Article Text

Download PDFPDF

Concise report
Outcomes of patients with systemic sclerosis-associated polyarthritis and myopathy treated with tocilizumab or abatacept: a EUSTAR observational study
  1. Muriel Elhai1,
  2. Marine Meunier1,
  3. Marco Matucci-Cerinic2,
  4. Britta Maurer3,
  5. Gabriela Riemekasten4,
  6. Tifenn Leturcq1,
  7. Raffaele Pellerito5,
  8. Carlos Alberto Von Mühlen6,
  9. Alessandra Vacca7,
  10. Paolo Airo8,
  11. Francesca Bartoli2,
  12. Ginevra Fiori2,
  13. Maria Bokarewa9,
  14. Valeria Riccieri10,
  15. Mike Becker4,
  16. Jérôme Avouac1,
  17. Ulf Müller-Ladner11,
  18. Oliver Distler3,
  19. Yannick Allanore1,
  20. on behalf of EUSTAR (EULAR Scleroderma Trials and Research group)
  1. 1Rheumatology A Department, Paris Descartes University, Cochin Hospital, Paris, France
  2. 2Department of Biomedicine, Section of Rheumatology, Florence, Italy
  3. 3Department of Rheumatology, University Hospital of Zurich, Zurich, Switzerland
  4. 4Department of Rheumatology and Clinical Immunology, German Rheumatology Research Centre, A Leibniz Institute, Charity University Hospital, Berlin, Germany
  5. 5Division of Rheumatology, “Ordine Mauriziano” Hospital, Torino, Italy
  6. 6Rheuma Clinic of Rheumatic Diseases, Porto Alegre, Brazil
  7. 7Chair and Unit of Rheumatology, University Clinic A.O.U. of Cagliari, Monserrato, Italy
  8. 8Rheumatology and Clinical Immunology Unit, Spedali Civili and University of Brescia, Brescia, Italy
  9. 9Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Hospital, University of Gothenburg, Gothenburg, Sweden
  10. 10Rheumatological Unit, Department of Internal Medicine and Clinical Specialities, University of Rome ‘Sapienza’, Rome, Italy
  11. 11Department of Rheumatology and Clinical Immunology, Justus-Liebig University Giessen, Kerckhoff Clinic Benekestrasse 2, Bad Nauheim, Germany
  1. Correspondence to Professor Yannick Allanore, Service Rhumatologie A, hôpital Cochin, 27 rue du faubourg St Jacques, Paris 75014, France; yannick.allanore{at}


Objective To evaluate the safety and effectiveness of tocilizumab and abatacept in systemic sclerosis (SSc)-polyarthritis or SSc-myopathy.

Methods 20 patients with SSc with refractory polyarthritis and seven with refractory myopathy from the EUSTAR (EULAR Scleroderma Trials and Research) network were included: 15 patients received tocilizumab and 12 patients abatacept. All patients with SSc-myopathy received abatacept. Clinical and biological assessments were made at the start of treatment and at the last infusion.

Results After 5 months, tocilizumab induced a significant improvement in the 28-joint count Disease Activity Score and its components, with 10/15 patients achieving a EULAR good response. Treatment was stopped in two patients because of inefficacy. After 11 months’ treatment of patients with abatacept, joint parameters improved significantly, with 6/11 patients fulfilling EULAR good-response criteria. Abatacept did not improve muscle outcome measures in SSc-myopathy. No significant change was seen for skin or lung fibrosis in the different groups. Both treatments were well tolerated.

Conclusions In this observational study, tocilizumab and abatacept appeared to be safe and effective on joints, in patients with refractory SSc. No trend for any change of fibrotic lesions was seen but this may relate to the exposure time and inclusion criteria. Larger studies with longer follow-up are warranted to further determine the safety and effectiveness of these drugs in SSc.

  • Systemic Sclerosis
  • Treatment
  • Arthritis

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.


Joint involvement is common and disabling in systemic sclerosis (SSc).1 ,2 Of patients with SSc, 46–97% complain about joint stiffness or pain, and up to 30% exhibit inflammatory clinical signs.1 ,2 Moreover, ultrasound shows that a large proportion of patients with SSc exhibit synovitis (∼50%) and tenosynovitis (∼1/3), respectively.3 Myopathy is also common in SSc, with a prevalence ranging from 16% to 81%; clinical presentations are broad and vary from myalgias to muscle weakness.4

