Patricia B. Lehane

Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients.

Objectives Evaluation of long-term safety of rituximab in rheumatoid arthritis (RA). Methods Pooled observed case analysis of data from patients with moderate-to-severe, active RA treated with rituximab in a global clinical trial programme. Results As of September 2010, 3194 patients had received up to 17 rituximab courses over 9.5 years (11 962 patient-years). Of these, 627 had >5 years’ follow-up (4418 patient-years). A pooled placebo population (n=818) (placebo+methotrexate (MTX)) was also analysed. Serious adverse event and infection rates generally remained stable over time and multiple courses. The overall serious infection event (SIE) rate was 3.94/100 patient-years (3.26/100 patient-years in patients observed for >5 years) and was comparable with placebo+MTX (3.79/100 patient-years). Serious opportunistic infections were rare. Overall, 22.4% (n=717) of rituximab-treated patients developed low immunoglobulin (Ig)M and 3.5% (n=112) low IgG levels for ≥4 months after ≥1 course. SIE rates were similar before and during/after development of low Ig levels; however, in patients with low IgG, rates were higher than in patients who never developed low IgG. Rates of myocardial infarction and stroke were consistent with rates in the general RA population. No increased risk of malignancy over time was observed. Conclusions This analysis demonstrates that rituximab remains generally well tolerated over time and multiple courses, with a safety profile consistent with published data and clinical trial experience. Overall, the findings indicate that there was no evidence of an increased safety risk or increased reporting rates of any types of adverse events with prolonged exposure to rituximab during the 9.5 years of observation.

Longterm Safety of Rituximab: Final Report of the Rheumatoid Arthritis Global Clinical Trial Program over 11 Years

Objective. Final evaluation of the longterm safety of rituximab (RTX) in rheumatoid arthritis (RA) up to 11 years. Methods. Pooled observed case analysis of data from patients with moderate to severe, active RA in a global clinical trial program. Results. As of September 2012, 3595 patients received a mean of 4 courses (range 1–20) of RTX over 11 years [14,816 patient-years (PY)]. Of these, 1246 patients had > 5 years of followup (8970 PY). A pooled placebo population (n = 818) was included in the analysis. The overall serious infection event (SIE) rate was 3.76/100 PY (2.71/100 PY in patients observed for > 5 yrs) and comparable with rates reported previously at 9.5 years (3.94/100 PY and 3.26/100 PY, respectively). SIE rates continued to be similar before and during/after development of low immunoglobulin levels, and serious opportunistic infections remained rare. Rates of cardiac events remained consistent with previous analysis and with rates in the general RA population. No increased risk of malignancy over time was observed. Conclusion. This final report demonstrates that RTX remains well tolerated over time and multiple courses. No new safety risks were identified and there was no increase in the rate of any types of adverse events with prolonged exposure to RTX during 11 years of observation.

Multiple Courses of Rituximab Produce Sustained Clinical and Radiographic Efficacy and Safety in Patients with Rheumatoid Arthritis and an Inadequate Response to 1 or More Tumor Necrosis Factor Inhibitors: 5-Year Data from the REFLEX Study

Objective. This 5-year observational posthoc analysis of the REFLEX study and its open-label extension assessed clinical efficacy, radiographic response, and safety of rituximab (RTX) in patients with rheumatoid arthritis (RA) who had an inadequate response to tumor necrosis factor (TNF) inhibitors. Methods. Patients in REFLEX were originally randomized to placebo (PBO) + methotrexate (MTX; PBO-randomized) or RTX + MTX (RTX-randomized). PBO-randomized patients were rescued with RTX as appropriate. Patients responding to initial RTX treatment could receive further RTX courses. For clinical efficacy and safety analyses, PBO-randomized patients were re-baselined prior to first RTX treatment and the data were pooled with RTX-randomized patient data. Efficacy outcomes 24 weeks after each course were calculated relative to first RTX pretreatment baseline. Radiographic outcomes were assessed relative to randomization baseline for both PBO-randomized and RTX-randomized groups. Results. A total of 480 patients received ≥ 1 RTX course. At 24 weeks, American College of Rheumatology 20/50/70 responses were 62.0%, 30.8%, and 13.0%, respectively at course 1 (n = 400) and 70.3%, 41.8%, and 22.0% at course 5 (n = 91). European League Against Rheumatism good/moderate responses were 77.2% and 84.4% at courses 1 (n = 390) and 5 (n = 90). Rates of adverse events (AE), serious AE, and infections generally remained stable. Rate of progressive joint damage (PJD; change in mean Total Sharp Score) decreased over time in both PBO-randomized (n = 79) and RTX-randomized (n = 105) groups. Mean change from baseline in PJD over 5 years was greater in PBO-randomized versus RTX-randomized patients (5.51 vs 3.21). Conclusion. RTX re-treatment over 5 years is associated with maintained or improved efficacy, continued inhibition of PJD, and a safety profile consistent with that previously reported. A delay in initiating RTX treatment may result in increased PJD.

