Prompt efficacy of very low-dose rituximab on monoclonal B lymphocytosis in a rheumatoid arthritis patientписьмо
Аннотация: Therapy with rituximab – an anti-CD20 monoclonal antibody – is mainly performed in patients affected by B-cell lymphoproliferative disorders, including B-cell lymphoma and B-cell chronic lymphocytic leukemia (B-CLL).1 Rituximab doses of 375 mg/m2 and 500 mg/m2 have been generally used in B-cell lymphoma and B-CLL, respectively, with different therapeutic schedules when used as monotherapy or combined with chemotherapy. A maintenance therapy for 2–3 years has been also advised in some B-cell lymphoma sub-types, such as follicular lymphoma. Recently, rituximab therapy has been applied in different autoimmune disorders, including rheumatoid arthritis (RA), particularly when other biological therapies, such as anti TNF-alpha drugs, have failed.2 In RA patients, rituximab is administered at a fixed dose of 2000 mg (1000 mg in two infusions, 2 weeks apart from each other) every 6 months, achieving a deep and sustained CD20 depletion.3 However, we previously observed that very low doses (50–100 mg) of rituximab in two RA patients were unexpectedly associated with a deep B-cell reduction and RA disease control was achieved with only a 100 mg dose.4, 5 Hereby, we report the case of a RA patient with monoclonal B-cell lymphocytosis who experienced a complete normalization of CD20 cells shortly after the infusion of only 200 mg rituximab. A 69-year old patient, with allergic diathesis (rhinitis, conjunctivitis) and RA diagnosed 9 years before, was referred to our Unit due to a severe disease relapse. He was in long-term therapy with prednisone (5 mg daily) with an inadequate disease control. At 67 years, sulphosalazine (2 g daily) therapy was added, due to methotrexate intolerance, without a relevant clinical benefit. At entry, both rheumatoid factor and anti-cytrulline antibodies were positive, and the Disease Activity Score (DAS28) was 5.3. The radiological study with magnetic resonance imaging documented sinovitis of hands and wrists, with erosions of carpal bones. After negative results at chest radiography, Mantoux test, and hepatitis (HBV and HCV) screening, an anti-TNF-α monotherapy (Etanercept 50 mg/week) was started, achieving a clinical improvement with DAS28 (3.0) reduction. After 30 months of therapy, leukocytosis occurred (white blood cell count [WBC]: 12 910) with 29% neutrophils and 63% lymphocytes. Lymphocyte characterization with cytofluorometry (FACS) showed that 60% of WBCs were monoclonal B-lymphocytes CD20, CD22, CD25, CD5 and FMC-7 positive, while only a weak positivity for the CD79b and CD10 was shown, the CD38 being negative. A weak expression of CD23 on few lymphocytes was also detected with a light immunoglobulin Kappa restriction. Absolute circulating B-cell count was < 5.0 × 106/L. The immunophenotype was compatible with a diagnosis of B-cell monoclonal lymphocytosis (MBL) with a 3/5 CCL scoring according to the Matutes score.6 No lymph node enlargement was detected, and both chest radiography and abdominal computed tomography scan were negative, so that a ‘wait and see’ approach was suggested by the hematologist. Etanercept therapy was discontinued, and prednisone (5 mg daily) was re-introduced. However, a RA reactivation (DAS28: 5.6) occurred 9 months later, and no clinical response was achieved by increasing steroid dose (methylprednisolone 16 mg/day). A low-dose (7.5 mg/week) methotrexate therapy was not tolerated due to gastrointestinal side-effects. Due to both RA activity and MBL persistence (CD20: 49.9%; 2006 cells/μL), with a reduction of natural killer lymphocytes (136 cells/μL; normal values: 140–420), we opted for rituximab therapy. Based on the reported allergic diathesis and the reported side-effects with methotrexate, we cautiously started an empiric therapy with only 200 mg rituximab, upon a standard pre-medication with methylprednisolone, paracetamol and chlorphenamine. The 10-day control revealed a deep depletion of monoclonal B-cells with CD20 count as low as 4.3% and a total of 73 cells/μL. A marked improvement of RA activity was also observed (DAS28: 3.4). Since no allergic reactions occurred, we increased rituximab dose to the standard 1000 mg at the second infusion 15 days following the first one. At 6-month control, neither MBL recurrence nor RA relapse were observed. Follow-up is still ongoing. RA patients are at increased risk of developing lymphomas,7 while leukemia is a rare event.8 However, leukemia onset during anti-TNF-α therapy has been reported.9 In our patient, MBL occurred 3 years following etanercept therapy. The concomitant presence of MBL and the previous intolerance to methotrexate therapy prompted us to attempt therapy with rituximab. Based on the allergic diathesis, we chose to start with a very low dose (200 mg) anti-CD20 therapy. Surprisingly, we observed a prompt normalization of the CD20 count within 10 days, despite the monoclonal nature of lymphocytes. Indeed, although we previously reported a CD20 depletion following a single infusion of either 50 mg or 100 mg rituximab therapy in two RA patients, no monoclonal component was present in these cases.4, 5 Such a therapeutic response in our patient would indicate an elevated expression of superficial antigens on monoclonal B-cells (MBL), rather than a B CCL that typically expresses low antigens. We also observed a prompt improvement of RA symptoms, with DAS28 decreasing from 5.6 to 3.4. A similar result was observed with 100 mg, but not with 50 mg rituximab therapy.4, 5 All these observations would suggest that very low doses (100–200 mg) of rituximab could be effective in controlling both RA symptoms and the associated MBL. Therefore, pilot studies aiming to confirm that very low doses of rituximab therapy are effective as rescue therapy in RA patients or sufficient to control indolent lymph-proliferative diseases are urged. Indeed, such a therapeutic approach is definitively cheaper than the proposed schedules, and it could be potentially safer for the patients.
Год издания: 2013
Издательство: Wiley
Источник: International Journal of Rheumatic Diseases
Ключевые слова: Chronic Lymphocytic Leukemia Research, Systemic Lupus Erythematosus Research, Rheumatoid Arthritis Research and Therapies
Другие ссылки: International Journal of Rheumatic Diseases (PDF)
International Journal of Rheumatic Diseases (HTML)
PubMed (HTML)
International Journal of Rheumatic Diseases (HTML)
PubMed (HTML)
Открытый доступ: bronze
Том: 16
Выпуск: 6
Страницы: 764–765