New Evidence reports on presentations given at ACR Improving Radiographic, Clinical, and Patient-Reported Outcomes with Rituximab

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1 New Evidence reports on presentations given at ACR 2009 Improving Radiographic, Clinical, and Patient-Reported Outcomes with Rituximab

2 From ACR 2009: Rituximab Rituximab in combination with methotrexate significantly inhibits joint damage and improves clinical outcomes in patients with early active RA who are refractory to methotrexate (IMAGE) (Tak P-P, et al. ACR 2009: Abstract 636) Rituximab improved physical function and quality of life in patients with early rheumatoid arthritis who were naïve to methotrexate (IMAGE-PRO) (Rigby W, et al. ACR 2009: Abstract 1665) Identification of biomarkers for enhanced benefit to rituximab in rheumatoid arthritis: role of autoantibodies and inflammatory markers (Silverman G, et al. ACR 2009: Abstract 1680)

3 From ACR 2009: Rituximab (cont d) Multiple courses of rituximab produce sustained efficacy in rheumatoid arthritis patients with an inadequate response to one or more TNF inhibitors (Keystone E, et al. ACR 2009: Abstract 1683) Long-term safety of rituximab: follow-up of the rheumatoid arthritis clinical trials and re-treatment population (Van Vollenhoven RF, et al. ACR 2009: Abstract 1952) Safety of rituximab in combination with a TNF inhibitor and methotrexate in patients with active rheumatoid arthritis: results from a randomized, controlled trial (TAME) (Greenwald M, et al. ACR 2009: Abstract 1957)

4 Rituximab in combination with methotrexate significantly inhibits joint damage and improves clinical outcomes in patients with early active RA who are refractory to methotrexate (IMAGE) Tak P-P, et al. ACR 2009: Abstract 636.

5 Background In Canada, rituximab is currently indicated in combination with MTX for the treatment of moderate-to-severe active rheumatoid arthritis in patients with an inadequate response to tumour necrosis factor inhibitors (TNF-Is). 1 The IMAGE study is an ongoing phase III study designed to evaluate the efficacy of rituximab plus MTX, compared to MTX alone, in patients with active RA who are MTX-naïve. At ACR 2009, Tak P-P and colleagues presented the primary efficacy endpoint results of the IMAGE study PR RITUXAN Product Monograph. September 25, Tak P-P, et al. ACR 2009: Abstract 636. MTX = methotrexate TNF-I = tumour necrosis factor inhibitor

6 Study design Tak P-P, et al. ACR 2009: Abstract 636.

7 Study design (cont d) Key inclusion criteria for the IMAGE study were as follows: no prior exposure to MTX, with a disease duration of <4 years; SJC and TJC of 8 each; CRP concentration of 1.0 mg/dl; RF positive or erosive damage. MTX was initiated in all groups at 7.5 mg/wk and titrated to 20 mg/wk by week 8. Rituximab was given by intravenous infusion on days 1 and 15. Radiographs were taken at screening, week 24, and week 52. The primary endpoint was the change from screening in mtss at week 52. Secondary endpoints included ACR and EULAR responses, MCR defined as an ACR70 response maintained for at least 6 months, and change in DAS28-ESR. Tak P-P, et al. ACR 2009: Abstract 636. CRP = C-reactive protein; DAS28 = 28-joint Disease Activity Score ESR = erythrocyte sedimentation rate; MCR = major clinical response mtss = modified total sharp score; MTX = methotrexate SJC = swollen joint count; TJC = tender joint count;

8 Key findings A total of 755 patients were randomized, and 715 patients were radiographically evaluable at 52 weeks. Groups were well matched at baseline, with a mean RA duration of 0.9 years and DAS28 >7. The mean change in DAS28-ESR score was 3.21, 3.05, and 2.06 in the rituximab (2 x 1000 mg) plus MTX, rituximab (2 x 500 mg) plus MTX), and placebo plus MTX groups, respectively (p < for all comparisons with MTX). SAEs occurred in 10%, 9%, and 10% of patients in the rituximab (2 x 1000 mg) plus MTX, rituximab (2 x 500 mg) plus MTX, and placebo plus MTX groups, respectively; the rate of SIEs per 100 patient-years was 3.73, 4.61, and 6.09, respectively. Tak P-P, et al. ACR 2009: Abstract 636. DAS28 = 28-joint Disease Activity Score ESR = erythrocyte sedimentation rate; MTX = methotrexate RA = rheumatoid arthritis; SAEs = serious adverse events SIEs = serious infection events

