Rituximab in the treatment of rheumatoid arthritis, systemic lupus, and other autoimmune diseases: past, present, and future

1. Background
2. Initial Research in Ra
3. ACR 2002 Annual Scientific Meeting Reports in Ra
4. Benefits in SLE
5. Other Autoimmune Diseases
6. Adverse Effects
7. The Future
8. Addendum re synergy with methotrexate in rheumatoid arthritis

Rituximab (Rituxan, Mabthera) is a chimeric monoclonal antibody that has been FDA-approved for non-Hodgkin's lymphoma and used in more than 50,000 patients. At the American College of Rheumatology Annual Scientific Meeting in 2000, reports of its off-label success in treating rheumatoid arthritis (RA) caused significant excitement. Since then, further research in RA and other autoimmune diseases has been reported, and new findings are being presented at ACR 2002 Annual Scientific Meeting. Clearly, it's not the "miracle cure" that made the early headlines, but rituximab may indeed have an important role to play in rheumatic disease.

Background
Directed at the CD20 antigen on B cells, rituximab (RTX) has mouse variable and human constant regions. Since it kills both normal and malignant B cells in the periphery, but not early B-cell precursors, the marrow is able to repopulate with B lymphocytes after treatment. (CD20 is not expressed on plasma cells or T cells.)

The success of RTX in lymphoma helped raise interest in attacking the rheumatoid arthritis process on the B-cell side, in contrast to the emphasis on T cells and their products since the success of thoracic duct drainage in RA in some 20 years ago. B cells are under-represented in RA synovium and in rheumatoid nodules; yet, anti-B-cell therapy appears to have effectiveness.

Initial Research in RA
Since RTX alone did not provide sufficiently long remissions in lymphoma, it was used in combination therapy. Thus, early study of RTX in RA used it in combination with cyclophosphamide. At ACR 2000, Vane, et al, of the U.K., reported an uncontrolled, open-label study of five patients who received RTX (four intravenous doses at weekly intervals), prednisolone (high dose over 22 days), and cyclophosphamide (CTX) (750mg i.v. x 2)[1]. All patients achieved an ACR70 at 18 months, although two had required a re-treatment.

Many rheumatologists wondered whether RTX itself, or in combination with less toxic drugs than cyclophosphamide, would also be successful, and how long the improvements would last - and evidence has been accumulating.

Leandro, et al (from the original Edwards group in the U.K.) reported on an expansion of their research -- 22 RA patients treated with five different combinations of RTX (at different doses), cyclophosphamide and high dose prednisolone[2]. They found that the dose of RTX needed to total at least 600mg/m[2] for effectiveness and that the addition of cyclophosphamide was required for major improvement. The addition of prednisolone appeared to prolong the RTX benefit. No significant adverse effects of RTX were noted.

Vita, et al of Italy, reported on five patients with active erosive RA treated with RTX alone (four weekly infusions of 375 mg/m[2]) and allowed only low-dose steroids, non-steroidal anti-inflammatory agents, or antimalarial drugs as concomitant therapy[3]. Four had significant clinical improvement, lasting between five and 12 months, demonstrating the efficacy of B cell blockade alone and confirming the importance of B cells in RA pathogenesis.

ACR 2002 Annual Scientific Meeting Reports in RA
At the 2002 ACR Annual Scientific Meeting, the U.K. group (with colleagues from Poland) is presenting further expanded data on a randomized, double blind, placebo-controlled trial of RTX in 161 seropositive RA patients, all receiving methotrexate (MTX) at doses of 10mg/week or more[4]. They were randomized to one of four treatment groups: MTX alone, RTX alone, RTX + continuing MTX, or RTX + CTX. All received a 17-day course of corticosteroids, at a total dose of 960 mg. In an interim report at 24 weeks, the RTX alone group did better than the MTX alone group, and both MTX and CTX along with RTX led to the best results. All the RTX regimens were well tolerated, self-limited, with mild to moderate toxicity. This suggests that MTX in combination with RTX is effective, which is reassuring because many rheumatologists have distinct discomfort with the adverse effects of CTX. This group's reports of long-term maintenance of improvement, and any further adverse effects, will be eagerly awaited.

