Abstract Background Biologic therapies are often prescribed for patients with rheumatoid arthritis (RA) who have inadequate responses to or are intolerant of methotrexate (MTX) and patients with poor prognostic indicators. This post hoc analysis evaluated effectiveness and safety of intravenous golimumab + MTX vs golimumab without MTX in RA patients. Methods AWARE, a real-world, prospective and pragmatic, Phase 4 study, compared effectiveness and safety of golimumab and infliximab in biologic-naïve and biologic-experienced patients. All treatment decisions were at the discretion of the treating rheumatologist. Effectiveness was evaluated by mean change in CDAI scores at Months 6 and 12. Safety was monitored through approximately 1 year. Results Among 685 golimumab-treated patients, 420 (61%) received concomitant MTX during the study and 265 (39%) did not receive MTX after enrollment; 63% and 72%, respectively, discontinued the study. Relative to golimumab without MTX, golimumab + MTX patients had shorter mean disease duration (8.7 vs 10.0 years) and a lower proportion received prior biologics (60% vs 72%); mean ± standard deviation (SD) baseline CDAI scores were similar (30.8 ± 15.1 and 32.6 ± 15.4). Mean ± SD changes from baseline in CDAI scores at Months 6 and 12, respectively, were similar with golimumab + MTX (− 10.2 ± 14.2 and − 10.8 ± 13.8) and golimumab without MTX (− 9.6 ± 12.9 and − 9.9 ± 13.1). The incidence of adverse events/100 patient-years (PY) (95% confidence interval [CI]) was 155.6 (145.6, 166.1) for golimumab + MTX and 191.2 (176.2, 207.1) for golimumab without MTX; infections were the most common type. The incidence of infusion reactions/100PY (95% CI) was 2.1 (1.1, 3.6) for golimumab + MTX versus 5.1 (2.9, 8.3) for golimumab without MTX; none were considered serious. For golimumab + MTX versus golimumab without MTX, rates/100PY (95% CI) of serious infections, opportunistic infections, and malignancies were 2.6 (1.5, 4.3) versus 7.0 (4.4, 10.6), 0.9 (0.3, 2.0) versus 2.6 (1.1, 5.0), and 3.0 (1.7, 4.7) versus 1.0 (0.2, 2.8), respectively. Conclusions Mean change in CDAI score in the golimumab without MTX group was generally similar to that of the golimumab + MTX group through 1 year, regardless of prior biologic therapy. Adverse events were consistent with the known IV golimumab safety profile. These results provide real world evidential data that may assist healthcare providers and patients with RA in making informed treatment decisions. Trial registration: clinicaltrials.gov NCT02728934 05/04/2016.

Background: AWARE is a real-world evidence-based (RWE) study evaluating the safety and efficacy of IV golimumab (GLM) and infliximab (IFX) in adults with RA. Objectives: Evaluate safety and efficacy of IV GLM and IFX in elderly AWARE participants. Methods: AWARE, a prospective non-interventional study (88 US sites), enrolled patients (pts) initiating either IV GLM or IFX. Pt management was at the discretion of treating rheumatologists. In a post hoc analysis, pts were grouped by age (<65/≥65/≥75 yrs). Adverse events (AEs) were collected through the Week (W) 52 database lock (DBL; completed W52 or discontinued study) and at the end-of-study DBL (W104). The primary endpoint was proportion of pts with ≥1 infusion reaction through W52. Change from baseline in Clinical Disease Activity Index (CDAI) scores at Months 6 and 12 were secondary endpoints evaluated in bionaïve pts, including those with IFX dose escalation. Results: 1270 pts were enrolled (685 IV GLM; 585 IFX). 1047 (82%) pts were female; mean age was 60 yrs (57% <65 yrs, 43% ≥65 yrs, and 7% ≥75 yrs). Mean disease durations were 9 yrs (IV GLM) and 7 yrs (IFX). Comorbidities were generally similar between IV GLM and IFX groups but more common among pts ≥65 vs <65 yrs. Through W52, 66% of IV GLM pts and 62% of IFX pts discontinued the study. Discontinuation due to lack of efficacy was generally similar across age groups within treatment groups, although somewhat higher for IV GLM (29%) vs IFX (19%). For both treatments, AEs and discontinuations due to AE through W52 were more common in pts ≥65 vs <65 yrs (Table 1). Consistent with general trends observed in elderly individuals, 1 rates of serious AEs (SAEs) and serious infections increased with age for both IV GLM and IFX; however, increases were more notable in IFX- than IV GLM-treated