9 Tak P-P, et al. ACR 2009: Abstract 636. Figure 1. Mean change in mtss score after 52 weeks of treatment

10 Tak P-P, et al. ACR 2009: Abstract 636. Figure 2. Percentage of patients with an mtss score 0 after 52 weeks of treatment

11 Figure 3. Change in radiographic scores by six month periods Tak P-P, et al. ACR 2009: Abstract 636.

12 Figure 4. ACR responses and MCR after 52 weeks of treatment Tak P-P, et al. ACR 2009: Abstract 636.

13 Tak P-P, et al. ACR 2009: Abstract 636. Figure 5. EULAR responses after 52 weeks of treatment

14 Key conclusions After 52 weeks of treatment in patients with early active rheumatoid arthritis, rituximab (2 x 1000 mg) significantly inhibited joint damage, as compared to methotrexate alone. Both higher (2 x 1000 mg) and lower (2 x 500 mg) doses of rituximab plus methotrexate significantly improved clinical outcomes, as compared with methotrexate alone. A significantly higher proportion of patients achieved a major clinical response with both doses of rituximab, as compared to methotrexate alone. Safety outcomes were consistent with previous data, and no new or unexpected safety signals were identified. Tak P-P, et al. ACR 2009: Abstract 636.

15 Rituximab improved physical function and quality of life in patients with early rheumatoid arthritis who were naïve to methotrexate (IMAGE-PRO) Rigby W, et al. ACR 2009: Abstract 1665.

16 Background Patients with rheumatoid arthritis (RA) live with considerable physical, social, and emotional disabilities. Improving HRQoL is therefore an important treatment goal, with the value of collecting PROs in clinical trials becoming increasingly apparent. IMAGE-PRO is an ongoing study using PRO data from the IMAGE study to examine the effect of rituximab in combination with MTX, as compared with MTX alone, in patients with active RA who are MTX-naïve. At ACR 2009, Rigby and colleagues presented data from the IMAGE-PRO study. Rigby W, et al. ACR 2009: Abstract HRQoL = health-related quality of life MTX = methotrexate PRO = patient-reported outcome

17 Study design Patients included in the IMAGE study: had no prior exposure to MTX, with a disease duration of <4 years had a swollen and tender joint count of 8 each had a C-reactive protein concentration of 1.0 mg/dl were rheumatoid factor positive or exhibited erosive damage Patients were randomized to receive placebo plus MTX, rituximab (2 x 500 mg) plus MTX, or rituximab (2 x 1000 mg) plus MTX. MTX was initiated in all groups at 7.5 mg/wk and titrated to 20 mg/wk by week 8. Rituximab was given by intravenous infusion on days 1 and 15. PRO instruments included the SF-36 PCS and MCS scores; the HAQ-DI; the FACIT-Fatigue scale; and the PGA and Pain, measured using the VAS. Rigby W, et al. ACR 2009: Abstract FACIT = Functional Assessment of Chronic Illness Therapy HAQ-DI = Health Assessment Questionnaire Disability Index; MCS = Mental Component Summary score; MTX = methotrexate PCS = Physical Component Summary score PGA = Patient Global Assessment of Disease Activity SF-36 = 36-item Short Form Health Survey VAS = Visual Analogue Scale

18 Key findings A total of 755 patients were randomized, and 748 were included in the ITT population and received at least one treatment dose. Of these, 620 (83%) patients had early RA (<2 years). Patient demographics, baseline disease characteristics, and PRO scores were well balanced across groups. In post hoc analyses, greater numeric improvements from baseline to week 52 were observed for both rituximab plus MTX dose groups, versus MTX alone, in all eight domains of the SF-36. An MCID of >0.22 for HAQ was achieved by a greater proportion of patients in both rituximab plus MTX dose groups, compared with patients who received MTX alone (p <0.05). MCID was achieved in a greater proportion of patients in the rituximab (2 x 1000 mg) plus MTX group, compared with the placebo plus MTX group, for SF-36 (both PCS and MCS) and FACIT-Fatigue (p <0.05). Rigby W, et al. ACR 2009: Abstract FACIT = Functional Assessment of Chronic Illness Therapy HAQ-DI = Health Assessment Questionnaire Disability Index MCID = minimal clinically important difference MCS = Mental Component Summary score MTX = methotrexate; SF-36 = 36-item Short Form Health Survey PCS = Physical Component Summary score; PRO = patient reported outcomes;