The group is also presenting in poster immunologic findings in 33 of their RA patients receiving RTX[5]. They found that RTX led to a drop in IgA-RF, IgG-RF, and anti-cyclic citrinulated peptide which was significantly greater than the drop in their corresponding serum immunoglobulin classes. The time to relapse after B lymphocytes were depleted was very variable in this group of patients (0-17 months), and it correlated closely with the rise in one or more autoantibodies. The findings were taken to suggest that clinical benefit after RTX may be more closely related to the return of circulating autoantibodies than to the level of B lymphocytes.

In another ACR 2002 poster, Tuscano, et al of the University of California at Davis, reported on seven RA patients previously refractory to multiple DMARDs, including infliximab[6]. They were treated with four successive weeks of escalating intravenous RTX alone. At five months, all had improved joint scores, and three met ACR 20 criteria. These results are consistent with prior data, in that RTX alone seems to have some effect, but full effect requires a concomitant additional DMARD.

Benefits in SLE
In response to the initial reports of RTX benefits in RA in 2000, a number of rheumatologists immediately wondered what the benefits would be in systemic lupus erythematosus - a rheumatic disease more definitively identified with a central role of B-cell abnormalities.

At ACR 2001, Anolik, et al of the University of Rochester, reported on 12 SLE patients who had clinical but not serologic improvement with RTX treatment[7]. At ACR 2002, the same group reported on 18 patients with lupus treated with "low, medium or full dose" RTX[8]. Full dose was 375mg/m[2] weekly for four weeks. Analysis was incomplete at the time of abstract submission, but improvement in SLAM score was noted in those patients with good B cell depletion, and the treatments were well-tolerated. (A paper earlier this year reported that a patient with SLE and hemolytic anemia responded well to RTX without adverse effect[9].

Leandro, et al, reported this month[10] on six patients with active lupus treated with rituximab. On an open-label basis, these women (three with type IV nephritis) received a 500mg infusion of rituximab and a 750mg infusion of cyclophosphamide, along with five days of high-dose prednisolone, weekly for two weeks. Of the six, one was lost to follow-up, but the other five all were improved at the six-month mark. Using the British Isles Lupus Assessment Group global scores, they improved from a median of 14 to a median of six over the six months. Hemoglobin level increased in four patients, and C3 levels increased in all five patients who were low at study initiation. No significant adverse effects were noted. The authors suggested that two useful future studies will be (1) non-renal lupus treated with rituximab alone compared with placebo, and (2) lupus nephritis treated with rituximab and cyclophosphamide in the NIH regimen vs. the NIH regimen alone.

Other Autoimmune Diseases
Further reports of RTX therapy in autoimmune diseases, have included:

• effectiveness in one patient with refractory type II essential mixed cryoglobulinemia (MC) and one with refractory Goodpasture's syndrome[11],
• some degree of improvement in 12 out of 12 type II MC patients , with relative safety (an ACR Annual Scientific Meeting 2002 presentation from the Italian group)[12]
• complete remission in a patient with refractory Wegener's granulomatosis who was treated with RTX (four weekly infusions of 375mg/m[2] and a repeat course eight months later)[13]; and
• "dramatic and sustained improvement" in five patients with refractory adult or pediatric dermatomyositis who were treated with low dose RTX, again with very mild adverse effects (an ACR Annual Scientific Meeting 2002 presentation from Phoenix Neurological Associates)[14].

In view of the clear pathogenicity of antibodies in MC and in Wegener's granulomatosis, the theoretical basis for an attack on B cells is sound. Further study in these diseases will be of great interest.

