Diagnostic strategy for patients with hypogammaglobulinemia in rheumatology Maxime Samson

Transcription

Diagnostic strategy for patients with hypogammaglobulinemia in rheumatology Maxime Samson
Joint Bone Spine 78 (2011) 241–245
Review
Diagnostic strategy for patients with hypogammaglobulinemia in rheumatology
Maxime Samson a,b , Sylvain Audia a,b , Daniela Lakomy b,c , Bernard Bonnotte a,b ,
Christian Tavernier d , Paul Ornetti d,∗,e
a
Department of Internal Medicine and Clinical Immunology, Dijon University Hospital, 21079 Dijon, France
CR Inserm U866, Lipids Nutrition Cancer, 21000 Dijon, France
c
Laboratory of Immunology, Dijon University Hospital, 21079 Dijon, France
d
Department of Rheumatology, hôpital général, Dijon University Hospital, 3, rue du Faubourg-Raines, 21000 Dijon, France
e
Inserm U887, 21078 Dijon, France
b
a r t i c l e
i n f o
Article history:
Accepted 4 August 2010
Available online 30 October 2010
Keywords:
Hypogammaglobulinemia
Chronic inflammatory rheumatism
Primary immunodeficiency
Diagnosis
Etiologies
a b s t r a c t
The discovery of hypogammaglobulinemia, which is defined as a plasmatic level of immunoglobulin
(Ig) under 5 g/L is rare in clinical practice. However, the management of immunodepressed patients
in rheumatology, sometimes due to the use of immunosuppressive treatments such as anti-CD20 in
chronic inflammatory rheumatisms, increases the risk of being confronted to this situation. The discovery
of hypogammaglobulinemia in clinical practice, sometimes by chance, must never be neglected and
requires a rigorous diagnosis approach. First of all, in adults, secondary causes, in particular lymphoid
hemopathies or drug-related causes (immunosuppressors, antiepileptics) must be eliminated. A renal
(nephrotic syndrome) or digestive (protein-losing enteropathy) leakage of Ig is also possible. More rarely,
it is due to an authentic primary immunodeficiency (PID) discovered in adulthood: common variable
immunodeficiency (CVID) which is the most frequent form of PID, affects young adults between 20 and
30 years and can sometimes trigger joint symptoms similar to those in rheumatoid arthritis; or Good
syndrome, which associates hypogammaglobulinemia, thymoma and recurrent infections around the
age of 40 years. In most cases, after confirming hypogammaglobulinemia on a second test, biological
examinations and thoracic-abdominal-pelvic CT scan will guide the diagnosis, after which the opinion of
a specialist can be sought depending on the findings of the above examinations. At the end of this review,
we provide a decision tree to guide the clinician confronted to an adult-onset hypogammaglobulinemia.
© 2010 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
The discovery of hypogammaglobulinemia (< 5 g/L) during a
check-up or the follow-up of a patient with chronic inflammatory
rheumatism is a rare but not exceptional situation in everyday
clinical practice. This biological abnormality is a real diagnostic
challenge for practitioners. Indeed, a deficit in immunoglobulins
(Ig) brings into question the management of the rheumatism (iatrogenic effect of immunosuppressors, hematological complication of
the chronic arthritis, or possibly polyarthritis directly related to Ig
deficiency). All of these etiologies must be considered when complementary examinations are conducted to guide the diagnosis in
cases of hypogammaglobulinemia.
The first question that needs to be answered is the possible iatrogenic cause of the hypogammaglobulinemia, in particular
when a patient with inflammatory rheumatism is treated by
immunosuppressors. The growing use of anti-CD20 antibodies
in rheumatology, such as rituximab and soon ocrelizumab, has
increased the risk of hypogammaglobulinemia occurring during
∗ Corresponding author. Tel.: +33 3 80 29 37 45; fax: +33 3 80 29 36 78.