19 Rigby W, et al. ACR 2009: Abstract Figure 1. Mean change from baseline to week 52 in HAQ-DI

20 Rigby W, et al. ACR 2009: Abstract Figure 2. Mean change from baseline to week 52 in FACIT-Fatigue

21 Rigby W, et al. ACR 2009: Abstract Figure 3. Mean change from baseline to week 52 in Patient Global Score

22 Rigby W, et al. ACR 2009: Abstract Figure 4. Mean change from baseline to week 52 in Pain Score

23 Figure 5. Mean change from baseline to week 52 in SF-36 summary and domain scores Rigby W, et al. ACR 2009: Abstract 1665.

24 Key conclusion Rituximab in combination with methotrexate showed significant improvement in physical function and health-related quality of life outcomes, as compared with methotrexate alone. Rigby W, et al. ACR 2009: Abstract 1665.

25 Identification of biomarkers for enhanced benefit to rituximab in rheumatoid arthritis: role of autoantibodies and inflammatory markers Silverman G, et al. ACR 2009: Abstract 1680.

26 Background Identifying markers associated with improved outcomes after rituximab therapy enables the selection of patient groups with an enhanced response to rituximab. Knowledge of these markers can aid in the management of patients with rheumatoid arthritis (RA). A study by Silverman and colleagues used data from the REFLEX and SERENE trials to examine markers, clinical features, and/or combinations of these associated with improved outcomes after rituximab therapy. At ACR 2009, Silverman and colleagues presented data from their study. Silverman G, et al. ACR 2009: Abstract 1680.

27 Study design The REFLEX study was a double-blind, placebo-controlled, phase III RCT conducted in RA patients with a previous inadequate response to TNF-Is. SERENE was a second double-blind, placebo-controlled, phase III RCT conducted in RA patients with an inadequate response to MTX. The study by Silverman and colleagues was a post hoc analysis of selected biomarkers, clinical features, and serologic markers using data from the REFLEX study, and further examining promising markers that showed potential response prediction in the SERENE data set. Baseline pre-treatment samples and clinical data from the REFLEX and SERENE studies were used to conduct this analysis. Silverman G, et al. ACR 2009: Abstract REFLEX = randomized evaluation of long-term efficacy of rituximab in RA SERENE = study evaluating rituximab s efficacy in methotrexate inadequate responders MTX = methotrexate; RCT = randomized controlled trial TNF-Is = tumour necrosis factor inhibitors

28 Study design (cont d) Silverman G, et al. ACR 2009: Abstract 1680.

29 Study design (cont d) A threshold sensitivity method was used to identify candidate markers/ clinical features that enriched for placebo-corrected ACR50 response rate at 24 weeks and were able to identify at least 20% of patients from the REFLEX study. The top four markers and five of their two-marker combinations were then prioritized and further investigated in the SERENE data set. For the combination of two markers, the hypothesis that CRP-high and RF IgA high patients have improved clinical efficacy was tested. Subgroups were determined by 30th 70th percentile categories of CRP and RF IgA, with the constraint that at least 20% of the patients were in each subgroup. Other combinations were investigated similarly. Exploratory analysis of other pre-specified baseline biomarkers and combinations of markers were also performed. Silverman G, et al. ACR 2009: Abstract CRP = C-reactive protein; IgA = immunoglobulin A RF = rheumatoid factor

30 Key findings Improved clinical benefit was observed in the REFLEX data set for the following serological markers: RF IgA, IgG anti-ccp antibodies, CRP, and soluble CD25. These four biomarkers, as well as clinical features of disease activity (DAS-ESR), and five of their two-marker combinations were then further investigated in the SERENE data set. CRP was selected over IL-6 to be further examined because of its clinical relevance and readily available standardized tests. The efficacy differentials were higher than 10% for RF IgA and CRP in SERENE, based on the optimal thresholds obtained from REFLEX. Silverman G, et al. ACR 2009: Abstract anti-ccp = anti-cyclic citrullinated peptide antibody; CRP = C-reactive protein DAS-ESR = disease activity score-erythrocyte sedimentation rate IgA = immunoglobulin A; IL-6 = interleukin-6; RF = rheumatoid factor;