Adverse Effects
So far, reported adverse effects of RTX in RA have been far less severe than in lymphoma patients, with no first-infusion deaths. Such deaths have been reported in lymphoma patients, presumably because of the "tumor lysis" effect, which may be seen, which may include acute renal failure. The cytokine release syndrome, with associated bronchospasm and hypotension (and potential myocardial infarction and death) appears to be much more of a risk in lymphoma patients than in those with RA. Also, as of May 2001, 20 reports of severe mucocutaneous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, had been reported after RTX infusion in lymphoma patients - but none in those with autoimmune disease.

In the Leandro RA study, two mild infusion reactions occurred (one with fever and one with tachycardia, each after the first infusion), as well as four lower respiratory infections, one episode of bacterial sinusitis, one patient with thrombocytopenia, and two with rash. In the Tuscano RA study, only low-grade infusion reactions were reported. One pneumonia death in the latest large Edwards RA study was felt unrelated to the study medication by the investigators.

In general, the adverse effects with rituximab in patients with RA and other autoimmune disorders have been mild, with side effects largely limited to non-life threatening infusion site reactions. Although infection remains a concern with rituximab, it this has not been a significant finding in studies so far. In this regard, the recovery of the B-cell population prior to evidence of return of autoantibodies presents a hopeful picture.

The Future
Studies to date suggest some exciting possibilities with rituximab, especially for patients refractory to our present armamentarium of long-term agents, including anti-TNF and anti-IL1-ra agents. The key factors in rheumatologist acceptance of rituximab will be its long-term safety and duration of effect, as well as its effectiveness in combination with various other agents.

The data so far suggest that rituximab may have a favorable infection risk profile, especially if it can be used without cyclophosphamide. The effectiveness of rituximab in RA, providing support for the importance of B cells and their products in pathogenesis, opens up the area of B- cell-focused therapy for this disease. The reported effectiveness of the combination of rituximab with methotrexate, if supported in further trials, will make the use of RTX much more attractive. If the present data on RTX are replicated, this biologic will be an important additional weapon in our efforts influence the immune system in a very focused manner.

In the future, RTX may well be part of the arsenal against RA, lupus, and a variety of other autoimmune diseases that are refractory to current agents. If its safety remains favorable in future trials, and in long-term follow-up of the present patients under study, and if it can be paired with agents with acceptable toxicity, such as methotrexate, rituximab may someday be an alternative to other biologics as the first agent added when methotrexate alone fails.

Addendum re synergy with methotrexate in rheumatoid arthritis (November 18, 2002)

As with the studies of etanercept and infliximab, the rituximab studies to date do not answer the question as to whether these medications with methotrexate are any better than these medications alone. The studies with methotrexate were done by adding these biologics to patients who were non- or partial- methotrexate responders. The needed studies would compare methotrexate-virgin patients who took a) methotrexate alone, b) methotrexate + biologic and c) biologic alone. This sort of study may be difficult with infliximab, in view of reported anti-DNA antibody development on infliximab alone. Preliminary data suggests that RTX alone, if given in sufficient dose for prolonged B-cell suppression, may be effective in rheumatoid arthritis (J. Edwards, personal communication). Only such further studies can allow us to make this treatment choice with more than anecdotal evidence.

_____________________________________________________

Abstracts from the ACR 2002 Annual Scientific Meeting published with the permission of the American College of Rheumatology

1. Efficacy and Safety of Rituximab,a B-Cell Targeted Chimeric Monoclonal Antibody: A Randomized, Placebo-Controlled Trial in Patients with Rheumatoid Arthritis
2. B Lymphocyte Depletion in Patients with Rheumatoid Arthritis: Serial Studies of Immunological Parameters
3. Successful Treatment of Infliximab-Refractory Rheumatiod Arthritis with Rituximab
4. B Lymphocyte Depletion in the Treatment of Systemic Lupus (SLE): Phase I/II Trial of Rituximab (Rituxan©) in SLE
5. Efficacy and Safety of Rituximab Treatment in Type II Mixed Cryoglobulinemia Category
6. A Pilot Study of Rituximab Therapy for Refractory Dermatomyositis