E-mail address: [email protected] (P. Ornetti).
the follow-up, with the subsequent risk of infectious complications [1]. The second question concerns the possible neoplastic
complication of the chronic inflammatory rheumatism (rheumatoid arthritis (RA), Gougerot-Sjögren syndrome, systemic lupus
erythematosus), notably lymphoma. The third question concerns a
possible link between polyarthralgia presented by the patient and
primary immunodeficiency (PID), even though the occurrence of
PID in the form of inflammatory rheumatism in adulthood is rather
exceptional.
All things considered, the discovery of hypogammaglobulinemia requires a coherent diagnostic approach to determine the
origin, so that an appropriate etiological treatment and if necessary
polyvalent Ig replacement therapy can be implemented.
After a short reminder about the physiopathology, this review
will describe in the first part the different etiologies that should be
considered in cases of hypogammaglobulinemia, focusing on the
most frequently causes seen in the field of rheumatology. In the
second part, a diagnostic decision tree is proposed to help practitioners confronted to this unusual clinicobiological situation in
order to guide the choice of complementary examinations, before
seeking the opinion of a specialist.
1297-319X/$ – see front matter © 2010 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.jbspin.2010.09.016
242
M. Samson et al. / Joint Bone Spine 78 (2011) 241–245
Table 1
Function, molecular weight, serum levels, roles and half-life of the different immunoglobulins in adults.
Heavy chain
Molecular weight (kDa)
Serum level (g/L) in adults
Half-life in serum (days)
Activation of classical complement pathway
Activation of alternative complement pathway
Placental transfer
Binding to Fc receptors
High affinity binding to mastocytes and basophils
a
IgG1
IgG2
IgG3
IgG4
IgM
IgA1
IgA2
IgD
IgE
␥1
146
9
21
++
−
+++
+
−
␥2
146
3
20
+
−
+
−
−
␥3
165
1
7
+++
−
++
+
−
␥4
146
0.5
21
−
−
+/−
+/−
−
␮
970a
1.5
10
++++
−
−
−
−
␣1
160
3.0
6
−
+
−
+
−
␣2
160
0.5
6
−
−
−
+
−
␦
184
0.03
3
−
−
−
−
−
␧
188
5 × 10−5
2
−
−
−
+
+++
Molecular weight of the pentamer.
1. Physiopathogenic aspects
Igs are glycoproteins encountered either as membranous receptor (BCR) on B cells or produced by plasma cells as soluble
molecules, called “antibodies” (Ab) and present in the serum and
extracellular fluids. There are different classes of Ig: IgG1 to IgG4,
IgA1 and IgA2 , IgM, IgD and IgE, the function and half-life of which
are very different, from several hours to several weeks (Table 1)
[2]. Only IgG, IgA and IgM play a role in anti-infectious immunity
[3], through different mechanisms: neutralization of the antigen,
bactericidal effect by activation of the classical pathways of complement (complement dependent cytotoxicity [CDC]), bactericidal
effect via mechanisms of Ab-dependent cytotoxicity (antibodydependent-cell-mediated cytotoxicity [ADCC]), opsonization of
rapidly developing extracellular bacteria such as Gram positive
cocci and enterobacteria, thus facilitating phagocytosis.
Concerning other classes of Ig, IgM are the predominant antibodies during the primary immune response and are essentially
confined to the intravascular compartment. IgM are powerful
activators of classical complement pathway. IgG are the most
abundant Ig and are equally distributed in the vascular and
extravascular compartments. IgG interact with various receptors
of the Fc fragment (Fc␥R) expressed by various subsets of immune
cells, especially from the myeloid lineage such as monocytes or
macrophages. IgG1 and IgG3 are also able to activate complement.
The main role of IgA is to inhibit the adherence of bacteria on the
mucosa of the respiratory, gastrointestinal and genital tracts.
On serum protein electrophoresis (SPE), Ig migrate mainly in
the zone of gammaglobulins. Normal levels vary with age. They
range from 8 to 12 g/L in healthy adults. Hypogammaglobulinemia
is defined by a level less than 5 g/L. The term agammaglobulinemia describes situations that associate a level of gammaglobulins
below 1 g/L and the absence of circulating B lymphocytes. As well
as the fall in the level of gammaglobulins, other elements must
be searched for on the SPE to begin the etiological investigation: a
monoclonal peak or hypoalbuminemia. The latter could suggest a
renal or digestive leakage of Ig.