31 Key findings (cont d) In discovery studies, it was determined that, compared to seronegative patients, seropositivity for any isotypes of RF or IgG anti-ccp antibodies was associated with a higher rate of placebocontrolled ACR50 response at 24 weeks. Enhanced benefit to rituximab was independently confirmed in the SERENE study, as observed by the association of elevated CRP and seropositive RF IgA. The greatest enhancement was seen with the CRP plus IgA RF combination. Silverman G, et al. ACR 2009: Abstract anti-ccp = anti-cyclic citrullinated peptide antibody CRP = C-reactive protein; IgA = immunoglobulin A IgG = immunoglobulin G; RF = rheumatoid factor;

32 Key findings (cont d) The optimal individual thresholds determined in SERENE for CRP (2.9 mg/dl) and IgA RF (25 U/mL) were used for the combination of these two biomarkers. These patients also had improved clinical responses across a spectrum of other clinical outcome measures. Elevated CRP in combination with seropositive RF isotypes showed enhanced clinical benefit to rituximab. The CRP/RF isotype combinations shown in the SERENE trial data set were confirmed in the REFLEX data set. Silverman G, et al. ACR 2009: Abstract CRP = C-reactive protein; IgA = immunoglobulin A RF = rheumatoid factor

33 Figure 1. ACR50 response rate differences at week 24 for the marker combination of elevated C-reactive protein and IgA rheumatoid factor in the SERENE data set Silverman G, et al. ACR 2009: Abstract 1680.

34 Table 1. Summary of marker combination versus clinical parameters in the SERENE data set Silverman G, et al. ACR 2009: Abstract 1680.

35 Key conclusions In the REFLEX study, seropositivity for rheumatoid factor or anti- CCP antibody and elevated CRP identified a subgroup of RA patients with an enhanced efficacy to rituximab; these findings were reproduced in the SERENE trial. The identified biomarkers and thresholds which confer enhanced benefit need to be verified in independent data sets. High CRP and seropositivity indicate that patients who have high levels of systemic inflammation and autoantibody driven disease seem to benefit from rituximab therapy. Further studies are needed to understand the pathophysiology of this subset of RA patients. Silverman G, et al. ACR 2009: Abstract anti-ccp = anti-cyclic citrullinated peptide antibody; CRP = C-reactive protein

36 Multiple courses of rituximab produce sustained efficacy in rheumatoid arthritis patients with an inadequate response to one or more TNF inhibitors Keystone E, et al. ACR 2009: Abstract 1683.

37 Background Despite the success of rituximab for the treatment of RA in patients who have had an inadequate response (IR) to TNF-Is, whether repeat courses result in sustained efficacy remains unclear. A meta-analysis of open-label extension studies examined the efficacy of repeat courses of rituximab in TNF-IR patients who had previously responded to a first or second course. At ACR 2009, Keystone and colleagues presented results of the meta-analysis. Keystone E, et al. ACR 2009: Abstract RA = rheumatoid arthritis; TNF-I = tumour necrosis factor inhibitor

38 Study design Studies included in the meta-analysis study 1 were REFLEX/ WA , DANCER 3, WA , WA , MIRROR 6, SIERRA 7, and SUNRISE 8. In the majority of studies, eligibility for re-treatment included a response to the first/second course (at least a 20% reduction in swollen and tender joint counts). Each course consisted of rituximab (2 x 1000 mg) given as intravenous infusions two weeks apart and concomitant MTX (10 25 mg/week). Before all infusions, patients received prophylactic intravenous methylprednisone (100 mg). Background stable-dose oral corticosteroids ( 10 mg/day prednisolone or equivalent) and nonsteroidal anti-inflammatory drugs (NSAIDs) were also permitted. 1. Keystone E, et al. ACR 2009: Abstract Keystone E, et al. Arthritis Rheum 2007;65: Cohen SB, et al. Arthritis Rheum 2006;54: Rubbert-Roth A, et al. Arthritis Rheum 2008; Abstract Emery P, et al. Arthritis Rheum 2006;54: Bingham C, et al. Arthritis Rheum 2007; Abstract Edwards JC, et al. N Engl J Med 2004;350: Mease PJ, et al. Arthritis Rheum 2008; Abstract MTX = methotrexate