No specific treatment is available for articular and muscle involvement in SSc and the use of low doses of oral corticosteroids in association with methotrexate is generally recommended, by analogy with rheumatoid arthritis (RA) in polyarthritis, and the use of steroids in myopathy.2 ,4 As major improvements in the treatment of RA using biological agents have been achieved in recent years, there is also a rationale for using some of these targeted treatments, such as anti-interleukin 6 (anti-IL-6) or cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA4-Ig), in SSc, although no trial has yet been performed. IL-6 appears to be overexpressed in both the skin and serum of patients with SSc,5–8 and it may induce collagen production by normal dermal fibroblasts and promote differentiation of dermal fibroblasts into myofibroblasts.9 ,10 Furthermore, the contribution of IL-6 to dermal fibrosis, but also to lung fibrosis, has been demonstrated in murine SSc models.11–13 Associations between high CTLA4 sera levels and SSc have also been reported.14 These molecular targets are of interest since there is accumulating evidence suggesting that T cells have a key role in SSc pathogenesis, which are also predominantly inflammatory cells in SSc myopathy.4 ,15 Consequently, it is worth studying the clinical effect on SSc of tocilizumab, a humanised anti-IL-6 receptor antibody, and abatacept, a recombinant CTLA4Ig fusion protein that selectively modulates costimulation resulting in downregulation of T cell activation. Therefore, we analysed the EULAR Scleroderma Trials and Research (EUSTAR) database to determine the off-label use of tocilizumab and abatacept in refractory polyarthritis or myopathy associated with SSc and performed a prospective multicentre observational study to assess the safety and effectiveness of these biological agents.16


By interrogating the EUSTAR network in June 2011, 20 patients with SSc with active polyarthritis and insufficient response to disease-modifying antirheumatic drugs (DMARDs) and seven patients with active myopathy refractory to DMARDs and cyclophosphamide were included.16 All patients fulfilled American College of Rheumatology criteria for SSc. Patients received tocilizumab or abatacept upon the decision of their doctor in routine practice: 15 patients received tocilizumab at 8 mg/kg/month, and 12 patients abatacept at 10 mg/kg/month. All patients with SSc-myopathy received abatacept. Clinical and biological data were collected at the start of treatment and before the last infusion. The characteristics of the patients and outcome parameters were all derived from the online Minimal Essential Data Set and have already been reported in detail.1 ,16 ,17

Clinical data were as follows: age, sex, disease duration, cutaneous subtype, presence of digital ulcers, lung involvement (pulmonary fibrosis and/or abnormal respiratory function tests (forced vital capacity <75% predicted and/or carbon monoxide transfer <70% predicted), heart involvement (according to EUSTAR standards16 ,17), modified Rodnan total skin score, swollen and tender joint counts, morning stiffness, visual analogue scale articular pain score, 28-joint count Disease Activity Score (DAS28) score, Health Assessment Questionnaire Disability Index (HAQ-DI) and treatment received (steroids, DMARDs). Biological tests included routine blood tests, erythrocyte sedimentation rate, C-reactive protein, creatine kinase (CK) level, liver enzymes, cholesterol level and antibodies (anti-Scl-70, anticentromere, rheumatoid factor, anti-cyclic citrullinated peptide, anti-U1 ribonucleoprotein (RNP) and anti-J01). In patients with myositis, visual analogue scale for disease activity, assessed by the doctor, and manual muscle strength were documented. Side effects were recorded. All data analyses were performed using MedCalc V. Data were presented as median (IQR) for continuous variables and numbers (percentages) for categorical variables. Data were statistically analysed using the Wilcoxon test for comparison between two continuous variables. A p value < 0.05 was considered statistically significant.


Fifteen patients with SSc-arthritis were treated with tocilizumab; median age was 56 (45–61) years and disease duration 5 (4–9) years. About two-thirds of the patients were co-treated with low-dose steroids and 60% received methotrexate. Previous treatments included rituximab (three patients), immunosuppressant drugs other than methotrexate (four patients), abatacept (one patient) and anti-tumour necrosis factor α (TNFα; two patients). Five patients with SSc-arthritis received abatacept; median age was 53 (39–64) years and disease duration 13 (11–16) years. Previous treatments included immunosuppressant drugs for two patients and for one patient both anti-TNFα and tocilizumab. Seven patients (median age 55 (47–63) years, disease duration 7 (2–8) years) received abatacept because of refractory myopathy. Muscle biopsy had been performed in five cases and showed inflammatory infiltrates in all cases, together with necrosis in two patients. Anti-Jo1 and U1 RNP antibodies were detected in three patients (43%) and one patient (14%), respectively. Six had pulmonary involvement and none had heart involvement. Five (71%) were treated with steroids (low dose for all, except one who received a dose of 60 mg/day) and DMARDs. Two were also treated with cyclophosphamide. Among these patients, six also had refractory polyarthritis and were included in the analysis of articular outcomes after treatment with abatacept. The patient's characteristics are shown in table 1.

Table 1

Main characteristics of SSc-arthritis and SSc-myopathy patients at baseline

Articular outcome

At baseline, patients treated with tocilizumab had a high disease activity (median DAS28 score of 5.2 (3.9–6.1)). After 5 months, the DAS28 score and all articular parameters, except HAQ-DI, decreased significantly with a median decrease of 2.7 in the DAS28 score (table 2). Ten patients (67%) fulfilled good EULAR response criteria, whereas four (27%) were moderate responders. Steroids were stopped in two patients and the dose was reduced in three patients. Treatment with tocilizumab was well tolerated, only one patient complained of one episode of slight nausea after the first infusion without recurrence despite the continuation of treatment. In one patient, treatment was stopped at the fourth infusion for 2 months because of an increase in liver enzymes and was restarted when transaminases returned to normal with subsequent good liver tolerance. In two patients, tocilizumab was stopped because of inefficacy after 3 months.

