed to alterations in the control of keratinocyte apoptosis, mediated by an
interaction between the cell surface death receptor Fas and its respective ligand. A therapeutic approach with
intravenous immunoglobulins (IVIG) associated with pulse methylprednisolone, based on the inhibition of Fasmediated keratinocyte death by naturally occurring Fas-blocking antibodies included in human immunoglobulin
preparations, has produced good preliminary results. OBJECTIVE: To analyse the efficacy of IVIG in the
treatment of TEN. Patients: Nine patients with erythematous body surface area ranging from 38 to 85% and
dermo-epidermal detachment from 4 to 37% were treated. RESULTS: Eight patients were healed and 1 died of
septic shock and multiple organ failure. Interruption of further epidermal detachment occurred after an average of
4.8 days from the onset of IVIG therapy. Complete wound healing occurred after an average of 12 days.
Concerning complications, 3 out of 8 surviving patients had acute respiratory failure requiring mechanical
ventilation and 1 acute renal failure was treated with dialysis. Late sequelae were limited to dyschromia and nail
dystrophies. No hypertrophic scars were observed. CONCLUSION: IVIG therapy represents a safe and valid
approach for TEN.
Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Viard I,
Wehrli P, Bullani R, Schneider P, Holler N, Salomon D, Hunziker T, Saurat JH, Tschopp J, French LE. Science.
1998 Oct 16;282(5388):490-3
Toxic epidermal necrolysis (TEN, Lyell'
s syndrome) is a severe adverse drug reaction in which keratinocytes die
and large sections of epidermis separate from the dermis. Keratinocytes normally express the death receptor Fas
(CD95); those from TEN patients were found to express lytically active Fas ligand (FasL). Antibodies present in
pooled human intravenous immunoglobulins (IVIG) blocked Fas-mediated keratinocyte death in vitro. In a pilot
study, 10 consecutive individuals with clinically and histologically confirmed TEN were treated with IVIG; disease
progression was rapidly reversed and the outcome was favorable in all cases. Thus, Fas-FasL interactions are
directly involved in the epidermal necrolysis of TEN, and IVIG may be an effective treatment.
High-dose intravenous immunoglobulin for severe drug reactions: efficacy in toxic epidermal necrolysis.
Campione E, Marulli GC, Carrozzo AM, Chimenti MS, Costanzo A, Bianchi L. Acta Derm Venereol.
2003;83(6):430-2
High-dose intravenous immunoglobulin has been proposed as an alternative treatment for several immunomediated inflammatory skin diseases, usually at a dosage of 1 - 2 g/kg. We describe the treatment of 10 patients
affected by toxic epidermal necrolysis using 400 mg/kg per day on 5 consecutive days--a schedule that is lower
than previously reported schedules. According to the SCORTEN, the earlier predicted mortality rate was 35%.
After high-dose intravenous immunoglobulin therapy, a mortality rate of 10% and a survival rate of 90% were
reached. In particular, nine patients showed a dramatic improvement already after one course of infusion started
at an early stage of the disease. It is our experience, and that of others, that high-dose intravenous
immunoglobulin can be considered the drug of first choice for toxic epidermal necrolysis, one of the most severe
life-threatening dermatological conditions, and a valid alternative therapy for different long-standing chronic
dermatological diseases. This therapy can also be effective in avoiding high steroid dosages and consequently
steroid-related or immunosuppressive-related side effects. It is therefore reasonable to propose high-dose
intravenous immunoglobulin treatment as a valuable therapeutic tool for dermatologists.
Toxic epidermal necrolysis : does immunoglobulin make a difference ?