39 Study design (cont d) Efficacy analyses were confined to TNF-IR patients who received continuous treatment with the approved dose of rituximab (2 x 1000 mg). 1 Patients who initially received placebo and were subsequently treated with rituximab (2 x 1000 mg) were included from the point at which they first received rituximab. Patients from the SIERRA 2 and SUNRISE 3 studies were not included in the efficacy population due to incompatible study designs. Efficacy data included: all observed data: all patients, all visits, all courses all data available at a given time point; within patient, within visit: data for patients who have received four courses of treatment and had efficacy data at week 24 after each course. 1. Keystone E, et al. ACR 2009: Abstract Bingham C, et al. Arthritis Rheum 2007; Abstract Mease PJ, et al. Arthritis Rheum 2008; Abstract MTX = methotrexate; NSAID = non-steroidal anti-inflammatory drugs TNF-IR = tumour necrosis factor inhibitor inadequate responder

40 Key findings In total 1,324 TNF-IR patients were exposed to at least one course of rituximab. The highest incidence of withdrawals due to adverse events occurred during the first treatment course and decreased with subsequent courses. A total of 595 TNF-IR patients were exposed to at least one course of rituximab (2 x 1000 mg). Of these, 500 patients had evaluable efficacy assessments at week 24 following their first course. Safety over repeated courses did not show any unexpected findings. Over 3, p-yrs of observation in TNF-IR patients, the overall rate of serious adverse events was 20.17/100 p-yrs, and the overall rate of serious infection events was 5.44/100 p-yrs. Keystone E, et al. ACR 2009: Abstract p-yrs = patient-years TNF-IR = tumour necrosis factor inhibitor inadequate responder

41 Keystone E, et al. ACR 2009: Abstract 1683.

42 Figure 1. ACR responses 24 weeks after each course in the within patient, within visit population Keystone E, et al. ACR 2009: Abstract 1683.

43 Keystone E, et al. ACR 2009: Abstract Figure 2. EULAR responses 24 weeks after each course in the within patient, within visit population

44 Figure 3. DAS28-ESR low disease activity and remission 24 weeks after each course in the within patient, within visit population Keystone E, et al. ACR 2009: Abstract 1683.

45 Key conclusions In RA patients with a previous inadequate response to TNF inhibitor(s) and an initial response to rituximab, multiple courses of rituximab were associated with sustained levels of efficacy. Signs, symptoms, and physical function were maintained, with a trend towards improvement. Keystone E, et al. ACR 2009: Abstract 1683.

46 Long-term safety of rituximab: follow-up of the rheumatoid arthritis clinical trials and re-treatment population Van Vollenhoven RF, et al. ACR 2009: Abstract 1952.

47 Background Despite the success of rituximab for the treatment of rheumatoid arthritis (RA) patients who have had an inadequate response (IR) to tumour necrosis factor inhibitors (TNF-Is), the safety of repeat courses is unclear. An ongoing study of pooled data from a global clinical trial program is examining the long-term safety of rituximab in combination with methotrexate (MTX) in patients with RA. At ACR 2009, Van Vollenhoven and colleagues presented interim results of this long-term safety study. Van Vollenhoven RF, et al. ACR 2009: Abstract 1952.

48 Study design The study by Van Vollenhoven and colleagues is a pooled analysis of data from a global clinical trial program. All patients in the program were offered repeat treatment with rituximab, as determined by clinical need. Patients receiving placebo during placebo-controlled studies were pooled to provide a placebo population. Data were collected on adverse events (AEs), including infusion reactions, infections, and malignancies. Serious infusion reaction events were defined as evidence of pruritus, fever, urticaria/rash, chills, pyrexia, rigors, sneezing, angioneurotic oedema, throat irritation, cough, bronchospasm, hypotension, or hypertension. Van Vollenhoven RF, et al. ACR 2009: Abstract 1952.

