Rituximab in Systemic Sclerosis

Study Overview
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Brief Summary
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The purpose of this study is to determine whether rituximab is effective in the treatment of articular symptoms that occur in systemic sclerosis related polyarthritis

Detailed Description
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Systemic sclerosis (SSc) is a rare disease, characterized by microvascular and immunological changes promoting extra-cellular matrix synthesis and widespread fibrosis. No treatment has yet proven any ability to alter the disease fibrosing process. Specific auto-antibodies are commonly found in this disease, and B lymphocytes are detected in cutaneous and pulmonary infiltrates. Studies derived from murine models suggest a role for B lymphocyte blocking strategies. This lead to observational trials of B-cell therapy using rituximab in SSc that provided encouraging results with no particular signal concerning tolerability. These trials included heterogeneous patients with variable disease stages and different involved organs, and were mostly unblinded, which preclude any definitive conclusion. However, they support the continuous development of this therapeutic approach. Taking up the early phase of the diffuse form of the disease is complicated by its rarity and the heterogeneous progression of its visceral complications. This raises the question of selecting a homogeneous group of patients to evaluate. The most convincing results for the use of rituximab in autoimmune conditions have been found in rheumatoid arthritis. Joint involvement is common in SSc with 75% of patients complaining about joint stiffness and pain, and 30% presenting with synovitis, tenosynovitis, or flexion contractures. No specific treatment has already addressed this issue, and it is generally proposed to use small doses of oral corticosteroids in association with methotrexate, by analogy with rheumatoid arthritis. We propose to evaluate the efficacy and safety of rituximab in SSc patients having active arthritis despite first line treatment. Improving the articular involvement would improve the quality of life f SSc patients and effectiveness of rituximab on skin and lung fibrotic involvements will be assessed as secondary outcomes to estimate the overall effects of this drug on SSc.

Official Title
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Evaluation of Rituximab in Systemic Sclerosis Associated Polyarthritis

Conditions
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Systemic Sclerosis

Intervention / Treatment
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* Drug: Rituximab
* Drug: Placebo (NaCl)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Systemic sclerosis fulfilling ACR or LeRoy's criteria Active polyarthritis defined by > 6/53 tender joints and > 4/53 swollen joints Ongoing first line therapy by prednisone (max 10 mg/d) and DMARDS (methotrexate, leflunomide, azathioprine or mycophenolate) Birth control if applicable Exclusion Criteria: Overlap syndrome defined by clinical symptoms and positive specific auto-antibodies (anti-CCP, anti-SSA, anti-DNA DNA anti-Sm) (Rheumatoid factors and anti-RNP are not exclusion criteria) Past therapy with Rituximab. Severe and uncontrolled disease with renal, liver or haematological (neutropenia < 1500 / mm3) failures, pulmonary (FVC < 50%) or cardiac insufficiencies (LVEF < 50%) Not stable corticosteroid therapy or cyclophosphamide use in the last 6 months Infectious risk : viral infections by B or C hepatitis or HIV, hypogammaglobulinemia (< 6 G/L), opportunistic infection or infection requiring IV antibiotics in the last 3 months. Neoplastic solid tumor in the last 5 years Drug or alcool abuses Receiving patient or having received a biotherapy (anti-TNF, abatacept or tocilizumab) in the last 3 months (possible inclusion beyond 3 months)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: NaCl<br>NaCl 500 ml IV day 1 and day 15 plus 100 mg methylprednisolone | Drug: Placebo (NaCl)<br>* Days 1 and 15, NaCl 500 ml plus 100 mg methylprednisolone<br>|
| Experimental: Rituximab<br>Rituximab 1G IV day 1 and day 15 plus 100 mg methylprednisolone | Drug: Rituximab<br>* Days 1 and 15, rituximab 1 gramme plus 100 mg methylprednisolone<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of tender and swollen joints | Measured out of 53 joints | at 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life: SSc-HAQ | Validated scores | at 6 and 12 months | 
| Scleroderma | modified Rodnan skin score | at 6 and 12 months | 
| Lung fibrosis | Pulmonary functional tests | at 6 and 12 months | 
| Quality of life: SF-36 | Validated scores | at 6 and 12 months | 
| Quality of life: Duruöz index | Validated scores | at 6 and 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Systemic sclerosis, Arthritis, B-cell therapy, Anti-CD20 therapy, Quality of life, Scleroderma, Lung fibrosis, Randomised controled trial