What is the Natural History of Scleroderma with its Onset in

What is the Natural History of Scleroderma with
its Onset in Childhood?
Dr Eileen Baildam
Consultant Paediatric Rheumatologist
BSR May 2012
Disclosures
• I have no relevant disclosures
Scleroderma
Natural History of Childhood Onset
Scleroderma: Problems
• Extreme rarity and multiple subtypes
• Disease heterogeneity from mild skin lesions
to disabling disease
• Different specialty managements
• Lack of established outcome measures or
biomarkers
• Published uncontrolled studies show
“improvement”
• “n of one” studies
PRES Proposed New Classification for Localised
Scleroderma -2004
• Circumscribed morphea
– Superficial
– Deep
• Linear Scleroderma
– Trunk/ limbs
– Head
• Generalised morphea (>4 in >2
sites)
• Pansclerotic
• Mixed morphea
(A combination of 2
or more of the previous
subtypes)
Localised Linear scleroderma Leg
and truncal
Localised scleroderma
Provisional classification criteria
for JSSc (PRES)Zulian 2007
Major Criteria required
 Proximal skin sclerosis/induration
And at least 2 minor criteria
 Cutaneous
Sclerodactly
 Peripheral vascular
Raynauds,nailfold capillary changes,
digital ulcers
 GIT
Dysphagia, GOR
 Cardiac
Arrythmias, Heart failure
 Renal
Renal crisis, new onset arterial hypertension
 Respiratory
Pulmonary fibrosis on HRCT, PAH, DLCO
reduced
 Neurological
Neuropathy, Carpal tunnel syndrome
 MSK
Tendon friction rubs, Arthritis, Myositis,
 Serology
ANA, SSc specific antibodies
Limited cutaneous systemic
sclerosis (lcSSc)
• Skin involvement confined to distal to
elbows, knees and face and neck.
• Raynauds may pre-exist for years
• Gradual onset
• Vascular component more prominent
with digital ulcers, PAH,
• Renal crises
• Some fibrosis
• GOR
• CREST
Diffuse Cutaneous
Systemic Sclerosis
• Skin involvement extends to proximal limb and to
trunk
• More inflammatory
• Widespread inflammation in the skin and
musculoskeletal system with oedema
• Extensive fibrosis
• Raynauds usually at onset or later
• Internal organ disease especially kidney
BPSU/BAD Incidence Study
Ariane Herrick, Holly Ennis, Monica Bushan, Alan Silman, Eileen Baildam
Arthritis Care and Res 2010
185
notifications
37 out of time-frame
20 duplications
34 reporting errors
91
excluded
94
verified
10
lost to
follow-up
84 followed up
at 12 months
87 cases of localised
scleroderma
= incidence rate of
3.47 per million
children per year
7 cases of SSc
= incidence rate
0.28 per million
children per year
Localized scleroderma: Clinical
subtypes BPSU/BAD Incidence Study
Ariane Herrick, Holly Ennis, Monica Bushan, Alan Silman, Eileen Baildam
Arthritis Care and Res 2010
7%
2%
26%
65%
linear scleroderma
Plaque morphea
Generalised morphea
Deep morphea
Pathogenesis of Scleroderma
1)
2)
3)
4)
Perivascular infiltration of mononuclear cells
(mainly activated T cells) into skin and
surrounding blood vessels shown in 84%.
Autoimmunity- ANAs, cytokines and soluble cell
adhesion molecules. Soluble CD23, CD8 and
CD4.