ABSTRACT: Efficacy and Safety of Rituximab,a B-Cell Targeted Chimeric Monoclonal Antibody: A Randomized, Placebo-Controlled Trial in Patients with Rheumatoid Arthritis

J C W Edwards[1], L Szczepanski[2], J Szechinski[3], A Filipowicz-Sosnowska[4], D Close[5], R M Stevens[6], T M Shaw[5]
[1]University Colledge London, London, United Kingdom [2]University of Lublin, Lublin, Poland [3]University of Wroclaw, Wroclaw, Poland [4]Institute of Rheumatology, Warsaw, Poland 5Roche Products Ltd, Welwyn Garden City, United Kingdom6Hoffmann-La Roche, Nutley, NJ

Presentation Number: 446

Rationale: A previous open label trial suggested that depletion of B-lymphocytes induced substantial and sustained improvement in rheumatoid arthritis (RA). This initial study used the chimeric monoclonal antibody, rituximab, against the B-cell antigen CD20, in combination with cyclophosphamide (CTX) and corticosteroids. A randomised, double-blind, placebo controlled trial was subsequently conducted.

Methods: 161 patients with RA were recruited. All patients were receiving methotrexate (MTX) at a dose ³ 10mg/wk and had active disease (SJC & TJC [3] 8 and an elevated ESR/CRP). All were rheumatoid factor positive. Patients were randomized to one of 4 treatment groups with appropriate double-dummy placebos: Group A: Continuing MTX alone; Group B: Rituximab alone (2 x 1g i.v. infusions); Group C: Rituximab (2 x 1g i.v. infusions) plus CTX (2 &multiply; 750 mg iv infusions); Group D: Rituximab (2 &multiply; 1g i.v. infusions) plus continuing MTX. Infusions of both rituximab and CTX were within the first 17 days. All groups also received a 17 day course of corticosteroids (total dose of 960mg).

Results: An interim analysis of the study was performed with the first 122 patients. The proportion of patients achieving ACR responses at 24 weeks were:

Click Thumbnail to Enlarge

p-values are from Fishers Exact test comparing MTX with each rituximab group The safety profile indicates that all 3 rituximab regimens were well tolerated with similar levels and type of adverse events compared to MTX alone. The majority of events were of mild or moderate intensity and resolved without sequelae.

Conclusions: In a 24 week controlled study a short induction regimen with rituximab alone or in combination with either MTX or CTX produced substantial clinical benefit in RA. Combination with MTX or CTX produced the highest levels of ACR20, 50 and 70 responses. All 3 rituximab regimens were well tolerated.

Addendum: One patient receiving rituximab without continued methotrexate died from bronchopneumonia five months in to the study period. The local investigator considered this event unrelated to trial medication.

ABSTRACT: B Lymphocyte Depletion in Patients with Rheumatoid Arthritis: Serial Studies of Immunological Parameters

Geraldine Cambridge[1], Maria J Leandro[1], Jonathan C W Edwards[1], Michael R Ehrenstein[1], Martin Salden[2], David Webster[3]
[1]university college london, London, United Kingdom[2]Euro-diagnostica, Arnhem, Netherlands[3]Royal Free Hospital, London, United Kingdom

Presentation Number: 1350

Purpose: B lymphocyte depletion has recently been used as a therapy for rheumatoid arthritis (RA) and a range of other autoantibody-associated disorders including IgM-associated neuropathies, immune thrombocytopenic purpura, autoimmune haemolytic anaemia, systemic lupus erythematosus and dermatomyositis. Whether clinical benefit in patients with RA results from removal of B lymphocytes per se, of B lymphocytes as precursors of autoantibody producing plasma cells or a combination of these is not known. We have therefore explored the relationship between clinical disease, B lymphocyte return and serological variables following B lymphocyte depletion in 22 patients with RA.
Methods: B lymphocyte depletion was achieved using combination therapy based on the monoclonal anti-CD20 antibody rituximab. Levels of anti-microbial antibodies (pneumococcal polysaccharide, tetanus toxoid) and of autoantibodies, including IgA, IgM and IgG class rheumatoid factors (RF) and antibodies to cyclic citrulinated peptide (anti-CCP), were measured by ELISA. C-reactive protein (CRP) was used as a serological indicator of inflammation.