Brown KM, Silver GM, Halerz M, Walaszek P, Sandroni A, Gamelli RL. J Burn Care Rehabil. 2004 JanFeb;25(1):81-8
Experimental evidence implicates Fas ligand-mediated keratinocyte apoptosis as an underlying mechanism of
toxic epidermal necrolysis syndrome (TEN). In vitro studies indicate a potential role for immunoglobulin (Ig)
therapy in blocking Fas ligand signaling, thus reducing the severity of TEN. Anecdotal reports have described
successful treatment of TEN patients with Ig; however, no study to date has analyzed outcome data in a large
series of patients treated with Ig using institutional controls. The SCORTEN severity-of-illness score ranks
severity and predicts prognosis in TEN patients using age, heart rate, TBSA slough, history of malignancy, and
admission blood urea nitrogen, serum bicarbonate, and glucose levels. A retrospective chart review was
performed that included all patients treated for TEN at our burn center since 1997. Ig therapy was instituted for all
patients with biopsy-proven TEN beginning in January 2000. Twenty-one TEN patients were treated before Ig (noIg group), and 24 patients have been treated with Ig. SCORTEN data were collected, as well as length of stay
(LOS) and status upon discharge. Each patient was given a SCORTEN of 0 to 6, with 1 point each for age greater
than 40, TBSA slough greater than 10%, history of malignancy, admission BUN greater than 28 mg/dl, HCO3 less
than 20 mg/dl, and glucose greater then 252 mg/dl. Outcome was compared between patients treated with Ig and
without Ig. Overall mortality for patients treated before Ig was 28.6% (6/21), and with Ig, mortality was 41.7%%
(10/24). There was no significant difference in age or TBSA slough. The average SCORTEN between the groups
was equivalent (2.2 in no-Ig group vs 2.7 in Ig group, P = 0.3), and no group of patients with any SCORTEN score
153
showed a significant benefit from Ig therapy. Overall LOS as well as LOS for survivors was longer in the Ig group.
This series represents the largest single-institution analysis of TEN patient outcome after institution of Ig therapy.
Our data do not show a significant improvement in mortality for TEN patients treated with Ig at any level of
severity and may indicate a potential detriment in using Ig. Ig should not be given to TEN patients outside of a
clinical trial. A multicenter, prospective, double-blinded randomized trial is necessary and urgently indicated to
determine whether Ig therapy is beneficial or harmful in the care of TEN patients.
Treatment of epidermal necrolysis with high-dose intravenous immunoglobulins (IVIg): Clinical experience to date
Faye O, Roujeau JC. : Drugs. 2005;65(15):2085-90
High-dose human intravenous immunoglobulins (IVIG) have now been used as a treatment for epidermal
necrolysis for several years.We have reviewed all series involving more than nine patients treated with high-dose
IV Ig for toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome (SJS) published in indexed journals.
Nine series included a total of 156 patients; among the 156 reported cases, 32 patients died (20.5%). When the
analysis was restricted to the five series that included some comparison with expected deaths, the mortality rate
observed in patients treated with IV Ig was 27% versus an expected rate of 30%. Because of high diversity in
study designs and dosages of IV Ig used, and because several series included duplicate cases, it was not
possible to make more detailed statistical analyses, including individual prognostic factors and IV Ig dosages.In
the absence of randomised controlled trials, this review does not provide a definite conclusion on the usefulness
of IV Ig in SJS or TEN; however, the analysis of published data does not suggest a dramatic efficacy.We
conclude that, in the absence of further studies, IV Ig cannot yet be considered the standard of care for SJS or
TEN.
Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobins : multicenter retrospective
analysis of 48 consecutive cases. Prins C, Kerdel FA, Padilla RS, Hunziker T, Chimenti S, Viard I, Mauri DN,
Flynn K, Trent J, Margolis DJ, Saurat JH, French LE; Arch Dermatol. 2003 Jan;139(1):26-32
OBJECTIVE: To evaluate the effect of high-dose intravenous immunoglobulin (IVIG) in toxic epidermal necrolysis
(TEN), parameters that may affect response to treatment, and the effect of different IVIG batches on Fasmediated cell death. DESIGN: Multicenter retrospective analysis of 48 consecutive TEN patients treated with
IVIG. SETTING: Fourteen university hospital dermatology centers in Europe and the United States. PATIENTS:
Forty-eight patients with TEN (skin detachment >10% of their body surface [mean, 44.8%; range, 10%-95%]).