2. Principal causes of hypogammaglobulinemia
2.1. Context of discovery
The most frequent context of discovery in everyday practice is
chance. A variety of clinical manifestations frequent in rheumatology (described as follows) may also lead to a prescription of SPE to
screen for hypogammaglobulinemia.
2.1.1. Infection
The main risk of a deficit in Ig, whether primary or secondary,
is an increased susceptibility to infections by encapsulated germs,
such as Streptococcus pneumoniae and Haemophilus influenzae but
also other Streptococci, Staphylococci or enterobacteria [4–6]. The
infections are mainly recurrent and/or severe and concern the ENT
or airways. In clinical practice, the onset of more than two episodes
of sinusitis or pneumopathy in a year, or more than eight episodes
of acute middle-ear otitis should bring to mind immune deficiency.
2.1.2. Autoimmune manifestations
Autoimmune cytopenia [7], polyarthritis [8] or any other manifestation of immune dysfunction must lead to an SPE. However, no
studies have validated the interest of the systematic prospective
SPE in the onset of inflammatory rheumatism of unknown origin.
2.1.3. Peripheral lymphadenopathy, hepatomegaly and
splenomegaly
This clinical picture should lead to systematic SPE, since there is
a question of hemopathy.
In the majority of cases, the rheumatologist is faced with
hypogammaglobulinemia with no clinical signs to help guide the
diagnosis. It is this embarrassing clinical situation for the clinician
that led us to propose the diagnostic decision tree in the next section. Simple biological surveillance is not recommended because
the etiology needs to be found quickly. Indeed, the therapeutic
approach may be totally different depending on the cause: interruption of an immunosuppressive treatment in case of iatrogenic
hypogammaglobulinemia or implementation of a cytotoxic treatment in case of lymphoid hemopathy.
2.2. Etiologies
It is possible to distinguish between primary causes (PID) and
secondary causes of hypogammaglobulinemia with a wide variety
of etiologies, which must be immediately searched for in adults.
2.2.1. Medication
Many medicines can induce hypogammaglobulinemia, among
which some are widely prescribed by rheumatologists (Table 2).
Among the medicines on this list, all of which require a pharmacovigilance investigation, we can focus on the following:
• antiepileptics and in particular carbamazepine (Tegretol® ),
phenytoin (Dihydan® , Dilantin® ) and clonazepam (Rivotril® ). The
deficiency affects all classes of Ig and is usually reversible and disappears with cessation of the treatment [9–11]. Complications
due to infections are generally rare [12–16];
• disease modifying treatments for chronic inflammatory rheumatism, in particular d-penicillamine (Trolovol® ), gold salts and
sulfasalazine (Salazopyrine® ). They principally cause IgA deficiency, but hypogammaglobulinemia has also been described,
often with no clinically important consequences [17–22]. Some
observations have suggested that methotrexate may also cause
such deficiencies, but the risk seems to be lower in comparison
with the treatments above [23];
• targeted biotherapies, employed in oncohematology and more
recently in the treatment of immune dysfunction, in particular anti-CD20, such as rituximab (Mabthera® ). The onset of
M. Samson et al. / Joint Bone Spine 78 (2011) 241–245
243
Table 2
Principal medicines that cause hypogammaglobulinemia.
Frequent
Quite frequent
®
Cyclophosphamide (Endoxan )
Corticosteroids
Rituximab (Mabthera® )
Imatinib (Glivec® )
Rare
®
Carbamazepine (Tegretol )
Phenytoin (Di-hydan® ,
Dilantin® )
Sulfasalazine (Salazopyrine® )
Gold salts
d-penicillamine (Trolovol® )
hypogammaglobulinemia under rituximab was first described
in oncohematology, in which it is often prescribed with other
cytotoxic drugs. The princeps study reported hypogammaglobulinemia without infectious complications and with a deficiency
that concerned almost exclusively IgM [24]. Doubts were cast on
the findings of this study by later studies that reported authentic hypogammaglobulinemia complicated by sometimes severe
recurrent bacterial and viral infections, notably cytomegalovirus
and varicella-zoster [4,25,26]. A retrospective study involving 97
patients treated by rituximab and cytotoxic drugs for malignant
hemopathy, with a follow-up of 3 years, reported an incidence
of 43% of infections (bronchitis, sinusitis and pneumoniae) that
were not associated with episodes of neutropenia. In every case,
hypogammaglobulinemia was associated with these infections
[4]. Hypogammaglobulinemia under anti-CD20 has also been
reported in non-oncological indications, but generally the condition is moderately severe with no infectious complications
[27]. However, the risk of new-onset hypogammaglobulinemia
increases with iterative treatments by rituximab, rising from less
than 10% with the first course to 30% with the fourth course [28].