Results: The majority of patients (17/22) showed a significant clinical improvement with benefit lasting up to 33 months. Total serum immunoglobulins fell but mean values at nadir (IgM, 0.9±0.9g/L; IgG, 8.8±2.3 IgA, 2.0±1.1) remained within the normal range. Although the drop in the IgM-RF response followed total serum IgM levels, IgA-RF, IgG-RF and anti-CCP antibodies decreased significantly more than their corresponding serum immunoglobulin classes (p<0.001). The kinetics for the reduction in CRP levels also paralleled decreases in autoantibody levels. In contrast, anti-microbial antibodies measured at 3 months and at B lymphocyte return did not differ from baseline (p>0.05). The time to relapse after B lymphocyte return was often long and unpredictable (0-17 months) but was was closely correlated with rises in one or more autoantibodies. Rises in autoantibody levels were rarely observed in the absence of clinical change.

Conclusions: Therapeutic B lymphocyte depletion provides a new opportunity to assess the roles of B lymphocytes in the pathogenesis of RA and other autoimmune diseases. We found that B lymphocyte depletion in patients with RA had a selective effect on autoantibody levels. Relapse was associated with rises in specific autoantibody levels but not always with B lymphocyte return. These findings suggest that the clinical benefit seen following B lymphocyte depletion (and disease relapse) is related more closely to circulating autoantibodies than to the physical presence of B lymphocytes.

ABSTRACT: Successful Treatment of Infliximab-Refractory Rheumatiod Arthritis with Rituximab

Joseph M Tuscano
UC Davis, Sacramento, CA

Presentation Number: LB11 Poster Board Number: 444

Rheumatoid arthritis (RA) is a chronic, debilitating, autoimmune disorder affecting up to 2.6 million people in the United States. It is a multisystem disease of uncertain cause. Although many organs can be involved, the predominant feature is inflammatory synovitis, usually involving the peripheral joints in a symmetric pattern, leading to significant disability. Current treatments for RA is limited by cumulative toxicities and progressive disease. There is accumulating evidence that RA is initiated in humans by T cell recognition of ubiquitously expressed self-antigen; once initiated, pathology is driven almost entirely by autoreactive immunoglobulins. Rituximab is a recombinant human-mouse chimeric anti-CD20 monoclonal antibody developed for the treatment of patients with B cell lymphoma. Recent reports have suggested that RA may be successfully treated with the combination of rituximab and cyclophosphamide. Statement of purpose: Here we describe the initial data of a clinical trial using rituximab alone for the treatment of erosive RA in patients that have previously failed multiple DMARD's including infliximab. Methods: The treatment regime consisted of rituximab given as a total dose of 100mg on wk #1, followed by 375mg/m[2] on wk #2, and 500mg/m[2] on wks 3 and 4. Patients were evaluated for clinical response based on the criteria of the ACR 20. Laboratory correlates assessed included Rheumatoid factor (RF), C-reactive protein (CRP), ESR, complement levels (C3 and C4), immunoglobulin levels and absolute T and B lymphocyte counts. Results: To date a total of nine patients have been enrolled, of these 7 are evaluable. At a median follow-up of 5 months all seven patients had improved joint scores, and 3 met criteria for an ACR 20. All seven patients had reductions in RF and CRP titers. There was no consistent change in complement levels, ESR, or immunoglobulin levels. Absolute B lymphocyte levels were diminished by 8 weeks post-therapy. There was no significant change is absolute T lymphocyte levels. The therapy was well tolerated with only NCI grade 1 or 2 infusion-related toxicity. Conclusion: While the current patient numbers are small, and enrollment is ongoing, this data supports the hypothesis that B lymphocytes mediate pathology in RA, and that rituximab is a promising agent for patients with DMARD and infliximab-refractory RA.