INTERVENTIONS: Infusion of IVIG in all patients (range, 0.8-5.8 g/kg), and analysis of the ability of different IVIG
batches to inhibit Fas-mediated cell death. MAIN OUTCOME MEASURES: Objective response to IVIG treatment,
final outcome at day 45, parameters that may affect response to IVIG treatment, and tolerance. RESULTS:
Infusion of IVIG (mean total dose, 2.7 g/kg [range, 0.65-5.8 g/kg]; mean consecutive days, 4 [range, 1-5 days])
was associated with a rapid cessation (mean, 2.3 days [range, 1-6 days]) of skin and mucosal detachment in 43
patients (90%) and survival in 42 (88%). Patients who responded to IVIG had received treatment earlier in the
course of disease and, on average, higher doses of IVIG. Furthermore, analysis of 35 IVIG batches revealed
significant batch-to-batch variations in the capacity of IVIG to inhibit Fas-mediated cell death in vitro.
CONCLUSIONS: Early infusion of high-dose IVIG is safe, well tolerated, and likely to be effective in improving the
survival of patients with TEN. We recommend early treatment with IVIG at a total dose of 3 g/kg over 3
consecutive days (1 g/kg per day for 3 days).
Intravenous immunoglobulin does not improve outcome in toxic epidermal necrolysis. Shortt R, Gomez M,
Mittman N, Cartotto R. J Burn Care Rehabil. 2004 May-Jun;25(3):246-55
Intravenous Immunoglobulin (IVIG) has been proposed as a beneficial therapy for toxic epidermal necrolysis
(TEN). However, this has been based on a limited amount of Class 5 evidence. To compare outcomes in TEN
patients treated in our burn unit since 1999, when we began to use IVIG (IG group), with TEN patients treated
between 1995 and 1999 who did not receive IVIG (control group). Retrospective cohort review of the records of all
TEN patients admitted between April 5, 1995 and December 4, 2002. There were 16 patients in the IG group (age
53 +/- 21 years, with initial rash involving 65 +/- 29% TBSA) and 16 patients in the control group (age 52 +/- 20
years, with initial rash involving 65 +/- 27% TBSA). The IG group received 0.7 +/- 0.2 g/kg/day of IVIG for 4 +/- 1
days. There were no significant differences between the groups with respect to the length of stay, duration of
mechanical ventilation, severity of systemic inflammatory response syndrome and multiple organ dysfunction
syndrome, or the incidence of sepsis. Significant progression of the wound occurred in 13% of the IG patients and
in 27% of control patients, whereas no wound progression was observed in 47% of the IG patients and in 18% of
the control patients (P =.299). The time to healing did not differ between IG and control groups (11.2 +/- 3.6 vs
11.4 +/- 2.6 days, respectively). There was no significant difference in the mortality rate between the IG group
(25%) and the control group (38%). There were no complications from IVIG aside from one case of hyponatremia
from the hypotonic IVIG solution. Although there may have been a trend towards less severe wound progression
154
in patients who received IVIG, this was not associated with any substantial improvement in outcome in our TEN
patients. A prospective randomized study with a larger sample size is needed to confirm our findings.
Analysis of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis using SCORTEN : The
University of Miami Experience. Trent JT, Kirsner RS, Romanelli P, Kerdel FA. Arch Dermatol. 2003
Jan;139(1):39-43
BACKGROUND: Toxic epidermal necrolysis (TEN) is a rare, life-threatening condition caused by certain
medications. Keratinocytes affected by TEN have been found to undergo apoptosis mediated by Fas-FasL
interactions. Treatment with intravenous immunoglobulin (IVIG) has been proposed to inhibit this interaction.
OBJECTIVE: To demonstrate the effectiveness of IVIG therapy in reducing mortality in patients with TEN.