Effect of concomitant statins on rituximab efficacy in patients with rheumatoid arthritis

Patients with rheumatoid arthritis (RA) are at an increased risk for cardiovascular disease. In order to lower this risk, statins are used in clinical practice in addition to biologics.1 Rituximab, an anti-CD20 antibody approved for the treatment of RA, induces B-cell apoptosis by crosslinking and redistributing CD20 to cholesterol-rich lipid rafts.2 Statins have been shown in vitro to induce conformational changes on the CD20 epitope, potentially influencing the apoptotic effect of rituximab.3 There are conflicting reports about the effect of statins on the clinical efficacy of rituximab in RA.4–6 We investigated the impact of statin coadministration on rituximab efficacy in patients from a global clinical trial programme in RA. This was a retrospective, pooled, observed case analysis from four placebo-controlled phase II/III randomised clinical trials (DANCER, REFLEX, SERENE and IMAGE)7–10 in patients with moderate-to-severe active RA. All patients received concomitant methotrexate 10−25 mg/week at a stable dose and were permitted to receive stable background doses of oral corticosteroids (prednisolone ≤10 mg/day or equivalent) and non-steroidal anti-inflammatory drugs throughout. Efficacy responses (change in Disease Activity Score 28 using erythrocyte sedimentation rate (DAS28-ESR) from baseline, American College of Rheumatology 20% or 50% (ACR20/50) …

Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event

This report assesses the observed risk of PML in patients treated with the anti-CD20 monoclonal antibody rituximab in the regulatory authority-approved autoimmune indications rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA). This was a cumulative analysis of confirmed PML cases in patients receiving rituximab for RA or GPA/MPA from both spontaneous reports and clinical trial sources, as captured in the manufacturer global company safety and clinical databases. Overall reporting rates were calculated and patient case details were summarized. As of 17 November 2015, there were nine confirmed PML cases among patients who had received rituximab for RA and two for GPA. Corresponding estimated reporting rates were 2.56 per 100,000 patients with RA (estimated exposure ≈ 351,396 patients) and < 1 per 10,000 patients with GPA/MPA (estimated exposure 40,000–50,000 patients). In all cases, patients had ≥ 1 potential risk factor for PML independent of rituximab treatment. In the RA population, the estimated reporting rate of PML generally remained stable and low since 2009 despite increasing rituximab exposure. There was no pattern of latency from time of rituximab initiation to PML development and no association of PML with the number of rituximab courses. Global post-marketing safety and clinical trial data demonstrated that the occurrence of PML is very rare among rituximab-treated patients with RA or GPA/MPA and has remained stable over time.

Correction to: Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event

The article “Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event,” written by Joseph R. Berger, Vineeta Malik, Stuart Lacey, Paul Brunetta, and Patricia B. Lehane3, was originally published electronically on the publisher’s internet portal (currently SpringerLink).