ABSTRACT: B Lymphocyte Depletion in the Treatment of Systemic Lupus (SLE): Phase I/II Trial of Rituximab (Rituxan©) in SLE

Jennifer H Anolik[1], Debbie Campbell[1], Ray Felgar[1], Joseph Rosenblatt[2], Fay Young[1], R J Looney[1]
[1]University of Rochester School of Medicine, Rochester, NY;[2]University of Miami, Miami, FL

Presentation Number: 717 Poster Board Number: 182

Background: Because B cell abnormalities are postulated to be critical to the immuno-pathogenesis of SLE, specific depletion of B cells may have lasting clinical benefit and offer valuable insights into B cell homeostasis in this disease. Rituximab is a chimeric mouse/human monoclonal antibody against the B cell antigen CD20 that leads to prolonged depletion of B cells in the treatment of lymphoma. As CD20 is relatively specifically expressed on immature and mature B cells but not plasma cells or T cells, rituximab may be less immunosuppressive than other treatment regimens.

Methods: A phase I/II trial was initiated to investigate the safety, tolerability, and preliminary clinical efficacy of rituximab in the treatment of 18 patients with SLE. Requirements for enrollment include clinically active but non-organ threatening SLE (SLAM score = 6). The dose-escalation of rituximab is as follows: 1) low dose = one infusion of 100 mg/m[2] (first 6 subjects), 2) medium dose = one infusion of 375 mg/m[2] (next 6 subjects), and 3) full dose = four weekly doses of 375 mg/m[2] (final 6 subjects).

Results: At the time of abstract submission, 15/18 patients have been treated with no serious treatment related events. 3/12 patients developed elevated human anti-chimera antibody (HACA) titers at 2 months of unclear clinical significance, and patients in the high dose cohort are still being evaluated. One time treatment at 100mg and 375mg/m[2] rituximab depleted B cells in the peripheral blood to a variable degree, with full doses leading to more consistent and prolonged depletion. Subjects in the low and medium dose cohort who had good B cell depletion (<1% CD19+ lymphocytes) (7/12) experienced a statistically significant decrease in SLAM at 2 and 3 months post rituximab (p=0.03). In contrast, the group with poor B cell depletion had a trend towards an increase in SLAM at those same times. In the low and medium dose cohort, significant effects on anti-double stranded DNA titers and serum complements were not observed by 12 months of follow-up. Additional clinical and serologic data in all six patients treated with high dose rituximab is being collected and will be reported.

Conclusions: In this phase I/II trial, rituximab was well tolerated and significantly depleted B lymphocytes in patients with SLE. The lack of effect on anti-double stranded DNA titers is interesting and suggests either incomplete B cell depletion (perhaps in secondary lymphoid tissue) and/or the presence of very long-lived plasma cells. If the former, we expect to observe serologic improvement in the high dose cohort. Overall, rituximab appears safe and promising in the treatment of SLE and other autoimmune diseases induced by pathogenic autoantibody production and/or antigen presentation by autoreactive B cells.

ABSTRACT: Efficacy and Safety of Rituximab Treatment in Type II Mixed Cryoglobulinemia Category

Salvatore De Vita[1], Francesco Zaja[2], Stefania Sacco[1], Angela Michelutti[2], Ginevra De Marchi[1], Cesare Mazzaro[3], Renato Fanin[2], Gianfranco Ferraccioli[1]
[1]Department of Rheumatology, University of Udine, Udine, Italy[2]Department of Haematology, University of Udine, Udine, Italy[3]Division of Medicine, S.M. degli Angeli Hospital, Pordenone, Italy

Presentation Number: 469

The optimal treatment of type II mixed cryoglobulinemia (MC) has still to be defined. Antiviral treatment for the frequent underlying infectious trigger hepatitis C virus (HCV) may be not applicable, partially effective, or uneffective. On the other hand, current immunosuppressive treatments may lead to relevant complications. Thus, selective B-cell blockade with rituximab (anti-CD20 chimeric monoclonal antibody) was used in type II MC, based on favourable results in preliminary experience.