pts ≥65 yrs. The incidence of serious infections was highest in pts ≥75 yrs for both treatments, although small sample size may limit data interpretation. No increase in opportunistic infections, including Varicella, was observed in pts ≥65 vs <65 yrs. Infusion reactions were more common in pts <65 yrs in both treatment groups, and more prevalent in IFX- than IV GLM-treated pts within each age group through W52. Generally similar safety results were seen between W52 and W104 for each treatment group (data not shown). Both IV GLM and IFX in bionaïve pts showed improvement in CDAI scores across age groups, which was maintained over time (Figure 1). Table 1. % of pts with ≥1 AE through W52 DBL IV GLM IFX <65 yrs ≥65 yrs ≥75 yrs <65 yrs ≥65 yrs ≥75 yrs Patients, n 351 334 91 370 215 46 Discontinued due to AE 8.5% 12.6% 16.5% 15.1% 17.7% 21.7% AE 52.4% 58.4% 57.1% 63.5% 66.5% 71.7% Most common AEs (≥5% of pts in either treatment group) Nausea 3.7% 3.3% 3.3% 8.4% 6.0% 2.2% Worsening of RA 5.4% 4.5% 3.3% 7.3% 7.0% 4.3% Upper respiratory tract infection 5.7% 5.1% 4.4% 6.2% 5.6% 2.2% Pruritis 1.4% 2.4% 3.3% 6.8% 2.8% 2.2% Sinusitis 7.1% 3.3% 0% 3.8% 3.7% 2.2% Urinary tract infection 4.8% 5.1% 5.5% 4.3% 5.1% 6.5% SAE 7.7% 16.8% 20.9% 9.7% 18.6% 26.1% Infection 30.5% 27.2% 27.5% 32.2% 28.8% 32.6% Serious infection 3.7% 6.3% 7.7% 3.5% 7.9% 15.2% Neoplasms benign, malignant and unspecified 0.6% 2.7% 1.1% 0.8% 2.3% 6.5% Latent tuberculosis 0.3% 0% 0 0.3% 0% 0% Opportunistic infection 1.4% 1.8% 4.4% 1.9% 1.4% 4.3% Infusion reaction 5.1% 2.7% 1.1% 17.3% 8.8% 8.7% Death 0.3% 2.4% 2.2% 0% 2.3% 6.5% Conclusion: Elderly RA pts receiving IV GLM or IFX in this RWE study demonstrated similar safety and efficacy as reported in Phase 3 trials. 2,3 The higher rates of AEs, discontinuations due to AE, and SAEs (mainly serious infections) observed in pts ≥65 yrs are in line with increased safety events seen in elderly vs younger individuals in the general population. Rates of AEs, SAEs, and infusion reactions were higher for IFX vs IV GLM. Infusion reactions were more common in pts <65 vs ≥65 yrs for both GLM and IFX, but more prevalent with IFX. References: [1]Castle SC. Clin Infect Dis 2000;31:578–85. [2]Lipsky PE, et al. N Engl J Med 2000;343:1594-602. [3]Weinblatt ME, et al. Ann Rheum Dis 2013;72:381-9. Disclosure of Interests: Joy Schechtman: None declared, Aaron Broadwell Speakers bureau: Amgen, AbbVie, Eli Lilly, Horizon, Janssen, Mallinckrodt, Novartis, Pfizer, Radius, Sanofi/Regeneron, and UCB, Consultant of: AbbVie, Amgen, Aurinia, Celegene, Eli Lilly, Janssen, Novartis, Pfizer, and Sandoz, Shelly Kafka Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Shawn Black Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Stephen Xu Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Wayne Langholff Shareholder of: Johnson & Johnson, Employee of: Janssen Research & Development, LLC, Sergio Schwartzman Shareholder of: Amgen, Boston Scientific, Gilead, Medtronic, and Pfizer, Speakers bureau: AbbVie, Janssen, Eli Lily, Novartis, Pfizer, Regeneron, Sanofi, and UCB, Consultant of: AbbVie, Gilead, Eli Lilly, Janssen, Myriad, Novartis, Regeneron, Samsung, Sanofi, and UCB

Background AWARE (Comparative and Pragmatic Study of Golimumab IV Versus Infliximab in Rheumatoid Arthritis) is an ongoing Phase 4 comparator study designed to provide a real-world assessment of intravenous golimumab (GLM) and intravenous infliximab (IFX) in patients (pts) with rheumatoid arthritis (RA). The primary objective of AWARE is to assess the incidence of infusion reactions, the concomitant use of methotrexate (MTX) is also reported. The FDA approved label for GLM states that it is indicated for the treatment of patients with moderately to severely active RA in combination with MTX; however prospectively obtained real world evidence based data on the rate of GLM use without MTX has not been reported. Objectives Here we compare patient demographics, disease characteristics, response to therapy and discontinuation of GLM treated patients with and without concomitant MTX from an interim analysis (IA) of the AWARE study. Methods AWARE is a prospective, noninterventional, observational, multicenter 3-year study conducted in the US. RA pts (1,200 adults) were enrolled at the time of initiating treatment with GLM or IFX. All treatment decisions including MTX