The last few years have seen a renewed interest in the role of B cells as causative agents in autoimmune diseases. Although a better understanding of the pathophysiology of B lymphocytes deserves recognition, it is the promising results of recent small pilot studies applying anti-B-cell therapy toward autoimmune diseases like systemic lupus erythematosus, rheumatoid arthritis, primary Sjögren's syndrome, systemic vasculitis, sarcoidosis, and antisynthetase syndromes that has done the most to spark this revived interest.1,2 The most widely studied B-cell-depleting therapy uses rituximab, which is an anti-CD20 monoclonal antibody.
Success with rituximab has also recently been reported in the treatment of refractory autoimmune disease like rheumatoid arthritis, long considered a TH1-mediated disease. Similar to rheumatoid arthritis, the role of autoantibodies in dermatomyositis is controversial. Preliminary evidence suggests that rituximab can be used successfully to treat dermatomyositis.3 A recent open-label pilot study using 6 patients with clinical and objective data consistent with dermatomyositis demonstrated improvement in muscle strength and functional capacity.4 We present a further case report of dermatomyositis successfully treated with rituximab and offer insight into the future role B-cell depletion therapies in autoimmune diseases.
A 56-year-old man presented with a 3-week history of diffuse myalgias, arthralgias, and progressive proximal muscle weakness. He noted difficulty elevating his arms and legs, getting up from bed, and bilateral lower extremity paresthesias. The patient was status post L4–L5 laminectomy 1 month before admission. Review of systems was significant for an erythematous rash on the chest and neck in addition to fatigue. He denied loss of appetite, weight loss, constitutional symptoms, Raynaud phenomenon, sicca symptoms, oral ulcers, fever, chills, chest pain, shortness of breath, or gastrointestinal symptoms.
A diffuse erythematous rash involving the upper extremities and neck, in a V-neck distribution, was present. Neither Gottron papules nor a heliotropic rash was present. Mild tenderness was noted over the metacarpal–phalangeal joints, the wrists, and knees. The knees demonstrated bilateral effusions. Proximal upper extremities demonstrated 3/5 motor strength, whereas strength in proximal lower extremities was 2+/5. Sensory examination and deep tendon reflexes were normal. The left lower extremity demonstrated mild clonus, attributed to postsurgical changes from prior laminectomy. Laboratory evaluation revealed mild normocytic anemia, a creatine kinase of 11,321 U/L, and transaminases in the range of 300 U/L. Erythrocyte sedimentation rate was 32 mm/h. He was found to have normal thyroid function, negative ANA, anti-Mi-2, and anti-SRP antibodies. Anti-Jo-1 was 490 U/mL (normal, <120 U/mL). Full pulmonary function tests as well as high-resolution computed tomography scan of the chest was performed. Results did not suggest underlying pulmonary involvement. A thorough evaluation for malignancy, which included computed tomography scans of the chest, abdomen, and pelvis along with age-appropriate screening, was negative.
Electromyography demonstrated 2+ positive waves, 2+ fasciculations, and few polyphasic motor unit action potential (MUP) consistent with an inflammatory myopathy. Muscle biopsy demonstrated mild perifascicular atrophy with evidence of myophagocytosis. Solumedrol at a dosage of 60 mg every 12 hours was started with minimal improvement. Intravenous immunoglobulin was added at a total dose of 2 g/kg over 2 days. Finally, methotrexate at a dosage of 20 mg per week was begun; however, the patient continued to have significant muscle weakness.
During the next year, hydroxychloroquine, azathioprine, and oral cyclophosphamide were added to his regimen. He continued to have progressive weakness and increasing creatine kinase levels. Infliximab was subsequently started, with an initial reduction in creatine kinase to 2193 U/L. (See Table 1 for the detailed course of medications and creatine kinase levels.) The patient developed right middle lobe pneumonia 2 weeks after his third infusion of infliximab. His symptoms resolved after 14 days of antibiotics. All immunosuppressive agents, except prednisone, were discontinued. No evidence of underlying pulmonary involvement secondary to dermatomyositis was present. Within 1 month, the patient's creatine kinase reached 15,084 U/L. He became wheelchair-dependent. Proximal motor strength was 3/5 in all extremities except his left lower extremity, which was 2/5. The patient was started on rituximab. He received 6 weekly infusions of 210 mg (100 mg/m2) followed by maintenance doses of 210 mg/m2 every 3 months.
Three weeks after the initial 6 weekly infusions, the patient's absolute B lymphocyte count was zero as determined by flow cytometry. Clinically, the patient responded, as indicated by an objective increase in muscle strength (all proximal muscles were 4/5 strength, except the left lower extremity, which was 3/5), resolution of his rash, ability to ambulate without assistance, and a decline in his creatine kinase to 1413 U/L.
Approximately 20 months have passed since the patient's initial presentation. He is currently on 7.5 mg prednisone a day, 25 mg azathioprine a day, 20 mg methotrexate a week, and 210 mg rituximab every 3 months. The dosing in terval of rituximab will eventually be extended pending maintenance of current laboratory and clinical responses. His most recent creatine kinase is 64 U/L and he has regained full strength (5/5) in all his proximal muscles, except in the left lower extremity (4/5). Interestingly, Anti-Jo-1 antibody titers did not coincide with clinical response. His most recent titer was 485 U/mL.