Microvascular change, including endothelial cell
activation
Fibrosis
Inflammatory phase Th1/Th2/Th17 driven
Fibrotic stage Th2 predominant
Congenital Linear Scleroderma,
•
•
•
•
6/750 pts (0.8%)
All linear
4 facial
Delay in diagnosis 3.9
yrs
Zulian 2006
Linear morphea follows
Blaschko’s lines
L Weibel BJDerm 2008; 159(1):175-181
•
•
•
65 children’s clinical
photographs
Adobe Illustrator
overlays
Excellent correlation
with Blaschko’s lines
Unusual courses
• Single whole leg
petechia progressing to
severe linear
scleroderma
• Bx pigmented purpuric
dermatosis or
Majocchi's Schamberg's
Disease
Juvenile localised scleroderma: clinical and
epidemiological features in 750 children. An
international study (from 70 centres) Zulian Rheum 2006
• Age at onset mean 7.3 yrs (0-16)
• Disease duration at diagnosis 1.6 yr (0-17)
• Triggers
–
–
–
–
53 Trauma ( including GM 3 and DM 2)
11 Insect bites
3 Vaccination site
25 Infections
Delay to accessing care in juvenile scleroderma
Hawley, Baildam et al Rheum July 2011
• 89 cases 8 UK centres
• Mean time from first symptom to diagnosis
– 13 m (1-102m) in localised scleroderma
– 8 m (0-50m) in jSSc
Morphea in adults and Children: Patients
experience delay in diagnosis with large variation
in treatment Johnson 2012
• 141/224 ( 63%) diagnosed after 6 months of onset
• Dermatologists diagnosed and treated 83.5%
Tx with topical treatment
• Rheumatologists the more severe forms ( linear and
generalised)
Tx with systemic immunosuppression and
physiotherapy
Natural history questions
• Is there spontaneous resolution?
• What proportion have a poor outcome?
• Does treatment actually make a
difference?
• Where are the longitudinal studies?
BPSU/BAD Incidence Study
Outcome
Ariane Herrick, Holly Ennis, Monica Bushan, Alan Silman, Eileen Baildam
Arthritis Care and Res 2010
100
90
80
70
60
Localised
% 50
SSc
40
30
20
10
0
Resolved
Improved
Deteriorated
No change
• 84 cases (89%) followed up at 12 months
• Majority of cases followed up showed signs of improvement
Possible Outcome Measures
In Localised Scleroderma
• Size/ area/ volume/ clinical skin scores eg the
LoSCAT score
• Global VAS
• Limb length discrepancy (scattergram)
• Gait Analysis
• Colour changes
• Temperature changes
• Scores for investigations eg US
• Change in serum markers eg eosinophil count
Disease Activity Measures
Measuring skin involvement?
Durometry
Use of a durometer to assess skin hardness. Falanga and Bucalo, 1993. J Am Acad
Dermatol.
Elastometry
Non-invasive measurement of biomechanical skin properties in systemic sclerosis.
Balbir-Gurman et al, 2002. Ann Rheum Dis.
Ultrasound
Seventeen-point dermal ultrasound scoring system-a reliable measure of skin
thickness in patients with systemic sclerosis. Moore TL et al, 2003.
Rheumatology.
Biochemical correlates
Skin thickness and collagen content in progressive systemic sclerosis and localized
scleroderma. Rodnan et al,1979. Arthritis Rheum.
New computerised method of assessment
– F Zulian Rheumatology 2007;46:856-860
Laser Doppler
– L Weibel Arth Rheum 2007;56:3489-3495
Rx of Localized Scleroderma
Author
Worie
Falanga
Joly
Kersher
Cunningham
Wach
Moh.schlager
Elst
Seyeger
Uziel
Walsh
Kreuter
Kreuter
Fitch
Weibel
Cox
Yr
1990
1990
1994
1998
1998
1995
1999
1999
1998
2000
2000
2001
2005
2006
2006
2008
Treatment
Cyclosporin A
D-Penicillamine
Prednisolone
UVA
Topical VitD
Plasmapheresis
Penicillin G
Calcitriol
Methotrexate
MTX & steroids
MTX & steroids
UVA/ Vit D
Methotrexate &steroids
Methotrexate &steroids
Methotrexate &steroids
MTX & pulsed steroids
Improved
1
11
17
18/20
12
3
1
6/ 7
7
9/10
19
19
14/15
16/17
24/34
8/10
Localised scleroderma: treatment
only two RCTs with placebo
1)
Hunzelmann, J Am Acad Dermatol 1997
24 pts: IFN or placebo sc for 6 weeks.