Table 2

Outcomes of patients with SSc-polyarthritis treated with tocilizumab and abatacept

At baseline, patients treated with abatacept had a moderate disease activity with DAS28 score of 4.5 (3.5–5.0). After 11 months, there was a significant decrease in disease activity with a decrease in both DAS28 score and other articular parameters (except C-reactive and HAQ-DI). Six patients (55%) were good EULAR responders, whereas two patients (18%) were moderate responders. Steroids were stopped in two patients. The steroid dose was reduced in five patients. Treatment was maintained in all patients. Side effects were as follows: in the group with associated myopathy, one patient reported headache after each infusion and three infections occurred (two episodes of bronchitis in one patient treated with antibiotics and one herpes simplex virus infection). There was no significant change in skin or lung fibrosis with either abatacept or tocilizumab. Additional clinical data are reported in table 2.

Muscular outcome

In patients with SSc-myopathy, after a follow up of 18 months, myopathy tended to improve, but the results were not statistically significant. Outcomes are shown in table 3.

Table 3

Outcomes of the seven patients treated with abatacept for refractory myopathy


The data of this observational study suggest that tocilizumab and abatacept are safe and effective approaches to improving joint involvement after 5–11 months in refractory SSc-arthritis.

Inflammatory joint involvement is a heavy burden in SSc with no standard treatment.2 Despite the advent of biological agents in RA and a subsequent rationale for their use in SSc,2 ,5–15 targeted treatments have not yet been developed in SSc. One short report suggested some efficacy of anti-TNFα agents on inflammatory joint involvement in SSc.18 However, their use is limited by the risk of exacerbation of lung fibrosis.19 Our study suggests that patients with SSc, with refractory arthritis may benefit from tocilizumab or abatacept as do patients with RA. Both treatments were associated with a significant decrease in DAS28 score after 5 and 11 months. About two-thirds of patients with SSc could be classified as good responders. Interestingly, both treatments allowed reducing or stopping steroids, which are known to increase the risk of renal crisis in SSc. A trend towards a decrease in HAQ-DI was seen, although not reaching significance. This may be related to features other than articular involvement that were previously identified to affect the HAQ-DI score—for example, dermal thickness, age or raised platelet count.20 The efficacy on joints was partly explained by some overlap with RA, as reflected by the prevalence of anti-cyclic citrullinated peptide in the cohort. However, all patients fulfilled American College of Rheumatology criteria for SSc and almost all had antibodies specific to SSc. To date, there is only case report on treating two patients with SSc (without inflammatory joint disease) with tocilizumab.21 Contrary to our results, dermal fibrosis improved in both these patients, which was confirmed by histological assessment. However, lung fibrotic changes were unchanged.21 It has to be emphasised that neither of these studies was designed to detect the effects of tocilizumab and abatacept on fibrosis in view of their sample size; their selection of patients, which was not stratified according to disease duration; their duration of follow-up and their outcome criteria.

Treatment with abatacept was associated with a trend towards improvement of refractory myopathy, but this was not statistically significant. Two hypotheses might be derived from this observation: the number of patients included might have been too small to reach significance or abatacept might be effective only on joint involvement. Study of a larger number of cases with EUSTAR network support is expected to clarify the effect of abatacept on myopathy.16 Our study should be interpreted within its limitations, such as the lack of monitoring of radiological changes. In addition, despite all the efforts made by EUSTAR to homogenise the care of patients with SSc, the participation of several centres might have introduced some heterogeneity in their assessment.

Our study suggests that tocilizumab and abatacept do have the potential to improve the outcome of SSc-related arthritis. These results underline the need for larger prospective studies with a longer follow-up and radiological monitoring to better assess the safety and effectiveness of these drugs in SSc, and to facilitate also the off-label use of these drugs in selected patients.



  • OD and YA contributed equally.

  • Contributors All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the version. ME had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design: ME, MM, OD, YA. Acquisition of data: ME, MM, MM-C, BM, GR, TL, RP, CAvM, AV, PA, FB, GF, MBo, VR, MBe, JA, UM-L, OD, YA. Analysis and interpretation of data: ME, OD, YA.

  • Disclosure ME, MM, MM-C, BM, GR, TL, RP, CAvM, AV, PA, FB, GF, MBo, VR, MBe, JA, YA: none, UM-L: speaker and adviser to BMS and Roche/Chugai; OD had consultancy relationship and/or has received research funding from Actelion, Bayer, Pfizer, Ergonex, BMS, Sanofi-Aventis, Sinoxa, United BioSource Corporation, Medacs, Biovitrium, Boehringer Ingelheim Pharma, Novartis, 4 D Science and Active Biotec for investigation of potential treatments of scleroderma and its complications.

  • Funding Funded in part by an unrestricted educational grant to EUSTAR by EULAR.

  • Competing interests None.

  • Ethics approval CPP ile de France 3.

  • Provenance and peer review Not commissioned; externally peer reviewed.