DESIGN: A retrospective analysis of 16 consecutive patients with TEN who were treated with IVIG. The
SCORTEN system, a validated predictor of TEN mortality, was used to analyze the data of these patients. Using
SCORTEN, we compared the predicted mortality of our patient population with observed mortality. SETTING:
Dermatology inpatient unit at a university-affiliated hospital. INTERVENTION: All 16 patients received IVIG
treatment daily for 4 days. Fifteen patients received 1 g/kg per day and 1 patient received 0.4 g/kg per day. MAIN
OUTCOME MEASURES: For each patient, causes of TEN and other medical problems were documented prior to
IVIG therapy, as were the 7 independent SCORTEN risk factors. RESULTS: One patient died. Based on the
SCORTEN system, 5.81 patients were expected to die. These mortality rates were compared using the
standardized mortality ratio (SMR) analysis ([Sigma observed deaths/Sigma expected deaths] x 100) to determine
the efficacy of this treatment, which showed that patients with TEN treated with IVIG were 83% less likely to die
than those not treated with IVIG (SMR = 0.17; 95% confidence interval, 0.0-0.96). CONCLUSION: Based on
comparison of our observed mortality rate with the SCORTEN-predicted mortality rate, treatment with IVIG
significantly decreased mortality in patients with TEN.
High-dose intravenous immunoglobulin in the treatment of toxic epidermal necrolysis : a study of ocular benefits
Yip LW, Thong BY, Tan AW, Khin LW, Chng HH, Heng WJ. Eye. 2005 Aug;19(8):846-53
PURPOSE: To compare acute ocular complications of toxic epidermal necrolysis (TEN) following treatment with
high-dose human intravenous immunoglobulin (IVIG) with a historical cohort not treated with IVIG. METHODS:
Retrospective, historically controlled study. In all, 10 consecutive patients with TEN (treatment cohort) presenting
between 1 July 2001 and 30 June 2002. Totally, 18 consecutive patients with TEN (historical cohort).SettingTan
Tock Seng Hospital, Singapore. The treatment cohort received high-dose IVIG (2 g/kg body weight over 2 days).
Patients'records were retrospectively reviewed for their demographic characteristics, causative drug, treatment,
ocular involvement (if any, as assessed by an ophthamologist), and its severity. The historical cohort comprised
patients coded with a diagnosis of TEN (ICD Code 695.1) between 1 July 1995 and 30 June 2001. RESULTS:
Nine (90%) of 10 patients treated with IVIG had ocular involvement. Phenytoin was the implicated drug in three
(37.5%) patients. Of the nine patients, 1 died of septic shock. Of the eight survivors, IVIG was initiated
immediately upon onset of TEN as all the patients were hospitalized by the time of onset of an exanthema. Acute
ocular complications were mild in two (25%) (lid oedema or mild conjunctival injection), moderate in four (50%)
(pseudomembranes) and severe in two (25%) (nonhealing epithelial defect with visual loss and symblepharon). In
total, 10 (55.6%) of 18 patients in the historical cohort with TEN had acute ocular involvement. Two patients died.
Ocular involvement in survivors was mild in five (62.5%) cases and moderate in three (37.5%), with no severe
cases. CONCLUSIONS: IVIG did not appear to reduce the severity of visually significant ocular complications.
Larger studies are needed to confirm this finding.
Intravenous immunoglobulins and plasmapheresis combined treatment in patients with severe toxic epidermal
necrolysis: preliminary report. Lissia M, Figus A, Rubino C. Br J Plast Surg. 2005 Jun;58(4):504-10
Toxic epidermal necrolysis (TEN) is an acute drug-induced life-threatening disorder characterised by extensive
epidermal exfoliation and high rate of mortality. Between October 2000 and April 2003, five severe TEN patients
were evaluated using a specific TEN severity-of-illness scale (SCORTEN) and treated for the first time, with a
combined therapy using Intravenous Human Immunoglobulins (IVIG) and plasmapheresis. The standardised
mortality ratio (SMR) analysis ([Sigma observed deaths/Sigma expected deaths]x100) was applied to establish
how IVIG and plasmapheresis treatment could reduce TEN patient mortality. The observed mortality was one out
of five patients corresponding to 20%. The expected mortality based on SCORTEN was 3.319 corresponding to
66%. The SMR analysis revealed a 70% reduction in mortality (SMR=0.30; 95% confidence interval, 0.0-0.96).