utilization are made at the discretion of the treating rheumatologist. Imputations of CDAI data were not performed at this IA. Data shown are mean ± standard deviation. Results 678 GLM pts were enrolled; of these 487 (71.8%) were GLM Plus-MTX and 191 (28.2%) were GLM No-MTX. Demographics are shown in the table. Response to therapy was assessed with CDAIs and shown in the figure below. Overall, 92.6% of GLM Plus-MTX and 91.5% of GLM No-MTX pts had a baseline (BL) categorical CDAI disease activity of moderate or high, and 7.4% of GLM Plus-MTX and 8.5% of GLM No-MTX pts had a BL categorical CDAI disease activity of low or remission. Discontinuation from the study during the period of this IA was similar between the GLM Plus-MTX (173/487; 35.5%) and GLM No-MTX (64/191; 33.5%). 7.9% of GLM No-MTX pts reported leflunomide use. GLM Plus-MTX GLM No-MTX Number of Patients 487 191 Age (years) 61.7 ± 12.85 58.7 ± 14.55 Sex (% Female) 87.1% 81.7% Disease Duration (yr) 9.0 ± 9.67 9.6 ± 10.74 Baseline CDAI 30.9 ± 14.58 33.2 ± 16.61 Race White 86.2% 87.4% African American 8.6% 8.4% Other 5.1% 4.2% Weight (kg) 83.6 ± 24.55 84.0 ± 22.21 BMI (kg/m2) 31.0 ± 8.45 30.8 ± 7.89 Conclusion At BL 28.2% of pts on GLM did not report concomitant MTX use. The demographics of the GLM Plus-MTX pts did not differ remarkably from GLM No-MTX pts. The reported early response to treatment, assessed by CDAI score after 3 months and 6 months was similar in the GLM Plus-MTX and GLM No-MTX groups. These preliminary IA data suggest that in a real-world rheumatology practice setting, use of GLM with or without concomitant MTX led to similar CDAI scores at 3 and 6 months in RA pts with predominantly moderate to high BL CDAI disease category. Disclosure of Interests Aaron Broadwell Grant/research support from: Janssen Scientific Affairs, LLC, Vance Bray Grant/research support from: Janssen Scientific Affairs, LLC, Douglas Conaway Grant/research support from: Janssen Scientific Affairs, LLC, Joy Schechtman Grant/research support from: Janssen Scientific Affairs, LLC, Alan Kivitz Shareholder of: Novartis, Consultant for: Abbvie, Janssen, Pfizer, UCB, Genzyme, Sanofi, Regeneron, Boehringer Ingelheim, Sun Pharma Advanced Research, Flexion., Paid instructor for: Celgene, Horizon, Merck, Novartis, Pfizer, Genzyme, Sanofi, Regeneron, Speakers bureau: Celgene, Horizon, Merck and Genetech, Flexion, Dennis Parenti Employee of: Janssen Research & Development, LLC, Shawn Black Employee of: Janssen Research & Development, LLC, Stephen Xu Employee of: Employee of Janssen Research & Development, LLC, Wayne Langholff Employee of: Janssen Research & Development, LLC, Shelly Kafka Shareholder of: J&J, Employee of: J&J

The hand is commonly affected by osteoarthritis (OA). The development and progression of OA are believed to involve inflammation, even in the early stages of the disease. Inflammatory and proinflammatory cytokines have also been shown to be elevated in the flexor tenosynovium of idiopathic carpal tunnel syndrome (CTS). A large percentage of patients with hand OA also have a concomitant CTS. This study evaluated the results of a pulsed electrical joint stimulator in patients who had hand OA with or without CTS. Pain, tenderness, and swelling; grip strength and pinch force; and Patient and Physician Global Assessment and Disabilities of the Arm, Shoulder and Hand (DASH) results were evaluated. The primary efficacy outcome was pain due to OA in the study hand in the past 48 hours. Secondary outcomes consisted of OA pain in the study thumb in the past 48 hours, grip strength, pinch force, and Patient and Physician Global Assessment and DASH results. All 7 outcome parameters improved in OA patients. On physical examination, individual finger and wrist joints had also improved regarding pain, swelling, and tenderness. In the subset of patients with CTS, CTS pain, paresthesia, weakness, and all CTS symptoms had significantly improved. Patient and Physician Global Assessment and DASH results and pinch force were also significantly improved. This pulsed electrical joint stimulator is effective in providing clinically relevant and statistically significant reductions in the signs and symptoms of OA of the hand and CTS. It could be a useful modality for the treatment of patients who have one of these conditions or both. [ Orthopedics . 2018; 41(4):e550–e556.]