Patients and Methods: Fourteen consecutive patients with type II MC syndrome (10F, 4M; mean age 65.2 years; range 43-79; HCV-related in 11/14) gave their informed consent to rituximab treatment, 375 mg/m[2] i.v. weekly for 4 times. Only low-dose steroids were also allowed, when necessary. All the patients had active disease, unresponsive to prednisone, cyclophosphamide, azathioprine, or plasma exchange. Antiviral therapy had proved uneffective, counterindicated, or poorly tolerated in all. The mean follow-up after treatment was 7 months (range: 2-25).

Results: Peripheral B-cell depletion occurred in all cases after treatment. Clinical response was evaluated from month +1 to month +6 after the first drug infusion, and positive response (usually within month +3) was seen for vasculitic skin ulcers, purpura or urticaria in 12/12, subjective symptoms of peripheral neuropathy in 6/8; fever in 2/2, low-grade B-cell lymphoma in 3/3, nephritis in 0/1 (under evaluation in another patient), hyperviscosity syndrome in 1/1. The serum rheumatoid factor decreased in 61%and became negative in 23% of cases, cryos became negative in 30%, and C4 increased in 50%. Treatment was well tolerated, with no infectious complications or worsening of HCV-related liver disease. Thrombosis of retinal artery or self-limiting panniculitis occurred in one patient each during the follow-up.

Conclusions: Rituximab may represent a safe and effective alternative to standard immunosuppression in type II MC. The efficacy for the different organ manifestations and response duration deserve additional investigation and follow-up

ABSTRACT: A Pilot Study of Rituximab Therapy for Refractory Dermatomyositis

Todd D Levine
Phoenix Neurological Associates, Phoenix, AZ

Presentation Number: 1299 Poster Board Number: 254

Dermatomyositis is believed to be an autoimmune disease associated with B-cell-mediated attack on capillaries in the skin and muscle. Traditional therapeutic agents for dermatomyositis include corticosteroids, IV gammaglobulin, and other immunosuppressive agents. Despite the wide variety of available therapeutic options, up to 25% of patients with dermatomyositis remain refractory to treatment either because of unwanted side effects or incomplete response. Therefore, a better-tolerated, effective therapy would fulfill a significant unmet medical need. Rituximab is a monoclonal antibody directed against CD20, an antigen present on B cells. In previous studies rituximab was shown to be effective and well tolerated in IgM-mediated neuropathies and completely eliminated circulating B cells (Levine TD, et al. Neurology. 1999;52:1701-1704). This abstract describes findings for the first 5 patients to receive rituximab for refractory dermatomyositis. Three patients were adults, 2 of whom had failed previous therapies including steroids, IV gammaglobulin, methotrexate, and cyclosporine. The third adult patient had received no treatment since diagnosis. Two additional patients were ages 11 and 12 years, who had failed numerous previous therapies. Adult patients received 4 weekly doses of rituximab (100 mg/m[2]) and juvenile patients received 2 weekly doses (100 mg/m[2]). Muscle strength was objectively quantified by dynamometry. Rituximab treatment was well tolerated and completely eliminated circulating B cells. No patients experienced significant side effects; however, 2 patients complained of generalized asthenia for 24 to 48 hours after the first infusion. Within 1 to 3 months all patients experienced a dramatic and sustained ([3] 6 months in duration) improvement in muscle strength and dermatitis. The 2 previously treated adult patients had overall improvements in quantitative muscle strength of 60% and 20%, and the previously untreated patient had a 55% improvement. The juvenile patients had overall improvements in quantitative muscle strength of 30% and 45%, respectively. The previously untreated adult patient continues to maintain normal muscle strength after 12 months of followup. These preliminary findings suggest that rituximab may be efficacious for refractory dermatomyositis and warrant the investigation of rituximab in the first-line setting. Based on these results we are conducting a larger, phase II/III study.