Systemic Sclerosis
Jacob M van Laar
Professor of Clinical Rheumatology
Newcastle University, UK
Systemic sclerosis is a rare, heterogeneous, slow-motion disease,
with (allegedly) a small window of opportunity to fundamentally
change the course of the disease.
Early diffuse disease
Dermal inflammation
Established disease
Immunosuppression disrupts inflammation-driven
fibrogenesis (or does it?)
Early diffuse disease
Dermal inflammation
Established disease
Early targeted intervention prevents fibrosis
Early diffuse disease
Dermal inflammation
Established disease
Cardiac fibrosis
Lung fibrosis
Pericarditis
Intima fibrosis
Hunzelmann & Brinckmann, Ann Rheum Dis 2010
30-yr young woman with progressive systemic sclerosis since 2 years
Raynauds and digital ulcers, contractures, heartburn, swallowing problems
bibasilar interstitial abnormalities
What is the most concerning manifestation?
A. Raynauds?
B. Contractures?
C. Skin score?
D. GI-problems?
E. Lungs?
F. All of the above?
Survival of pooled groups of scleroderma patients
Organ involvement:
No
Yes
Ioannidis et al, Am J Med 2005
Rate of loss of percent vital capacity in
76 SSc patients with severe fibrosis.
Steen VD, J Clin Rheumatol 2005.
Survival of patients with systemic sclerosis
and pulmonary arterial hypertension,
with or without fibrosis.
Mukerjee et al. Ann Rheum Dis 2003;62:1088-93.
Severe organ involvement in systemic sclerosis,
results from the Pittsburgh study
• CHF
• symptomatic pericarditis
• arrhythmia requiring treatment
Steen & Medsger, Arthritis Rheum 2000
The Pittsburgh study
Steen & Medsger, Arthritis Rheum 2000
The Pittsburgh study
Steen & Medsger, Arthritis Rheum 2000
Work-up of systemic sclerosis patient
with or without cardiopulmonary symptoms
• 6MWT
• Echocardiography (LVEF, PAH, valves)
• MRI?
• Plasma BNP, troponin
• ECG, Holter
• Exercise test
• Myocardial biopsy?
Exercise performance, measured by maximum
oxygen uptake (max < 80% of predicted), was
impaired in 43/46 patients.
Cuomo et al. Scand J Rheumatol. 2010 May 17. Epub
Echocardiography and pulmonary function as screening
tests for pulmonary arterial hypertension in systemic
sclerosis.
The positive predictive accuracy of currently used non-invasive tests are adequate for
the diagnosis of advanced PAH provided sufficiently high thresholds (TG > 45 mmHg or
DLCO < 55% predicted) are used..
Mukerjee et al. Rheumatol 2004;43:461-6.
30-yr young woman with progressive systemic sclerosis since 2 years
You decide to examine her incl skin score and request further investigations:
lab, PFT, echo, ECG, NFC.
No barium or manometry.
What’s next?
A. Treat her symptoms
B. Put her on immunosuppression
C. Refer her to a colleague with expertise in SSc
Hunzelmann & Brinckmann, Ann Rheum Dis 2010
Progress in understanding of pathogenesis of PAH has led
to breakthrough in its treatment.
McLaughlin et al. Rheumatology 2009
Endothelin-1 blockade delays clinical worsening of PAH;
Combination-therapy with iloprost is feasible and effective.
McLaughlin et al. Rheumatology 2009
Hunzelmann & Brinckmann, Ann Rheum Dis 2010
Myofibroblast is key effector cell in fibrosis
Varga and Abraham, JCI 2007
Preclinical data support use of Tyrosine Kinase Inhibitors
(TKI) in fibrotic conditions.
http://tyrosinekinaseinhibitor.com/
12/20 completed study, 7 discontinued because of AEs, 1 lost to followup.
Common AEs (>20%) included fatigue, facial/lower extremity edema,
nausea and vomiting, diarrhea, generalized rash, and new-onset
proteinuria.
Treatment with imatinib showed a trend toward improvement in the FVC %
predicted (1.74%; P not significant) and the MRSS (3.9 units; P<0.001).
Khanna et al, Arthritis Rheum 2011
Enrollment discontinued after 10 patients (9 imatinib, 1 placebo) due to poor
tolerability and high rates of AEs.
No difference in mean MRSS (imatinib 31>29 at months), CRP, ESR, physician’s
global assessment, patient’s global assessment, response to the Health Transition
query, or HAQ scores between those who did and those who did not complete 6
months of therapy.
Side effects: edema, fluid retention, fatigue, nausea, cramps/myalgias, diarrhea,
alopecia, and anemia. Most side effects occurred within the first week of treatment,
and even when imatinib was reintroduced at a lower dosage (200 mg daily), it was
poorly tolerated. Two patients were hospitalized because of side effects of the
medication. In general, biomarker levels in plasma and skin did not change.