Objective. To evaluate the humoral immune response to pneumococcal and influenza vaccination in adults with rheumatoid arthritis (RA) receiving certolizumab pegol (CZP). Methods. In this 6-week, single-blind, placebo-controlled trial with optional 6-month open-label extension (NCT00993668), patients were stratified by concomitant methotrexate (MTX) use and randomized to receive CZP 400 mg (loading dose; according to CZP label) or placebo at weeks 0, 2, and 4. Pneumococcal (polysaccharide 23) and influenza vaccines were administered at Week 2. Satisfactory humoral immune response, defined as ≥ 2-fold titer increase in ≥ 3 of 6 pneumococcal antigens and ≥ 4-fold titer increase in ≥ 2 of 3 influenza antigens, were assessed independently 4 weeks after vaccination. Results. Following pneumococcal vaccination, 62.5% of placebo patients and 54.5% of CZP patients without effective titers at baseline achieved a humoral response (difference in proportions was −8.0 percentage points; 95% CI −22.5 to 6.6%). Following influenza vaccination, 61.4% of placebo and 53.5% of CZP patients without effective titers at baseline achieved a humoral response (difference in proportions: −8.0 percentage points; 95% CI −22.9 to 7.0%). In all patients, including those with effective titers at baseline, 58.2% of placebo and 53.3% of CZP patients developed satisfactory pneumococcal titers, and 54.1% of placebo and 50.5% of CZP patients developed satisfactory influenza antibody titers. Vaccine responses to pneumococcal and influenza antigens were reduced similarly in both treatment groups with concomitant MTX use. Conclusion. Humoral immune responses to pneumococcal and influenza vaccination are not impaired when given during the loading phase of CZP treatment in patients with RA. (ClinicalTrials.gov NCT00993668).

The objective of this analysis was to determine the extent of antibody response to influenza and pneumococcal vaccination in adult patients with rheumatoid arthritis (RA) receiving certolizumab pegol (CZP) or placebo (PBO) and consider the application of these data to adult patients with Crohn’s disease (CD). Patients in this 6-week, single-blind, PBO-controlled, phase IV trial (NCT00993668) were randomized 1:1 and stratified by concomitant methotrexate to receive CZP 400 mg or PBO at Weeks 0, 2, and 4. All patients received commercially available 23-valent pneumococcal and 2009-10 trivalent subvirion influenza virus vaccines at Week 2, prior to dosing with CZP. The co-primary endpoints (assessed independently) were the percentage of patients in the per protocol set (PPS, included only those patients without protective titers at baseline) with a satisfactory humoral response, defined as a ≥2-fold titer increase in ≥3 of 6 pneumococcal antigens (6B, 9V, 14, 18C, 19F, and 23F), and a ≥4-fold increase for each of 3 influenza antigens (H1N1 [nonpandemic], H3N2, and B) at Week 6. Differences in proportions between groups were presented with a 95% confidence interval (CI). Of 224 randomized patients (CZP=110, PBO=114), 217 (96.0%) completed the study. Baseline demographics were similar between groups; 65.5% (72/110) of CZP and 68.4% (78/114) of PBO patients had concomitant methotrexate (mean dose, 16.6 mg/week). In the PPS, following pneumococcal vaccination 53.3% of CZP patients (48/90) and 62.2% (56/90) of PBO patients achieved humoral response at Week 6 (-8.9; 95%CI: -23.3, 5.5); following influenza vaccination, 54.0% (47/87) of CZP patients and 61.9% (52/84) of PBO patients achieved humoral response (-7.9; 95% CI: -22.7; 6.9). There was a >2-fold increase from baseline to Week 6 in titers in both treatment groups for each of the antigens tested in all patients including those with protective titers at baseline (full analysis set, FAS). Following vaccination, 62.6% (67/107) of CZP and 65.5% (72/110) of PBO patients and 71.0% (76/107) of CZP and 77.1% (84/109) of PBO patients in the FAS developed protective pneumococcal and influenza antibody titers, respectively. Responses to pneumococcal and influenza antigens were reduced in both groups who received concomitant methotrexate vs those who did not (CZP vs PBO: pneumococcal antigens, with methotrexate = 45.2% [28/62] vs 49.2% [30/61], without methotrexate = 71.4% [20/28] vs 89.7% [26/29]; influenza antigens, with concomitant methotrexate = 47.4% [27/57] vs 50.9% [29/57], without concomitant methotrexate = 66.7% [20/30] vs 85.2% [23/27]). Incidence of adverse events was comparable across groups; most events were mild to moderate in intensity. There was 1 death in the CZP group (unrelated to study drug) and none in the PBO group. Humoral responses to pneumococcal and influenza vaccines were comparable in patients receiving treatment with CZP and PBO. Vaccine responses were reduced in both treatment groups with concomitant methotrexate. These results indicate that patients receiving CZP can be effectively immunized with pneumococcal and influenza vaccines. Although these data were not collected in CD patients, they should be considered when CD patients require immunization with pneumococcal and influenza vaccines.