Dermatomyositis, along with polymyositis and inclusion body myositis, comprise a group of idiopathic inflammatory myopathies that are characterized by muscle weakness and inflammation, which is potentially treatable. In contrast to polymyositis and inclusion body myositis, humoral immune mechanisms appear to play a greater role in dermatomyositis. The cellular infiltrates are predominantly B cells, CD4 T cells, and MAC complex. Capillary damage leads to perifascicular atrophy. The vessels show upregulation of vascular adhesion molecules, clustering of inflammatory cells, deposits of immunoglobulins, and terminal membrane attack complex of complements.5 Cumulative experience supports a therapeutic approach of escalating treatments that begins with steroids followed by immunosuppressive agents such as methotrexate, azathioprine, intravenous immunoglobulin, cyclosporine, mycophenolate mofetil, and cyclophosphamide.6 The anti-TNF agents have also shown promise in treatment of refractory disease. Despite this armamentarium of potentially effective therapies, up to one third of patients with dermatomyositis continue to have mild to severe disability.7
The success of rituximab in the treatment of patients with cancer, combined with its good safety profile, has led to its off-label use in the treatment of autoimmune diseases such as idiopathic thrombocytopenic purpura, systemic lupus erythematosus, mixed cryoglobulinemia, and Goodpasture syndrome. In these diseases, autoantibodies are believed to play a pathogenic role. The case reports and open-label studies using rituximab in the treatment of refractory cases have been promising. Not only does rituximab appear to offer a new therapy that is well tolerated, its success as treatment has done much to shed new light on the role of B cells in autoimmune disease previously thought to be predominantly T-cell-mediated.
Use of rituximab in patients with lymphoma has provided evidence that plasma cells are not short-lived and that patients treated with rituximab have little change in total immunoglobulin (Ig) levels despite absence of circulating B lymphocyte autoantibodies. These autoantibodies do disappear relatively quickly after B-cell depletion, possibly reflecting a subpopulation of short-lived plasma cells. Studies also demonstrate that a significant decrease in circulating levels of rheumatoid factor in rheumatoid arthritis, antiplatelet antibodies in idiopathic thrombocytopenia purpura, and dsDNA in systemic lupus erythematosus correlate with clinical improvement after treatment with rituximab.8–10 There are an even greater number of studies in which patients with autoimmune diseases have shown significant clinical response to rituximab with a total depletion of circulating B cells despite having no change in the levels of circulating autoantibodies. As plasma cells, the principal source of disease-producing autoantibodies is CD20-negative and not affected by rituximab. It is therefore not surprising that most studies report little or no change in total Ig levels. This implicates that depletion of B lymphocytes alters the disease course by eliminating the other nonantibody-mediated functions of the B cell in disease pathogenesis. These include the B cell's role as antigen-presenting cells, cytokine production, cognate help for autoreactive T cells, and direct infiltration of end organs such as the muscle in dermatomyositis.11
FcγR IIIa ligation is now recognized as a key event in immune complex-mediated inflammation. It is suggested that the immunomodulatory effects of intravenous immunoglobulins in dermatomyositis work by saturating the Fcγ receptors with antiidiotypic antibodies. This interaction inhibits disease-related events. In vitro studies have shown complement dependent cytotoxicity (CDC) and antibody-dependent, cell-mediated cytotoxicity (ADCC) as some of the mechanisms by which rituximab depletes B cells. Additionally, B-cell apoptosis occurs when B cells are crosslinked between natural killer cells and macrophages through the Fcγ receptors.12
Long-term remission in autoimmune disease may require that B-cell depletion therapy be combined with some form of plasma cell depletion therapy. It is rituximab's limited ability to affect plasma cells and thus total Ig levels that may explain why rituximab has a low association of opportunistic infections in addition to being a generally well-tolerated therapy.9 For the time being, B-cell depletion therapy with rituximab used alone or in combination with other currently available immunosuppressive therapies is a viable option in patients with autoimmune diseases refractory to current therapies.
1. Gottenburg J, Guillevin L, Lambotte O, et al. Tolerance and short-term efficacy of rituximab in 43 patients with systemic autoimmune diseases. Ann Rheum Dis
2. Looney R. John, Anolik J, et al. B cells as therapeutic targets for rheumatic diseases. Curr Opin Rheumatol
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6. Dalakas M, Hohlfeld R. Polymyositis and dermatomyositis. Lancet
7. Sultan SM, Ionnou Y, Moss K, et al. Outcome in patients with idiopathic inflammatory myositis: morbidity and mortality. Rheumatology
8. Kneitz C, Wilhelm M, Tony HP. Effective B cell depletion with rituximab in the treatment of autoimmune diseases. Immunobiology
9. Edwards JC, Cambridge G. Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology
10. Stasi R, Stipa E, Forte V. Variable patterns of response to rituximab treatment in adults with chronic idiopathic thrombocytopenia purpura. Blood
11. Silverman GJ, Weisman S. Rituximab therapy in autoimmune disorders: prospects for anti-B cell therapy. Arthritis Rheum
12. Anolik JH, Campbell D, Felgar RE, et al. The relationship of FcγRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum
IOF World Congress on Osteoporosis
Toronto, Ontario, Canada
June 2–6, 2006
Contact: IOF Congress Secretariat, 73 cours Albert Thomas
69003, Lyon, France
Tel: 334 7291 4177
Fax: 334 7236 9052
Web site: www.osteofound.org
© 2005 Lippincott Williams & Wilkins, Inc.