Background 21 103 ® 60 30 90 89 29 48 27 41 31 25 31 58 Clinical use of rituximab 1 Table 1 Summary of published data from clinical studies of rituximab in autoimmune disorders other than RA Disorder/study type No. of pts Treatment regimen Summary of clinical results Systemic lupus erythematosus 59 18 2 n 2 n 2 n Improved SLAM score at 12 months in 11/17 (65%) evaluable pts  84 a 2 Partial remission (improvement in renal parameters) in 8/10 pts within a median (range) of 2 (1–4) months; of these, 5 pts had complete remission at 3 months (median); this was sustained for ≥12 months in 4 pts 55 24 RTX (1,000 mg) + CyP (750 mg): two infusions, 2 weeks apart  Improvements in global and all 8 individual BILAG scores at 6 months in 23/24 pts (96%)  85 11 2 6 complete and 5 partial responses (follow-up through 2 yrs) (overall, significant reduction in median BILAG scores)  Sjögren’s syndrome 73 15 2 Improvements in subjective and objective parameters of disease activity (salivary and lacrimal gland function) in all 14 pts who completed the study. Of the 7 pts with MALT-type lymphoma, 3 had complete remission, while disease was stable in 3 pts and progressive in 1 pt.  83 16 2 Efficacy observed in 9/11 pts with systemic manifestations (improvement in systemic symptoms) and in 4/5 pts with lymphomas (disease remission)  26 16 2 Significant improvement in mean VAS scores for fatigue and dryness, tender point count, and quality of life (at Week 12) and for all 4 VAS scores, tender joint count, tender point count, and quality of life (at Week 36)  Vasculitis 34 b 2 n n Remission (BVAS = 0) in 8 pts and partial remission (BVAS = 1) in 1 pt at 6 months 50 c 2 Remission (BVAS/WG = 0) in all 11 pts (10 pts within 6 months); tapering of prednisone dose (median = 0; range 0–1.5 mg/kg/day) in all pts 51 d 2 Remission (BVAS/WG = 0) in all pts within 3 months; tapering of prednisone dose to 0 in all pts by 6 months 88 e 2 Complete response (BVAS/WG = 0) in 9 pts and partial response (BVAS/WG = 1) in 1 pt at 6 months. Follow-up (median 34 months; range 26–45 months): 3 pts relapsed but had new sustained response following re-treatment 85 c 2 Remission in 9/11 pts (BVAS = 0) and partial remission in 1 pt (BVAS = 2); 6/10 pts subsequently relapsed but had new sustained response following re-treatment with RTX (2 × 1000 mg, 2 weeks apart) 8 d 2 Remission (BVAS = 0) in 2 pts, partial remission in 1 pt, unchanged disease activity in 3 pts, and progression in 2 pts 1 month after final cycle Myositis 56 f 2 Clinical improvement (increased muscle strength relative to baseline [assessed using dynomometry]) in all 6 evaluable pts  Idiopathic thrombocytopenic purpura 87 25 2 Clinical response (rise in platelet counts) at end of therapy without need for further treatment in 13/25 (52%) pts. Responses were sustained for ≥6 months in 7 pts 22 57 2 Clinical response (rise in platelet counts) at end of therapy without need for further treatment in 31/57 (54%) pts; 29/31 responses occurred within 8 weeks of initiating RTX therapy. 15/16 pts with complete clinical response (rise in platelet counts to normal levels) maintained response for ≥12 months  13 35 2 Clinical response (rise in platelet counts) within 3–8 weeks for 17/39 (44%) treatments (4 pts received 2 cycles); pts with complete or partial responses had been in remission for a median of 47 weeks g 71 89 2 n n n n n n Clinical response (rise in platelet counts) in 49/89 (55%) pts; 31 pts maintained response for a median (range) of 9 (2–42) months, 12 pts for >12 months  Thrombotic thrombocytopenic purpura 35 11 2 n Clinical remission (regression of visceral ischemic signs and normalization of blood parameters) in all patients with acute TTP; continued remission in patients with disease remission at enrolment (6–11 months’ follow-up). Biologic remission (≥10% recovery of ADAMTS-13 activity and disappearance of anti-ADAMTS-13 antibodies) in all pts  82 25 2 All patients achieved clinical remission (sustained normal platelet count, absence