Medical treatments and less invasive surgical approaches for knee osteoarthritis are variably effective, and total knee arthroplasty (TKA) is generally reserved for the most severe cases. The care gap between more conservative treatments and TKA leaves many patients with unresolved pain and loss of function for long periods. We conducted a study to determine if incorporating the BioniCare stimulator into an unloading brace would produce more rapid improvement and result in increased adherence and efficacy. Two hundred eighty-nine patients treated only with BioniCare served as historical controls and were compared with 225 patients treated with BioniCare combined with an unloading brace. Means and standard deviations of the changes in scores for pain intensity in the past 48 hours, pain and associated symptoms, patient global assessment, pain on going up or down stairs, and pain on walking on a flat surface and the effect sizes at 1, 3, 6, and 12 months, as well as the percentages of patients achieving at least 20% improvement, and at least 50% improvement, demonstrated that treatment with stimulator and unloading brace combined was significantly superior to treatment with the stimulator alone.

Aim: To test the hypothesis that a therapeutic dose of ocrelizumab (200 mg × 2), can be administered as a single-infusion (400 mg × 1) to achieve clinical efficacy and safety in patients with active rheumatoid arthritis. Patients & methods: Three hundred and fourteen patients were randomized to double-blind placebo, ocrelizumab single-infusion or dual-infusion. The primary end point is American College of Rheumatology (ACR)20 response at week 24 for single-infusion ocrelizumab versus placebo. Results: At 24 weeks, ACR20 responses for patients treated with single-infusion ocrelizumab were not statistically significantly superior to placebo (37.6% [95% CI: 28.8–46.4%] vs 28.1% [95% CI: 17.1–39.1%]; p = 0.2253). ACR20 for dual-infusion ocrelizumab was 52.7% (95% CI: 44.1–61.2%). Initial depletion of peripheral B cells appeared comparable after single and dual-infusions. However, subsequent B-cell repletion occurred earlier after single-infusion. Adverse events were comparable across groups. Conclusion: Ocrel...

Objective. To assess safety and clinical outcomes in patients with inflammatory arthritis after intraarticular (IA) injection of rAAV2-TNFR:Fc, a recombinant adeno-associated viral vector containing the human tumor necrosis factor (TNF) receptor-immunoglobulin (IgG1) Fc fusion (TNFR:Fc) gene. Methods. In this phase 1/2 randomized study, adults with persistent moderate or severe inflammation in a target joint, being treated with or without systemic anti-TNF therapy, received a single IA injection of either rAAV2-TNFR:Fc (1 × 1011, 1 × 1012, or 1 × 1013 DNase-resistant particles/ml joint volume) or placebo, followed by open-label rAAV2-TNFR:Fc 12–30 weeks later, depending on when the target joint met predetermined criteria for reinjection. Results. 127 subjects received the first injection of blinded study drug; 95 subjects received open-label rAAV2-TNFR:Fc. Administration site reactions, consisting of transient mild to moderate increases in tenderness and swelling of the injected joint, occurred after 23/191 (12%) rAAV2-TNFR:Fc injections and were dose-dependent. Rates of other adverse events were not dose-dependent. Notable serious adverse events (SAE) included culture-negative septic arthritis in a subject receiving leflunomide and fatal disseminated histoplasmosis considered unrelated to rAAV2-TNFR:Fc in a subject receiving adalimumab. In the phase 2 portion of the study, a 30% decrease in target joint global visual analog scale was observed in 21/50 (42%) rAAV2-TNFR:Fc subjects and 3/16 (19%) placebo subjects 12 weeks after first injection (p = 0.14). Conclusion. IA rAAV2-TNFR:Fc resulted in administration site reactions after 12% of injections. A fatal SAE, disseminated histoplasmosis, was considered not related to study agent. Patient-reported outcome measures of clinical response showed greater improvement in treated patients than placebo patients.