Our series show a low mortality rate (20%) related to the severity of the patients (66% expected mortality). The
use of IVIG in association with plasmapheresis has a rational basis and may be effective in severe TEN patients.
155
Efficacy of low dose intravenous immunoglobulins in children with toxic epidermal necrolysis : an open
uncontrolled study. Mangla K, Rastogi S, Goyal P, Solanki RB, Rawal RC. Indian J Dermatol Venereol Leprol.
2005 Nov-Dec;71(6):398-400
BACKGROUND: High dose intravenous immunoglobulins (IVIG) have emerged as a promising new therapy for
treating the rare but potentially fatal drug reaction toxic epidermal necrolysis (TEN). Experimental in vitro studies
support the view that IVIG can block the fas-fas ligand mediated apoptosis in TEN. METHODS: Ten pediatric
patients of TEN were treated with IVIG (0.05 - 0.1 gm/kg/day) along with antibiotics and supportive care.
RESULTS: Patients with 67% of mean body surface area of involvement showed an average of 2.1 days for
arrest of progression of lesions and 8.1 days for complete reepithelization. There was no mortality.
CONCLUSIONS: Low dose IVIG appears to be a safe and effective treatment for TEN in children. Randomized
trials are needed to further evaluate the efficacy of IVIG and compare it with other therapeutic modalities.
High-dose intravenous immunoglobulins in the treatment of toxic epidermal necrolysis : an Asian series. Tan AW,
Thong BY, Yip LW, Chng HH, Ng SK. J Dermatol. 2005 Jan;32(1):1-6.
Toxic epidermal necrolysis (TEN) is a severe, immune-mediated, mucocutaneous reaction resulting in extensive
keratinocyte apoptosis. High-dose human intravenous immunoglobulins (IVIG) have been proposed as an
effective treatment for TEN. Retrospective data from 8 patients with TEN and 4 patients with Stevens-Johnson
syndrome-toxic epidermal necrolysis (SJS-TEN) overlap treated with high-dose IVIG were analysed. The total
dose of IVIG administered was 2 g/kg body weight, with the exception of 2 patients who received a total dose of
1.5 g/kg body weight. Their mean age was 49.9+/-18.8 years (range, 19 to 70 years). The mean time from the first
sign of skin lesion or mucosal or epidermal detachment to commencement of IVIG was 8.7+/-5.5 days (range, 3 to
22 days). Of the 11 patients who survived, the mean time to objective response was 3.6+/-1.9 days (range, 2 to 8
days). The length of stay (LOS) in hospital was 20.4+/-8.0 days (range, 10 to 37 days). The survival rate was
91.6%. One patient developed permanent mucocutaneous sequelae following TEN. There were no adverse
reactions to IVIG. We conclude that high-dose IVIG may be a safe and effective therapy for Asian patients with
TEN.
156
•
Dermatite atopique sévère
La dermatite atopique (DA) (ou eczéma constitutionnel) est une affection inflammatoire prurigineuse
chronique commune chez l'
enfant (2 à 5% des enfants de moins de 5 ans) et l'
adulte jeune, qui est
sous la dépendance de facteurs héréditaires mais dont l'
augmentation de prévalence au cours des
dernières décennies s'
explique préférentiellement par l'
influence de facteurs environnementaux
encore mal compris.
La dermatite atopique sévère de l’adulte est une maladie chronique rare et invalidante. Les
traitements de première ligne (dermocorticoides, photothérapie) sont parfois insuffisants pour obtenir
un contrôle satisfaisant de la maladie au long cours. La ciclosporine et le tacrolimus topique sont les
seuls traitements de deuxième intention.