After 24 weeks
NO DIFFERENCE
2)
Hulshof, J Am Acad Dermatol 2000
20 pts: calcitriol or placebo po
After 9 months
NO DIFFERENCE
Topical Treatment Options for
Localised Scleroderma
Treatment
N
Reference
Tacrolimus (Protopic)
0.1% bd for 3 months
7/7 cleared skin lesions
Mancuso and Berdondini
BJ Dermatol 2005; 152:180
UVA1
20J/cm2 for 12 weeks
(30 sessions)
18/20 improved (skin score)
Kersher et al 1998
UVA1
30 J/cm2 3 times a week
for 10 weeks (30 Sessions)
7/7 improved (skin score)
Camacho et al 2001
UVA1
48J/cm2 4 times a week for
5 weeks
8/8 improved ( skin score)
De Rie 2003
Current Treatments of
Localised Scleroderma
Web based survey of 158/ 195 Paed Rheum from 70 centres in USA and
Canada
650 patients with Localised Scleroderma in previous year
• Nearly all used methotrexate and corticosteroids
• Most intensify treatment for lesions on the face or near a joint
• 1/2 intensify for recent disease onset< 6 months
Suzanne Li et al J Rheum 2009
Different morphea lesions
“An estimated 50% of
cases undergo
spontaneous remission
or skin softening 2.7 yrs
after onset” Peterson
1997
Evaluation of long term skin outcomes in
adults with pediatric-onset morphea
Saxton-Daniels Arch Dermatol 2010
• 27 pts mean onset age 11.5 (3-17)
• Mean age at follow up of 30.6 yrs (range18-78)
• 20/27 linear (7 with en coup de sabre and 2 with
partial hemi-facial atrophy)
• 15/27(56%) had permanent sequelae
– 11/15 limited ROM
– 6/15 deep atrophy
– 1/15 limb length discrepancy
– 2/15 joint contractures
Evaluation of long term skin outcomes in
adults with pediatric-onset morphea SaxtonDaniels Arch Dermatol 2010
• 21/27 (81%) had at least one of pain, itch or
numbness in lesions
• 24/27(89%) developed new or expanded lesions over
time
• 16 had periods of remission and relapse
• 8 had continuous activity
• Time to recurrence after initial onset ranged from 618 yrs
• Overall with increasing age lesions increased in
number and/or size
• All patients received treatment
Evaluation of long term skin outcomes in
adults with pediatric-onset morphea SaxtonDaniels Arch Dermatol 2010
Other features:
• 7/27 (26%) had at least 1 autoimmune
disease
• 21/27(78%) had non-cutaneous symptoms
• 18/27(67%) musculoskeletal
• 12/27(44%) neurological features
Location of lesions in 58 cases
of linear scleroderma
BPSU Incidence Study
Ariane Herrick, Holly Ennis, Monica Bushan, Alan Silman, Eileen Baildam
Arthritis Care and Res 2010
Face/head localisation
Both face-head and limb
Trunk and/or limb
26(45%)
3 (5%)
29 (50%)
Juvenile localised scleroderma: clinical and
epidemiological features in 750 children. An
international study Zulian Rheum 2006
• Linear scleroderma 65%
–
–
–
–
54% trunk and/or limbs
41% unilateral
11% bilateral
2% central lesions
Linear scleroderma: Limb
Length discrepancy
Breast Asymmetry
• Girl with linear
scleroderma at the
midline of the left
hypoplastic breast
Eidlitz-Markus 2010
Location of lesions in 58 cases
of linear scleroderma
BPSU Incidence Study
Ariane Herrick, Holly Ennis, Monica Bushan, Alan Silman, Eileen Baildam
Arthritis Care and Res 2010
Face/head localisation
Both face-head and limb
Trunk and/or limb
26(45%)
3 (5%)
29 (50%)
Juvenile localised scleroderma: clinical and
epidemiological features in 750 children. An
international study Zulian Rheum 2006
113(23% with face-head localisation)
• 21 neurological involvement
• 9 recent seizures
• 5 headaches
• 2 intracranial vascular abnormalities
• 2 behavioural changes
• 2 neuroimaging changes of white matter change
or intracranial calcifications
Hemi-facial Atrophy
15/54 patients (28%) had both
en coup de sabre and hemi-facial atrophy
Tollefson 2006
Facial lesions
orthodontic implications
Neurologic Manifestations of Localised
Scleroderma
Kister 2008
•
•
•
•
•
•
54 cases in the literature
16% preceded skin lesions
29% within one year of skin lesions
65% hemifacial atrophy
71% en coup de sabre
35% both