OBJECTIVE:Ocrelizumab, a humanized anti-CD20 monoclonal antibody, was studied in a first-in-human trial in rheumatoid arthritis (RA) patients receiving concomitant methotrexate (MTX).METHODS:The ACTION trial was a combined phase I/II study of placebo plus MTX versus ocrelizumab plus MTX in 237 RA patients (intent-to-treat population). During phase I, 45 patients were treated with 1 of 5 escalating doses of study drug (infusions on days 1 and 15, 10-1,000 mg per each infusion). An additional 192 patients were randomized during phase II. Eligible patients had active disease, an inadequate response to treatment with at least MTX, rheumatoid factor positivity, and elevated levels of acute-phase reactants. The total study duration was 72 weeks. B cell pharmacodynamics over time was investigated.RESULTS:Baseline demographics were similar among the treatment groups. Based on the entire 72-week data set, the incidence of serious adverse events in the ocrelizumab-treated patients was 17.9%, as compared with 14.6% in placebo-treated patients. The incidence of serious infections was 2.0% in all ocrelizumab-treated patients and 4.9% in placebo-treated patients. Infusion-associated adverse events were mostly grade 1 or grade 2 and were more frequent around the time of the first infusion. No serious infusion-associated adverse events were reported in the ocrelizumab group. Evidence of clinical activity was observed at all doses evaluated. Peripheral B cell depletion after infusion was rapid at all doses, with earlier repletion of B cells at doses of 10 mg and 50 mg. Human anti-human antibodies were detected in 19% and 10%, respectively, of those receiving 10 mg and 50 mg of ocrelizumab, compared with 0-5% of those receiving 200, 500, and 1,000 mg.CONCLUSION:Ocrelizumab therapy in combination with MTX was well tolerated. Doses of 200 mg (2 infusions) and higher showed better clinical responses, better reduction of C-reactive protein levels, and very low immunogenicity.

OBJECTIVE:To examine the efficacy and safety of different rituximab doses plus methotrexate (MTX), with or without glucocorticoids, in patients with active rheumatoid arthritis (RA) resistant to disease-modifying antirheumatic drugs (DMARDs), including biologic agents.METHODS:A total of 465 patients were randomized into 9 treatment groups: 3 rituximab groups (placebo [n = 149], 500 mg [n = 124], or 1,000 mg [n = 192] on days 1 and 15) each also taking either placebo glucocorticoids, intravenous methylprednisolone premedication, or intravenous methylprednisolone premedication plus oral prednisone for 2 weeks. All patients received MTX (10-25 mg/week); no other DMARDs were permitted.RESULTS:Significantly more patients who received 2 500-mg or 2 1,000-mg infusions of rituximab met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 24 (55% and 54%, respectively) compared with placebo (28%; P < 0.0001). ACR50 responses were achieved by 33%, 34%, and 13% of patients, respectively (P < 0.001), and ACR70 responses were achieved by 13%, 20%, and 5% of patients (P < 0.05). Changes in the Disease Activity Score in 28 joints (-1.79, -2.05, -0.67; P < 0.0001) and moderate to good responses on the European League Against Rheumatism criteria (P < 0.0001) reflected the ACR criteria responses. Glucocorticoids did not contribute significantly to the primary efficacy end point, ACR20 response at 24 weeks. Intravenous glucocorticoid premedication reduced the frequency and intensity of first infusion-associated events; oral glucocorticoids conferred no additional safety benefit. Rituximab was well tolerated; the type and severity of infections was similar to those for placebo.CONCLUSION:Both rituximab doses were effective and well tolerated when added to MTX therapy in patients with active RA. The primary end point (ACR20 response) was independent of glucocorticoids, although intravenous glucocorticoid premedication improved tolerability during the first rituximab infusion.