L’analyse de la littérature ne trouve qu’une étude randomisée en groupe parallèle de faible effectif (5
patients adultes par groupe) évaluant l’effet de 2 g/kg d’IgIV administrés soit immédiatement, soit à un
mois. L’évaluation du critère de jugement principal (SCORAD à J30) était réalisée en aveugle. Les
résultats n’ont montré aucune efficacité du traitement.
Le reste de littérature rapporte des cas isolés ou des études ouvertes de faible effectif (moins de 10
patients). Un total d’une quarantaine de patients adultes a été traité. Les résultats sont contradictoires.
Certains auteurs rapportent une meilleure efficacité du traitement en association. D’autres insistent sur
une efficacité meilleure chez l’enfant. Enfin, certains estiment que les IgIV doivent être utilisées au
long cours (plus de 4 mois).
Les données de littérature permettent d’exclure une franche efficacité du traitement en monothérapie
et aux doses usuelles. Au vu des études ouvertes, il est possible que l’effet soit faible ou qu’un sous
groupe de patients puisse bénéficier d’un tel traitement.
Effet des IgIV dans la dermatite atopique sévère
Auteur
Type d’étude
Posologie
Paul
(2002)
Contrôlée
randomisée
double - aveugle
n = 10 patients
adultes ayant une
dermatite atopique
sévère
. n = 5 patients
traités
immédiatement
. n = 5 patients
traités
par
les
traitements
conventionnels
puis par IgIV 1
mois après
IgIV :
2g /
totale)
kg
(dose
Suivi
J15
J30
J60
J90
Critères
d’évaluation
SCORAD : mesure
du score de sévérité
de
la
dermatite
atopique J30
Résultats
- Scorad J30 : NS
- IC 95 % : J30 : NS
- IC 95 % : J60 : NS
↓ du scorad J60 de
22 % : S
Bibliographie
Paul C, Lahfa M, Bachelez H, Chevret S, Dubertret L. : A randomized controlled evaluator-blinded trial of intravenous
immunoglobulin in adults with severe atopic dermatitis. Br J Dermatol. 2002 Sep;147(3):518-22
Résumé-abstract
. Paul C, Lahfa M, Bachelez H, Chevret S, Dubertret L. A randomized controlled evaluator-blinded trial of
intravenous immunoglobulin in adults with severe atopic dermatitis: Br J Dermatol. 2002 Sep;147(3):518-22
157
BACKGROUND: There is a need for alternative therapy in severe adult atopic dermatitis (AD). Intravenous
immunoglobulin (IVIG) treatment has been shown to be beneficial in a few open observations, but evidence of
effectiveness is still lacking. OBJECTIVE: To investigate whether treatment with IVIG is effective in adults with
severe AD. METHODS: In a randomized evaluator-blinded trial, 10 patients with severe AD were randomized to
immediate or delayed (by 1 month) treatment with IVIG 2 g kg-1. Patients received an 8-h infusion of 1 g kg-1
daily for two consecutive days. They were assessed clinically at days 15, 30, 60 and 90. The primary efficacy
criterion was measurement of the severity scoring of AD (SCORAD) index at day 30. RESULTS: The SCORAD
values were not significantly different between the two groups at day 30. Similarly, global evaluation of disease
severity by patients did not show any clinically significant change at day 30. In the cohort of 10 patients, the mean
percentage decrease in SCORAD as compared with baseline was, respectively, 15%[95% confidence interval
(CI) 6-24%] and 22% (95% CI 5-39%) at 30 and 60 days after IVIG infusion. CONCLUSIONS: IVIG treatment was
not associated with clinically significant improvement of AD signs and symptoms in this randomized study.
Although this study may have been too small to detect a beneficial effect in a small subset of patients, the results
do not support the common use of IVIG in refractory AD.
158

Consulter

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