of clinical manifestations of TTP, and cessation of PEX) in a median of 11 days after initiating rituximab. ADAMTS-13 activity returned to normal levels in 21/25 pts; anti-ADAMTS-13 antibodies disappeared in 23/25 pts  45 15 2 n n Clinical remission (absence of clinical manifestations of TTP and normalization of blood parameters): 100% (RTX group) vs. 66% (standard therapy group) (p = 0.0025) Mixed cryoglobulinemia 80 h 2 Complete response (improvement of clinical signs and decline in cryocrit) in 16/20 (80%) pts; response was maintained for ≥12 months in 12/16 responders 101 i 2 Improved clinical symptoms (including cutaneous manifestations, lymphoma features, neuropathic symptoms) in all 15 pts Cold agglutinin disease 11 27 2 Clinical response (improvement in anaemia, clinical symptoms, and histopathology) in 14/27 (52%) pts after first treatment and in 6/10 pts after re-treatment; median (range) time to response was 1.5 (0.5–4) months 81 j 2 One pt showed a complete response (normalization of hemoglobin levels, absence of signs of hemolysis, and loss of clinical symptoms), 8 pts had a partial response (increase in hemoglobin levels ≥1.0 g/dl for ≥1 month, no need for erythrocyte transfusions, improvement in clinical symptoms); of the 9 responders, 8 relapsed and 1 remained in remission at 48 weeks a b n n c d e n n f g h i n n n j n n ADAMTS-13 ANCA BILAG BVAS BVAS/WG CAD CyP HCV IVIG MALT PEX pts RTX SLAM VAS Systemic lupus erythematosus 46 33 57 78 59 6 96 55 64 85 40 42 84 95 92 38 Sjögren’s syndrome 37 43 2 73 76 93 83 2 26 24 Vasculitis 97 54 20 34 50 2 51 88 2 85 8 n n n 68 98 79 91 14 49 52 Thrombocytopenic purpura and other hematologic disorders A number of autoimmune disorders of hemostasis, most notably idiopathic thrombocytopenic purpura (ITP) and thrombotic thrombocytopenic purpura (TTP), have been examined for their potential responsiveness to rituximab in several small trials. 87 2 22 13 71 72 102 9 9 9 3 17 69 70 74 99 35 2 75 82 2 45 P 61 65 15 80 101 11 81 67 18 86 Myositis 19 56 2 7 12 16 28 53 62 66 Antiphospholipid syndrome 39 100 5 77 94 4 Still’s disease 47 32 1 Neurologic disorders 36 23 63 10 44 44 Conclusions Recent advances in our understanding of autoimmunity have opened up new avenues for exploring novel targeted therapies in a wide range of diseases. The role of B cells in many autoimmune disorders is now widely accepted, in many cases through the demonstration that B cell depletion using rituximab can often be very effective clinically. The potential utility of rituximab and other B cell-directed therapies is currently being studied in several of these diseases, including SLE, SS, and vasculitis. Although to date most of the findings have been encouraging, a significant proportion of the information derives from case reports and small case series. Together with the lack of randomized controlled trials in most of the diseases discussed in this review, it is likely that there has been a degree of positive reporting bias. Therefore, until large-scale clinical trial data are available, it would be prudent to proceed with caution regarding the use of rituximab outside its approved indications. Although rituximab tolerability was generally reported as favorable in most of the studies covered in this review, the true incidence of associated adverse events (e.g., serious infections, serum sickness-like reactions, and PML) will only become clear when larger numbers of patients have been treated in each disease entity. Important questions also remain regarding the optimal rituximab dosing modalities for each disease (for example, the dose and frequency of treatment, when re-treatment should be considered, and whether to use combination therapies). Nevertheless, based on the information published to date, it seems likely that B cell depletion therapy, using rituximab and—in the future—agents currently under development, will offer an effective new approach for the management of many of these burdensome and difficult-to-treat conditions.