Conclusion: imatinib was poorly tolerated.
Pope et al, Arthritis Rheum 2011.
Spiera et al. Ann Rheum Dis 2011.
Hunzelmann & Brinckmann, Ann Rheum Dis 2010
EULAR recommendations for the treatment of systemic sclerosis
Glucocorticoids:
low dose are commonly used for inflammatory arthritis, RCT lacking
Immunosuppressives:
Methotrexate: 2RCTs have shown benefit on skin in early dcSSc
Cyclophosphamide: 2 RCTs have shown benefit on skin and lung
MMF, azathioprine: uncontrolled studies support use.
Ciclosporin A: not recommended
Kowal-Bielecka et al, Ann Rheum Dis 2009
Nihtynova et al. Rheumatology 2007
Changes skin score in observational study in dcSSc
-UK Scleroderma Study GroupSkin Score during follow-up
50
40
mRSS
ATG then MMF
30
Other (MTX etc)
Cyclo then MMF
MMF
20
No active therapy
10
0
Baseline
Year1
Year2
Year3
Herrick et al, J Rheum 2010)
Slide kindly provided by C Denton
Mycophenolate mofetil has antifibrotic effects in vitro
MMF inhibits type I collagen gene expression
MMF increases MMP-1 gene expression
MMF inhibits fibroblast motility
Roos et al, J Phramacol Exp Therap 2007
30-yr young woman with progressive systemic sclerosis since 2 years
You treated her symptoms (max PPI), advised her to get fit, and after
extensive consultation (risk of infertility vs refractory disease) with
i.v. pulse cyclophosphamide: stabilisation for 6 m, then 10% drop in VC.
What do you do?
What to do with cyclophosphamide-refractory SSc?
A. Review the patient, exclude other causes
B. Try MMF
C. Try azathioprine
D. Something new, eg biological
Biologic therapy for systemic sclerosis: a systematic review.
23 studies: 3x infliximab, 3x etanercept, 3x antithymocyte globulin,
3x imatinib, 6x rituximab, 1x IFN-γ, IFN-α, relaxin, delipidated,
deglycolipidated Mycobacterium vaccae, human TGF-ß1 antibody, and
oral type I collagen.
Studies of etanercept and infliximab suggest improvements in arthritis
and HAQ-DI. None of the other biologic agents demonstrated
reproducible, statistically significant improvements in joint count, HAQDI, or skin score.
CONCLUSION:
TNFi may improve inflammatory arthritis and disability in SSc. The effect
on skin score is uncertain. Adequately powered trials are needed to
evaluate efficacy, and longitudinal studies are needed to evaluate
longterm safety of these agents in SSc.
Phumethum, Jamal, Johnson. J Rheumatol 2011;38:289-96.
Effects of rituximab in systemic sclerosis
Bosello et al, Arthritis Res Ther 2009
Study Design (n=86) TCZ trial, c/2012
Stem cell transplantation:
a treatment option for for systemic sclerosis?
Huegle & van Laar, Arthr Res Ther 2008
Changes in skin score, HAQ, lung/kidney/heart function
in 27 transplanted patients in USA
Skin score
HAQ
Lung function
Lung function
Kidney function
Heart function
Nash et al, Blood 2007
HSCT reverses fibrosis and vasculopathy
Reduction in dermal fibrosis
Nash et al, Blood 2007
Induction of neoangiogenesis
Aschwanden et al, Ann Rheum Dis 2008
Benefit
cure
Stem cell
transplantation
remission
Conventional
immunosuppression
Risks
ASTIS trial
Autologous Stem Cell Transplantation International Scleroderma trial
ISRCTN54371254
Mobilisation CYC 2x2 g/m2, G-CSF 10 µg/kg
Leukapheresis + CD34-selection
Conditioning CYC 200 mg/kg, rbATG 7.5 mg/kg
Reinfusion CD34+ PBSC
S
R
E
12x monthly i.v. pulse CYC 750 mg/m2
ASTIS trial Jan 2012 JvL
Inclusion criteria
• age 16-65 yrs
• diffuse scleroderma with:
I.
disease duration  4 yrs + skin score  15 (0-51) +
involvement heart/lung/kidney
II.
disease duration  2 yrs + skin score  20 + ESR>25mm/1st hr
and/or Hb<11 gr/dL
Exclusion criteria
• PHT > 50 mmHg, DLCO < 40%.
• creat.cl. < 40 ml/min.
• LVEF < 45%; uncontrolled arhythmia; cardiac tamponade, infection, etc.
• previous extensive treatment with cyclophosphamide (>5 gr iv,
>3 months oral)
Primary endpoint = event-free survival
EFS
SCT
Control
EFS = survival minus persistent major organ
failure (heart, lung, kidney)
sample size 150 patients based on 10-yr accrual, 11-yr followup; alpha = 0.05, power = 0.67, HR 0.5; intention-to-treat.