A recent study, with a follow-up of more than 6 years, showed
that repeated treatment with rituximab in RA was not associated
with a significant increase in the number of severe episodes of
infection. There was, however, a non-significant trend towards an
increase in severe infectious episodes in patients with a decrease
in levels of IgM and IgG after several courses of rituximab [29];
• classically, corticosteroids cause lymphopenia mainly involving T
CD4+ lymphocytes, but they may also induce hypogammaglobulinemia [30–34]. Generally speaking, the episodes are moderately
severe (between 4 and 5 g/L) and essentially concern IgG (IgG1 in
particular), and IgA and IgM to a lesser degree. These deficiencies have been reported in all types of corticosteroid therapy:
low-dose long-term therapy (> 5 mg/d for more than 2 years)
[31], or high-dose short-term therapy [32]. The prevalence of
hypogammaglobulinemia in these populations was around 12 to
17% [32,34]. The mechanism is still unclear: corticosteroids may
increase catabolism [33] and reduce the synthesis of Ig via their
action on intracellular pathways [35]. It seems that the infectious consequences of this deficiency are slight, even though
there is sometimes an impaired response to vaccines, notably
anti-pneumococcal vaccine [32,34];
• there have also been reports associated with the use of aspirin
and other immunosuppressors (azathioprine, ciclosporine), but
such reports are rather exceptional.
2.3. Lymphoid hemopathy
Once the medication-related etiology has been ruled out or put
to one side, the clinician must focus the investigations on the search
for malignant hemopathy in the case of new-onset hypogammaglobulinemia in adults, even in the absence of associated clinical
Sodium valproate (Dépakine® )
Levetiracetam (Keppra® )
Clonazepam (Rivotril® )
Phenobarbital (Gardenal® )
Acetylsalicylic acid (Aspirin® )
Azathioprine (Imurel® )
Ciclosporine (Neoral® ,
Sandimmun® )
Captopril (Lopril® )
Thyroxine (Levothyrox® ,
l-thyroxine® )
Chlopromazine (Largactil® )
signs. This mainly concerns lymphoid hemopathy: chronic lymphocytic leukemia (CLL), multiple myeloma (MM), Waldenström’s
disease or non-Hodgkin’s lymphoma (NHL). In MM, hypogammaglobulinemia may be linked to MM itself (light chain MM
or non-secretory MM), or may be secondary to AL amyloidosis
via nephrotic syndrome. Myelogram, serum immunofixation and
serum free light chain assay (FLC) will guide the diagnosis. A recent
study showed that a rise in FLC or a hypogammaglobulinemia may
precede the diagnosis of CLL by several years [38]. This highlights
how important it is to vigorously search for malignant hemopathy
when hypogammaglobulinemia is discovered in adults.
2.3.1. Hypogammaglobulinemia due to renal, digestive or
capillary leakage
These causes are less frequent and are generally accompanied
by clinical symptoms that guide the diagnosis, such as diarrhea
or diffuse edema. Hypogammaglobulinemia due to renal or digestive leakage is generally associated with severe hypoalbuminemia
(< 30 g/L).
The discovery of significant proteinuria will guide the diagnosis towards renal leakage. In cases of nephrotic syndrome, there
will be a leakage of IgG rather than IgM or IgA. In the absence of
significant proteinuria, it is necessary to screen for protein-losing
enteropathy. There may be rheumatological symptoms associated
with the underlying disease (Crohn’s disease, systemic sclerosis,
systemic lupus erythematosus. . .). The diagnosis is confirmed by
the discovery of an increase in fecal ␣1-antitrypsin clearance.