Neurologic Manifestations of Localised
Scleroderma
Kister 2008
•
•
•
•
•
58% seizures at onset/ 73% ever
11% focal symptoms at onset/34% ever
28% headaches
14% neuropsychiatric
22% uveitis, optic neuritis/atrophy
• Response to treatment 11/15
n=54
Neurologic Manifestations of Localised
Scleroderma
Kister 2008
• CSF leukocytosis 7/11 Oligoclonal bands 7/11
• MRI in 49/54
–
–
–
–
–
–
–
–
–
n=54
Normal 11%
Single small lesion 31%
Multiple or diffuse lesions 63%
Brain lesion ipsilateral only 88%
Calcifications 37%
Enhancement 8/16
Abnormal MRA or cerebral angiogram 6/19
Repeat MRI with new lesions 15/29
Inflammatory lesion on brain biopsy 7/10
Juvenile localised scleroderma: clinical and
epidemiological features in 750 children. An
international study Zulian Rheum 2006
• Severe cases
• Deep morphoea in 16 pts
• Eosinophilic fasciitis in 10 pts (Bx
9/10)
• Morphoea profunda 4 patients
• Disabling pansclerotic morphoea in 2
patients
Pansclerotic morphoea
Wollina 2007
• 30 cases onset 1-14 yrs
• Aggressive course, contractures
and immobility
• 17% chronic non-healing ulcers
• 4 deaths from gangrene or
sepsis
• 2 squamous cell carcinoma at
age 16 and 19
Localized scleroderma in childhood is not just a skin
disease – extra-cutaneous manifestations in 168 /
750 pts (22%) Zulian Arth Rheum 2005
• Articular
• Neurological
• Ocular
47.2%
17.1
8.3%
– 4 anterior uveitis, 3 episcleritis, 2 glaucoma, 1 keratitis
•
•
•
•
•
•
Vascular/ Raynaud’s
Gastrointestinal
Autoimmune disease
Cardiac
Renal
Systemic sclerosis
9.3%
6.2%
7.3%
1%
1%
1 patient
Localised scleroderma and
other autoimmune problems
• Autoimmune thyroiditis
• Thyroid peroxidase
antibodies 1305 iu/ml ( 0-50)
• Hypothyroid
• Blunted Synacthen test
hydrocortisone replacement
Characteristics of patients with juvenile onset systemic
sclerosis in an adult single-center cohort
Foeldvari I, J
Rheumatol 2010
52 pts with jSSc compared with 954 pts with adult-onset
disease.
• Overlap cases more common in jSSc
(37%v18%p=0.002)
• 10 yr survival significantly better in jSSc
(98%vs 14% p=0.032)
• Pulmonary hypertension less (2%v14% p=0.032)
• Pulmonary fibrosis equal 22%v21%
• Cardiac Scleroderma 3%v2%
Systemic sclerosis
in Childhood PRES and PRINTO
153pts Martini 2006
• Deaths
• 15/127 (11.8%)
–
–
–
–
Cardiac 10
Renal failure 2
Respiratory failure 2
Septicaemia 2
Cardiac effects
• Pericardial effusions
• Inflammatory myocarditis
• Diastolic dysfunction
• Conduction defects
• Restricted or dilated
cardiomyopathy
• Heart failure
Systemic sclerosis
in Childhood PRES and PRINTO 153 pts
mean follow-up 3.9 yrs (0.2-18.8 yrs)
• Raynauds
– 75% at onset 84% by follow-up
• Skin induration
– 75% at onset 76% by follow up
• Oedema
– 35% at onset, 46% by follow up
• Sclerodactyly
– 46% at onset, 66% by follow up
• Calcinosis
– 9% at onset, 19% by follow up
Martini 2006
Systemic sclerosis
in Childhood PRES and PRINTO
153pts Martini 2006
• Nail fold capillary changes
– 26% at onset, 40% by follow up
• Finger tip pitting
– 28% at onset, 38% at follow up
• Digital infarcts
– 19% at onset, 29% at follow up
Systemic sclerosis
in Childhood PRES and PRINTO
153pts Martini 2006
• Gastrointestinal involvement
– Dysphagia
• (10% at onset 24% at follow-up)
– GOR
• (8%at onset 30% at follow-up)
– Diarrhoea
• (2%at onset 10% at follow-up)
– Weight loss
• (18%at onset 27% at follow-up)
Systemic sclerosis
in Childhood PRES and PRINTO
153pts Martini 2006
• Renal system
– Raised creatinine/ proteinuria
• (3% at onset 5% at follow-up)
– Renal Crisis
• (none at onset 1% at follow-up)
– Hypertension
• (1%at onset 3% at follow-up)
•Nervous system
–Seizures
•(1% at onset 3% at follow-up)
–Peripheral neuropathy
•(1% at onset 1% at follow-up)
–Abnormal brain MRI findings
•(2%at onset 3% at follow-up)
Quality of Life in Scleroderma in Childhood:
Baildam,
Ennis, Foster, Shaw, Chieng, Kelly, Herrick, Richards. Influence of childhood