FRI0201 Analysis of infection risk in patients with limited return of peripheral B cells after a period of 2 years or more following any rituximab treatment course in RA clinical trials

Objectives To evaluate the infection risk and long-term safety of prolonged peripheral CD19+ B cell depletion (BCD) following rituximab (RTX) treatment in RA clinical trials. Methods Subgroups of patients (pts) with peripheral BCD from the RTX All Exposure population were analysed. Infection rates (from first RTX exposure until last valid observation, including safety follow-up) were compared to overall infection rates in “All Exposed” and “anti-TNF inadequate responder (TNF-IR)” pts. During the 2 yr period of BCD, pts did not receive additional RTX therapy, although some pts were subsequently retreated. B cell (CD19+) levels were measured every 4-12 wks, depending on clinical study protocol. Results As of Sep 2010, 3194 pts (All Exposure) had been treated with RTX (11962 patient-yrs [PY]), of whom 41% (n=1324) were TNF-IR pts. Limited return of peripheral B cells (defined as CD19 count less than lower limit of normal [LLN; <80 cells/μL] ≥2 yrs after any RTX course) occurred in 345/3194 pts (11%); 92 of these pts had CD19+ below lower limit of quantification (LLQ; <20 cells/μL) for ≥2 yrs. Pts with low CD19 for ≥2 yrs had lower circulating mean CD19 (123 cells/μL, with 35% pts <LLN) before RTX treatment. At baseline, these pts were on average older, had longer disease duration, higher disease activity, greater number of past DMARDs and oral corticosteroid use vs All Exposure, suggesting these pts may have higher a priori risk of developing serious infection (SIE). Infection rates/100 PY were lower in pts with low CD19 for ≥2 yrs vs All Exposure and TNF-IR pts (Table). SIE rates in pts were similar to other populations (overlapping 95% CIs) and were most comparable to TNF-IR pts (RTX-indicated population). There were no apparent differences in types or outcomes of SIEs and no opportunistic infections were reported during prolonged BCD. B-cell depletion/repletion patterns varied; however, many pts remained B cell depleted through multiple treatment courses, with no additional safety concerns observed. Table 1. Summary of Infection and Serious Infection Rates All Exposure TNF-IR CD19 below LLN* CD19 below LLQ* Pts (n) 3194 1324 345 92 PY observation 11962.34 4520.97 1804.64 491.04 Infections/100 PY 81.64 96.13 65.66 64.76  (95% CI) (80.04; 83.27) (93.31; 99.03) (62.03; 69.51) (58.02; 72.28) SIE (n) 471 232 83 30 SIE/100 PY 3.94 5.13 4.60 6.11  (95% CI) (3.60; 4.31) (4.51; 5.84) (3.71; 5.70) (4.27; 8.74) *For ≥2 yrs after any RTX course. Conclusions This analysis of 345 pts with limited return of peripheral CD19+ B cells ≥2 yrs after any RTX treatment course showed no clear association with an increased risk of infections, including SIEs. Limitations include low patient numbers (n=92) in the subgroup with CD19 < LLQ, therefore data comparisons should be interpreted with caution. Rates and infection profiles were comparable to other pts who received RTX, with baseline disease characteristics and SIE rates most closely resembling that of the anti-TNF IR population. Disclosure of Interest P. Mease Grant/Research support from: Abbott, Amgen, Biogen-Idec, BMS, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, Consultant for: Abbott, Amgen, Biogen-Idec, BMS, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB, Speakers Bureau: Abbott, Amgen, Biogen-Idec, BMS, Genentech, Janssen, Lilly, Pfizer, Roche, UCB, R. van Vollenhoven Grant/Research support from: Abbott, GSK, Merck, Pfizer, Roche, UCB, Consultant for: Abbott, GSK, Merck, Pfizer, Roche, UCB, P. Durez Speakers Bureau: BMS, Pfizer, Merck, Abbott, Roche, UCB, T. Sheeran Grant/Research support from: Roche, Abbott, Novartis, GSK, Speakers Bureau: Roche, M. Dougados Grant/Research support from: Roche,Abbott,Pfizer,BMS,UCB,Novartis,Merck, Consultant for: Roche,Abbott,Pfizer,BMS,UCB,Novartis,Merck, J. Gόmez-Reino Grant/Research support from: MSD, UCB, Consultant for: MSD, Pfizer, Roche, UCB, Speakers Bureau: MSD, Pfizer, Roche, N. Tyson Shareholder of: Roche Products Ltd, Employee of: Roche Products Ltd, A. Mehbob Employee of: Roche Products Ltd, P. Lehane Employee of: Roche Products Ltd

