Clinical trial NCT01748084: Rituximab in Systemic Sclerosis
Official title: Evaluation of Rituximab in Systemic Sclerosis Associated Polyarthritis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Systemic Sclerosis
Keywords: Systemic sclerosis
Arthritis
B-cell therapy, Anti-CD20 therapy
Quality of life
Scleroderma
Lung fibrosis
Randomised controled trial
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2012-12-12
Enrollment: 22
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Number of tender and swollen joints
timeFrame: at 6 months
Secondary outcomes:
measure: Quality of life: SSc-HAQ
timeFrame: at 6 and 12 months
measure: Scleroderma
timeFrame: at 6 and 12 months
measure: Lung fibrosis
timeFrame: at 6 and 12 months
measure: Quality of life: SF-36
timeFrame: at 6 and 12 months
measure: Quality of life: Duruöz index
timeFrame: at 6 and 12 months
Other outcomes:
Locations:
city: Paris
country: France
facility: Cochin Hospital
Study officials:
affiliation: Assistance Publique Hôpitaux de Paris, Université Paris Descartes
name: Yannick Allanore, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bosello S, De Santis M, Lama G, Spano C, Angelucci C, Tolusso B, Sica G, Ferraccioli G. B cell depletion in diffuse progressive systemic sclerosis: safety, skin score modification and IL-6 modulation in an up to thirty-six months follow-up open-label trial. Arthritis Res Ther. 2010;12(2):R54. doi: 10.1186/ar2965. Epub 2010 Mar 25.
citation: Simms RW, Lafyatis R. Rituximab: a potential therapeutic advance in scleroderma: what is the evidence? Rheumatology (Oxford). 2010 Feb;49(2):201-2. doi: 10.1093/rheumatology/kep421. Epub 2009 Dec 23. No abstract available.
citation: Daoussis D, Liossis SN, Tsamandas AC, Kalogeropoulou C, Kazantzi A, Korfiatis P, Yiannopoulos G, Andonopoulos AP. Is there a role for B-cell depletion as therapy for scleroderma? A case report and review of the literature. Semin Arthritis Rheum. 2010 Oct;40(2):127-36. doi: 10.1016/j.semarthrit.2009.09.003. Epub 2009 Dec 11.
citation: Daoussis D, Liossis SN, Tsamandas AC, Kalogeropoulou C, Kazantzi A, Sirinian C, Karampetsou M, Yiannopoulos G, Andonopoulos AP. Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology (Oxford). 2010 Feb;49(2):271-80. doi: 10.1093/rheumatology/kep093. Epub 2009 May 15.
citation: Lafyatis R, Kissin E, York M, Farina G, Viger K, Fritzler MJ, Merkel PA, Simms RW. B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum. 2009 Feb;60(2):578-83. doi: 10.1002/art.24249.