systemic sclerosis jacob m van laar professor of clinical rheumatology newcastle university, uk

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.