49 Key findings As of September 2008, this analysis was based on 7,198 p-yrs of rituximab exposure. A total of 3,095 patients with RA received multiple courses of rituximab: 2,365; 1,581; 1,038; and 497 patients received 2, 3, 4, and 5 courses, respectively. More than 750 patients were followed for >3 years from start of treatment. IRRs from rituximab were mainly grade 1 or 2 and occurred after the first infusion of the first course (23%). Fewer than 1% of IRRs were considered serious. The most frequent serious infections were of the lower respiratory tract, predominantly pneumonia (1%). No cases of TB or reactivation of hepatitis B were reported. Van Vollenhoven RF, et al. ACR 2009: Abstract IRR = infusion-related reaction; p-yrs = patient years SIE = serious infection event; TB = tuberculosis

50 Key findings (cont d) Serious opportunistic infections were uncommon, but included one confirmed case of Pneumocystis jiroveci pneumonia in each of the rituximab and pooled placebo groups, and one case of PML in the rituximab group. The causal relationship of PML to rituximab in this case was unclear due to recognized risk factors, including carcinoma of the oropharynx treated by chemoradiotherapy. Rates of MI and stroke were consistent with the general RA population. The SIR for malignancy compared with the SEER 2008 database was 1.06 (95% CI: ). The most frequently reported malignancy (excluding non-melanoma skin cancer) was breast cancer (SIR 0.69; 95% CI: ). Van Vollenhoven RF, et al. ACR 2009: Abstract MI = myocardial infarction PML = progressive multifocal leukoencephalopathy SIR = standardized incidence ratio

51 Van Vollenhoven RF, et al. ACR 2009: Abstract 1952.

52 Van Vollenhoven RF, et al. ACR 2009: Abstract 1952.

53 Key conclusion In a prolonged follow-up of RA patients treated with rituximab in clinical trials, rituximab has remained well tolerated over multiple courses with a stable safety profile similar to the placebo population. Van Vollenhoven RF, et al. ACR 2009: Abstract 1952.

54 Safety of rituximab in combination with a TNF inhibitor and methotrexate in patients with active rheumatoid arthritis: results from a randomized, controlled trial (TAME) Greenwald M, et al. ACR 2009: Abstract 1957.

55 Background Despite the success of rituximab for the treatment of rheumatoid arthritis (RA) patients who have had an inadequate response (IR) to TNF-Is, the safety of combination treatment with rituximab and TNF-Is is unclear. An ongoing open-label study (TAME) is examining the safety of rituximab in combination with a TNF-I, etanercept or adalimumab, plus methotrexate (MTX) in patients with active RA. At ACR 2009, Greenwald and colleagues presented preliminary data of the TAME study. Greenwald M, et al. ACR 2009: Abstract 1957.

56 Study design Patients included in the TAME study: had active RA (swollen joint count 5 and tender joint count 5); had been receiving etanercept (50 mg once per week) or adalimumab (40 mg every two weeks) plus MTX (10 25 mg once per week) for 12 weeks or more. Patients were randomized 2:1 to rituximab (500 mg) or placebo on days 1 and 15. After week 24, eligible patients could enter the open-label rituximab treatment arm. The primary endpoint was the proportion of patients who experienced 1 serious infection through week 24. Secondary endpoints included additional safety and efficacy parameters. Greenwald M, et al. ACR 2009: Abstract MTX = methotrexate

57 Key findings Fifty-one (51) patients received at least one dose of study treatment, 33 in the rituximab group and 18 in the placebo group. Baseline characteristics and concomitant TNF-Is were balanced between treatment groups, with the exception of oral steroid use (36% for the rituximab group versus 17% for the placebo group). There were 2 patients (6%) with SAEs in the rituximab group and 0 in the placebo group. Through week 24, there was 1 serious infection in p-yrs of exposure in the rituximab group (6.43 events per 100 p-yrs; 95% CI: ) and 0 in the placebo group. No further serious infections in p-yrs (2.16 events per 100 p-yrs; 95% CI: ) in patients receiving 1 or 2 courses of rituximab were observed. Greenwald M, et al. ACR 2009: Abstract p-yrs = patient-years; SAE = serious adverse event

58 Greenwald M, et al. ACR 2009: Abstract 1957.

59 Greenwald M, et al. ACR 2009: Abstract Figure 1. ACR20 and ACR50 response rates after 24 weeks of treatment with rituximab versus placebo

60 Key conclusions The preliminary safety profile for rituximab in combination with a TNF-I (etanercept or adalimumab) and MTX was consistent with the safety profile for rituximab with MTX in other RA trials without a TNF-I; no new safety signals were seen. A larger open-label study evaluating the safety profile for rituximab in combination with TNF-Is and DMARDs is in progress. Greenwald M, et al. ACR 2009: Abstract DMARD = disease-modifying anti-rheumatic drug MTX = methotrexate TNF-I = tumour necrosis factor inhibitor