This is the most sensitive screening test, though stool samples
need to be collected on three consecutive days. The association
of hypogammaglobulinemia and transient hypoalbuminemia may
also be encountered in systemic capillary leak syndrome (Clarkson’s syndrome), though this is rather rare [39]. The diagnosis is
based on episodes of severe acute shock associated with hemoconcentration and hypoprotidemia (with hypoalbuminemia), which
resolves during the acute episode.
2.3.2. Hypogammaglobulinemia due to impaired secondary
production
Etiologies of hypoalbuminemia associated with hypogammaglobulinemia is not restricted to extraplasma or extracorporeal
protein leakage. Transient hypogammaglobulinemia may be found
during an acute episode of infection or in contrast may indicate a
chronic inflammatory process or severe malnutrition.
2.3.3. Primary hypogammaglobulinemia in adults
PID is a rare cause of hypogammaglobulinemia and generally
affects younger patients with regard to hypogammaglobulinemia
due to a secondary cause. A family history of PID, a personal or
family history of severe recurrent infections or severe hypogammaglobulinemia (< 2 g/L) with a total deficiency of IgA (< 0.07 g/L)
suggest PID [40]. Most PID do not lead to hypogammaglobuline-
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M. Samson et al. / Joint Bone Spine 78 (2011) 241–245
mia [41]. In adults, the two main PID to consider in the context of
hypogammaglobulinemia are common variable immunodeficiency
(CVID) and Good’s syndrome.
2.3.3.1. CVID. This is the most frequent PID (20.7% in a European
cohort [42]) after selective IgA deficiency, with an incidence estimated at 1/75000 and a sex ratio of 1 [43]. Most of these cases
are sporadic and only 10 to 15% are familial [43]. The condition
is generally diagnosed between the age of 20 and 30 years. The
diagnostic criteria for CVID are hypogammaglobulinemia affecting
at least two isotypes of Ig, and recurrent sinopulmonary infections
associated with an impaired response to vaccines [5,43]. Antibioticresistant infections are the most frequent clinical manifestations of
CVID (85% of cases). These infections mainly concern the airways
or the digestive system (50% of patients with CVID have chronic
diarrhea). Approximately 25% of patients suffer from autoimmune
manifestations, principally autoimmune cytopenia [5,7,44] but
also: Biermer’s disease, autoimmune thyroiditis, vitiligo and less
often with chronic mono, oligo or polyarthritis often mimicking
RA [43]. Generally speaking, these types of arthritis respond to Ig
replacement treatment [8]. Then, 10 to 22% of patients with CVID
present a clinical picture of systemic granulomatosis similar to sarcoidosis. From an immunopathological point of view, CVID is an
extremely heterogeneous disease [43,45]. In certain cases, there
is an abnormal regulation of Ig gene expression. Certain CVID are
linked to genomic abnormalities of B cell activating factor belonging
to the TNF family (BAFF), a cytokine binding to different receptors (BAFF-R, TACI and BCMA) and playing an important role in
the differentiation and survival of B cells. Recently, CVID and IgA
deficiency have been associated with other mutations, most often
heterozygous, of the TACI gene. This autosomal dominant form
could account for 10 to 20% of CVID [46,47].
2.3.3.2. Good’s syndrome. This is a particular form of adult-onset
hypogammaglobulinemia, first described in 1956 [48]. The clinical presentation is similar to that in CVID but occurs at an older
age, between 40 and 50 years. The clinical picture associates severe
hypogammaglobulinemia, recurrent infections and thymoma. The
prognosis and life expectancy are not as good as those in CVID.
Certain biological abnormalities may guide the diagnosis: lymphopenia with an almost permanent absence of B cells, an increase
in T CD8+ lymphocytes and a decrease in T CD4+ lymphocytes
leading to an inbalance within the CD4/CD8 ratio; a deficiency in
NK cells and neutrophils; and auto-immune erythroblastopenia.