scleroderma on physical function and quality of life.J Rheumatol. 2011
Total sample
n=28
Localised
scleroderma
n = 24
SSc
n=4
Female, n(%)
19 (68)
15 (63)
4 (100)
White Caucasian, n(%)
24 (85)
20 (87)
4 (100)
Age at assessment, median
(range) years
13 (5-17)
13 (5-17)
11.7 (7-14)
Disease duration, median
(range) months
30 (2-135)
22 (20135)
68 (15-83)
Quality of Life Results
Total sample
n=28
Localised
scleroderma
n = 24
SSc
n =4
CHAQ physical function score,
median (range), 0-3
0.1 (0 – 1.6)
0 (0 – 1.6)
0.6 (0.1 – 1.2)
CHAQ VAS pain score, median
(range), 0-100
15 (0 – 85)
0 (0 – 85)
12.5 (10 – 55)
CDLQI total score, median (range),
0-30*
5 (0 – 10)
5 (0 – 10)
3 (0 – 6)
0
.5
1
1.5
Quality of Life Results
0
20
40
Pain assessment
localised
ssc
Positive relationship between CHAQ scores and
pain VAS scores (ρ=0.69,p<0.00)
60
80
si
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ou
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lth
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es
Pa
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io
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n
re
nt
tim
Fa
m
e
ily
ac
Fa
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m
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ily
co
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on
Ph
y
%
Quality of Life Categories
CHQ-PF50
100
80
60
40
20
0
Higher scores mean minimal or no impairment
Localised
SSc
• Lower self-esteem assessments made
by parents on the CHQ-PF50 were
significantly associated with higher
CHAQ function and pain scores (p=0.04
and p=0.03 respectively).
Conclusions
• Scleroderma had only a moderate impact on
quality of life and physical function measured by
5 validated questionnaires.
• Localised scleroderma had a more detrimental
impact on psychosocial than on physical
wellbeing.
• A reduction in physical function was associated
with impaired self-esteem
Childrens' and parents' beliefs about childhood onset
scleroderma are influenced by child age and physical
function impairment. H Ennis, A Herrick, E Baildam, H
Richards. Rheumatology July 2011
• Most common perceived causes of scleroderma were
the immune system (54%) and chance/bad luck (46%).
• ≥ 80% believed treatment would control scleroderma.
• ≥ 46% believed scleroderma contributed to depressed
mood.
• There was a positive relationship between age and
belief in personal control. (p<0.01)
Conclusion
• Work to be done
• Long term longitudinal study needed
• More placebo controlled studies
Quality of Life Measures
1
2\
3
First dermatologyspecific
quality of life measure
Generic self-report
disability measure,
widely used in rheimatic
disease
Dermatology
Life Quality
Index
(DLQI)
Health
Assessment
Questionnaire
(HAQ)
Validated for use by children
CDLQI
Cartoon version
validated for use by children
The trouble
with skin
Validated
Validated
for children for parents /
> 11
guardians if
child < 11
Child
CHAQ
Parent /
guardian
CHAQ
Generic measure assessing
a child’s physical, social
and emotional wellbeing.
Validated for use by
parents / guardians.
Child Health
Questionnaire
CHQ-PF50
Children’s Dermatology Life
Quality Index (CDLQI)
• Dermatology-specific
measure to assess quality of
life in children with skin
conditions.
• Cartoon version was found
to be more user-friendly.
• Scored 0-30
Children’s Health Questionnaire
(CHQ-PF50)
• Generic measure to assess
a child’s physical, emotional
and social wellbeing.
• Completed by parents or
guardians.
• Scores 0-100
• Lower scores worse
Child Health- Related Quality of
Life Questionnaire (CQOL)
• A generic measure to assess
quality of life in children with
chronic physical disorders.
• Completed by children aged
≥ 11 and by parents for
children under 10.
• Scored 0-105
Illness Perceptions Questionnaire
(IPQ)
• Assesses beliefs about the
experience of illness.
• Completed by children aged
≥ 11 and by parents for
children under 10.