ASTIS trial Jan 2012 JvL
Overall survival
overall survival (%)
100
80
Time-dependent hazard, P=0.011
60
FU (yr): HR (95%CI), P-value
¼ : 2.45 (.76 - 7.89), 0.13
½ : 1.42 (.58 - 3.51), 0.44
1 : 0.39 (.18 - .82), 0.014
2 : 0.22 (.08 - .58), 0.002
4 : 0.22 (.08 - .58), 0.002
6 : 0.22 (.08 - .58), 0.002
8 : 0.22 (.08 - .58), 0.002
40
20
Control
0
Transplant
0
1
2
3
4
6
7
8
9
10
Number at risk
Control 77
Transplant 79
5
Years
69
68
65
67
55
64
40
55
31
39
21
26
15
19
10
12
7
11
3
7
Smoking status is a determinant of overall survival
Smoking status / (no)
Smoking status / (yes)
100
Projected overall survival (%)
100
80
60
40
20
Control
0
0
Number at risk
Control
Transplant
43
41
1
39
33
2
37
32
3
34
31
4
25
24
80
60
40
20
Transplant
5
Years
6
21
20
14
13
7
10
11
8
7
7
Control
0
9
5
7
10
2
5
Number at risk
Control
Transplant
Transplant
0
1
2
3
4
5
Years
6
7
8
9
10
34
38
30
35
28
35
21
33
15
31
10
19
7
13
5
8
3
5
2
4
1
2
Changes in secondary outcome parameters*
100
P<0.001 0.04
0.006
0.84
0.017
0.96
80
Worsening Improvement
60
40
HSCT
CYC
20
0
mRSS
HAQ
VC
DCLO
Creat cl
LVEF
-20
* Measured as % change AUC in first 2 years.
30-yr young woman with progressive systemic sclerosis since 2 years
You treated her symptoms (max PPI), advised her to get fit, and after
extensive consultation (risk of infertility vs refractory disease) with HSCT,
which stopped disease progression. She has been stable since 1997.
Take home messages (‘learning objectives’)
• Systemic sclerosis is a complex connective tissue disease,
requiring expert management.
• Medication is reasonably effective for organ manifestations.
• HSCT induces long-term remission in early, severe dcSSc.
Organ-based treatment options for systemic sclerosis
Vasculopathy: Calcium-channel blockers, ET-1RA, sildenafil
SRC: ACEi, ATRA
Lung: cyclophosphamide, MMF, rituximab
Skin: MMF, MTX, cyclophosphamide, HSCT
Heart: ICD, nifedipine
Gut: somatostatin, PPI
Joints: NSAID, low dose prednisone
How to identify poor prognosis patients?
Principal investigator:
Sponsors:
Study chairpersons:
Study administration:
Statistician:
Co-investigators:
IDMC:
Financial support:
EBMT/EULAR Scleroderma Study Group
EBMT, EULAR, AP-HP
JM van Laar, CI (Newcastle), D Farge (Paris), A Tyndall (Basel)
S Hales, K Naraghi (Middlesbrough), A Versluys-van Duinhoven,
I de Jonge (Leiden), M Bettar, S Parlier (Paris), I Gerber, C Bocelli-Tyndall
(Basel), L Clark, R Uddin, K Champion, Z Doran (EBMT Clinical Trials
Office, London)
JK Sont (Leiden)
Z Marjanovic, J Larghero, G Socie (Paris), A Schuerwegh, E Marijt,
WE Fibbe (Leiden), M Vonk, FHJ van den Hoogen, AVMB Schattenberg
(Nijmegen), I Miniati, R Saccardi, M Matucci-Cerinic (Florence),
A Voskuyl, A van de Loosdrecht, P Huygens (Amsterdam), I Koetter,
M Schmalzing (Tübingen), S Weiner, A Kreuter (Bochum-Herne-Trier),
T Martin, J Sibilia (Strasbourg), I Gerber, T Daikeler, P Hasler, P Villiger,
A Gratwohl (Aarau-Basel-Bern), K Warnatz, HH Peter, J Finke (Freiburg),
K Machold (Vienna), S Dass, M Buch, P Emery (Leeds), F Sarrot-Reynauld
(Grenoble), JM Durand (Marseille), HP Tony, S Kleinert (Wurzburg),
J Constans (Bordeaux), D Adoue (Toulouse), D Launay (Lille), I Quere
(Montpellier), C Deligny, S Arfi (W Indies), E Rich (Montreal), A Fassas
(Thessaloniki), A Lo Monaco (Ferrara), N Del Papa (Milan), R Westhovens
(Leuven), B Griffiths, M Collin (Newcastle-Middlesbrough).
J Apperley (London), D Furst (Los Angeles), F Wolheim (Lund)
EBMT, EULAR, AP-HP, NIHR, Amgen Europe, Genzyme (Sangstat),
Miltenyi Biotec.