Diagnosis is confirmed by the discovery of thymoma on thoracic
imaging. Thymectomy does not modify the course of the disease.
The presence of this syndrome justifies a systematic thoracic CT
scan in any case of adult-onset hypogammaglobulinemia with no
obvious causes [49].
Other PID leading to hypogammaglobulinemia are much more
rare and generally diagnosed in childhood: Purtilo syndrome, hyper
IgM syndromes [43,50], X-related agammaglobulinemia (Bruton)
in boys and autosomal recessive or dominant agammaglobulinemia
(which may manifest itself as rheumatism).
Fig. 1. Diagnostic strategy in the face of adult-onset hypogammaglobulinemia
(< 5 g/L). The grey boxes are diagnostics classically associated with hypoalbuminemia (< 30 g/L). HMG: hepatomegaly; SMG: splenomegaly; ADP: adenopathy; ENT:
ear nose and throat; SPE: serum protein electrophoresis; FBC: fool blood count;
ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; CVID: common variable immunodeficiency. *A thoracic-abdominal-pelvic CT scan is recommended if
there is no obvious cause of the hypogammaglobulinemia.
3.1. The first step
The first step is to confirm hypogammaglobulinemia. It is
essential to confirm the condition with a second assay to avoid
unnecessary explorations. Moreover, cryoglobulinemia may lead
to “false” hypogammaglobulinemia, and thus needs to be screened
for early on. This diagnosis may be revealed by the discovery of
hypogammaglobulinemia in the presence of clinical signs compatible with cryoglobulinemia: polyarthritis, vascular purpura,
neuropathy. . . In such cases, SPE at 37 ◦ C gives the precise levels
of different gammaglobulins. However, in certain affections, cryoglobulinemia and authentic hypogammaglobulinemia may exist
together: MM, NHL or lupus in particular.
3.2. The second step involves searching for a secondary cause
3. Diagnostic strategy in cases of adult-onset
hypogammaglobulinemia
Once hypogammaglobulinemia has been confirmed in a second
sample, a biological examination is necessary to narrow down the
investigation. Then, depending on the clinical orientation, complementary examinations and specialist opinion reveal in most cases
the origin of hypogammaglobulinemia (Fig. 1).
In practice, a pharmacovigilance investigation needs to be carried out as well as further biological tests. In the absence of an
obvious cause, a thoracic-abdominal-pelvic CT scan is required.
Even after the pharmacovigilance investigation, the implication of
a particular drug is sometimes difficult to prove. From a therapeutic
point of view, if possible, the interruption of a medical treatment
must be considered. This may also serve as a diagnostic test. The
time needed for the resolution of hypogammaglobulinemia varies
M. Samson et al. / Joint Bone Spine 78 (2011) 241–245
considerably: several months for carbamazepine [11], up to 2 years
for corticosteroids, and sometimes several years for anti-CD20
[36–37]. When the link is weak and the hypogammaglobulinemia
severe (< 4 g/l) or when the resolution of hypogammaglobulinemia
after cessation of the suspected drug is incomplete, it is essential
to search for another cause of hypogammaglobulinemia.
In the initial biological examination, a full blood count (FBC),
inflammatory tests (ESR and C-reactive protein), albuminemia,
proteinuria over 24 h, quantified Ig assay and serum immunofixation will be performed systematically. Albuminemia < 30 g/L would
guide the diagnosis towards a renal or digestive origin, whereas
albuminemia > 30 g/L would suggest a hematological, drug-related
or immunological cause.
3.3. The third step is the opinion of a specialist
This is to complete the complementary investigations depending on the findings. At this stage, immunologists, internists, hematologists, nephrologists or gastroenterologists are most frequently
consulted. After this consultation, treatment of hypogammaglobulinemia will be discussed. The treatment will comprise three
distinct elements: etiological treatment, treatment of the complications (first of all infections and eradication of potential sites of
infection) and Ig replacement therapy, which principally concerns
PID and more rarely secondary hypogammaglobulinemia
Conflict of interest statement
The authors have no conflicts of interest to declare.
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