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Systemic Sclerosis
Jacob M van LaarProfessor 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 Established diseaseDermal inflammation
Early diffuse disease Established diseaseDermal inflammation
Immunosuppression disrupts inflammation-driven fibrogenesis (or does it?)
Early diffuse disease Established diseaseDermal inflammation
Early targeted intervention prevents fibrosis
Cardiac fibrosis Pericarditis
Lung fibrosis 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 problemsbibasilar 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
Ioannidis et al, Am J Med 2005
Organ involvement:
No
Yes
Steen VD, J Clin Rheumatol 2005.
Rate of loss of percent vital capacity in 76 SSc patients with severe fibrosis.
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
Steen & Medsger, Arthritis Rheum 2000
• CHF• symptomatic pericarditis • arrhythmia requiring
treatment
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
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..
Echocardiography and pulmonary function as screening tests for pulmonary arterial hypertension in systemic sclerosis.
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
McLaughlin et al. Rheumatology 2009
Endothelin-1 blockade delays clinical worsening of PAH; Combination-therapy with iloprost is feasible and effective.
Hunzelmann & Brinckmann, Ann Rheum Dis 2010
Varga and Abraham, JCI 2007
Myofibroblast is key effector cell in fibrosis
http://tyrosinekinaseinhibitor.com/
Preclinical data support use of Tyrosine Kinase Inhibitors (TKI) in fibrotic conditions.
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 Group-
0
10
20
30
40
50m
RSS
Baseline Year1 Year2 Year3
Skin Score during follow-up
Herrick et al, J Rheum 2010)Slide kindly provided by C Denton
Cyclo then MMF
ATG then MMF
MMF
No active therapy
Other (MTX etc)
Mycophenolate mofetil has antifibrotic effects in vitro
Roos et al, J Phramacol Exp Therap 2007
MMF inhibits type I collagen gene expression MMF increases MMP-1 gene expression
MMF inhibits fibroblast motility
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, HAQ-DI, 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
Huegle & van Laar, Arthr Res Ther 2008
Stem cell transplantation: a treatment option for for systemic sclerosis?
Skin score
Lung function
Kidney function
HAQ
Lung function
Heart function
Changes in skin score, HAQ, lung/kidney/heart function in 27 transplanted patients in USA
Nash et al, Blood 2007
Nash et al, Blood 2007
Reduction in dermal fibrosis
Aschwanden et al, Ann Rheum Dis 2008
Induction of neoangiogenesis
HSCT reverses fibrosis and vasculopathy
Benefit
Risks
cure
remission
Conventional immunosuppressio
n
Stem cell transplantation
Mobilisation CYC 2x2 g/m2, G-CSF 10 µg/kgLeukapheresis + CD34-selectionConditioning CYC 200 mg/kg, rbATG 7.5 mg/kgReinfusion CD34+ PBSC
12x monthly i.v. pulse CYC 750 mg/m2
RS E
ASTIS trialAutologous Stem Cell Transplantation International Scleroderma trial
ISRCTN54371254
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)
sample size 150 patients based on 10-yr accrual, 11-yr follow-up; alpha = 0.05, power = 0.67, HR 0.5; intention-to-treat.
SCT
Control
EFS
Primary endpoint = event-free survival
EFS = survival minus persistent major organ failure (heart, lung, kidney)
ASTIS trial Jan 2012 JvL
Time-dependent hazard, P=0.011
FU (yr): HR (95%CI), P-value
0
20
40
60
80
100
overa
ll su
rviv
al (%
)
79 68 67 64 55 39 26 19 12 11 7Transplant77 69 65 55 40 31 21 15 10 7 3Control
Number at risk
0 1 2 3 4 5 6 7 8 9 10Years
Control Transplant
Overall survival
¼ : 2.45 (.76 - 7.89), 0.13 ½ : 1.42 (.58 - 3.51), 0.44
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
1 : 0.39 (.18 - .82), 0.014
0
20
40
60
80
100
Pro
ject
ed o
vera
ll su
rviv
al (
%)
41 33 32 31 24 20 13 11 7 7 5Transplant43 39 37 34 25 21 14 10 7 5 2Control
Number at risk
0 1 2 3 4 5 6 7 8 9 10
Years
Control Transplant
Smoking status / (yes)
0
20
40
60
80
100
Pro
ject
ed o
vera
ll su
rviv
al (
%)
38 35 35 33 31 19 13 8 5 4 2Transplant34 30 28 21 15 10 7 5 3 2 1Control
Number at risk
0 1 2 3 4 5 6 7 8 9 10
Years
Control Transplant
Smoking status / (no)
Smoking status is a determinant of overall survival
mRSS HAQ VC DCLO Creat cl LVEF
-20
0
20
40
60
80
100
HSCT
CYC
Changes in secondary outcome parameters*
* Measured as % change AUC in first 2 years.Wors
en
ing Im
pro
vem
ent
P<0.001 0.04 0.006 0.84 0.017 0.96
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.
• 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.
Take home messages (‘learning objectives’)
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: EBMT/EULAR Scleroderma Study Group Sponsors: EBMT, EULAR, AP-HPStudy chairpersons: JM van Laar, CI (Newcastle), D Farge (Paris), A Tyndall (Basel)Study administration: 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)Statistician: JK Sont (Leiden)Co-investigators: 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).IDMC: J Apperley (London), D Furst (Los Angeles), F Wolheim (Lund)Financial support: EBMT, EULAR, AP-HP, NIHR, Amgen Europe, Genzyme (Sangstat), Miltenyi Biotec.