SAT0131 Long-Term Safety of Rituximab: Pooled Analysis of the Rheumatoid Arthritis Global Clinical Trial Programme Over 11 Years

Objectives To conduct an updated overall safety analysis of rituximab (RTX) in RA patients in the global clinical trial programme. Methods Pooled observed case analysis of safety data from patients with moderate to severe active RA treated with RTX+MTX. Patients were retreated based on physician’s determination of clinical need and evidence of active disease (defined as either SJC and TJC ≥8 or DAS28 ≥2.6). Pooled data from patients who received placebo during placebo-controlled study periods were also analysed. Results As of Sep 2012, 3595 patients (All-Exposure population) had received up to 20 courses of RTX over the 11-yr observation period (14 816 pt-yrs). Of these patients, 1246 had >5yrs follow-up. The placebo population comprised 818 patients (1107 pt-yrs) with a mean follow-up of 1–1.5 yrs. In the All-Exposure population, infusion-related reaction (IRR) was the most frequent adverse event (AE); most were grade 1 or 2, were rarely serious (0.5%), and primarily occurred following the 1st infusion of the 1st course (799/3595 patients; 22%). Rates per 100 pt-yrs for AEs, serious AEs (SAEs), and infections were not increased when compared to placebo (Table). Overall the serious infection rate in RTX-treated patients was comparable to that observed in placebo patients. Pneumonia was the most frequently reported serious infection (2% of RTX patients). There were no cases of hepatitis B reactivation. Serious opportunistic infections were rare (0.05/100 pt-yrs in RTX patients vs 0.09/100 pt-yrs in placebo). One confirmed case of PML in the RA clinical trial programme has been reported, as previously described.1 Following RTX treatment low immunoglobulin (Ig) concentrations (particularly IgM, less often IgG) were observed. For both Ig classes, serious infection rates were similar before and during/after development of low Ig. No increased risk of malignancy over time or course was evident, and MI rates (0.39/100 pt-yrs) were consistent with rates in the general RA population (0.48–0.59/100 pt-yrs).2 Conclusions These long-term data from 3595 patients with up to 11-yr follow-up (14 816 pt-yrs) confirm that RTX remains well tolerated over time and multiple courses with a consistent safety profile. No new safety signals were observed with increasing duration of exposure. Apart from IRRs and low Ig (where there was a lack of placebo comparator), the overall safety profile of RTX remains similar to that of the pooled placebo population and is consistent with published data for moderate to severe RA and with previous analyses of this patient cohort. References Fleischmann RM. Arthritis Rheum 2009;60:3225; British Society for Rheumatology Biologics Register, 2007 Disclosure of Interest R. van Vollenhoven Grant/research support from: Abbott, GSK, Merck, Pfizer, Roche, UCB, BMS, Consultant for: Abbott, GSK, Merck, Pfizer, Roche, UCB, BMS, P. Emery Consultant for: Pfizer, Merck, Abbott, BMS, Roche, Novartis, C. Bingham Grant/research support from: Roche, Genentech Inc., Biogen/IDEC, Consultant for: Roche, Genentech Inc., E. Keystone Grant/research support from: Abbott, Amgen, AstraZeneca, Bristol-Meyers Squibb, Janssen, Roche, Genzyme, Merck, Novartis, Pfizer, UCB, Consultant for: Abbott, AstraZeneca, Biotest, Bristol-Meyers Squibb, Roche, Genentech Inc., Merck, Nycomed, Pfizer, UCB, R. Fleischmann Grant/research support from: Genentech Inc, Roche, Consultant for: Genentech Inc, Roche, D. Furst Grant/research support from: Abbott, Actelion, Amgen, BMS, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech Inc., UCB, Consultant for: Abbott, Actelion, Amgen, BMS, BiogenIdec, Centocor, CORRONA, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech Inc., UCB, Speakers bureau: Abbott, Actelion, UCB (CME ONLY), E. Hessey Shareholder of: F. Hoffmann La-Roche, Employee of: Roche Products Limited, A. Vashishtha Employee of: Genentech Inc., A. Mehbob Employee of: Roche Products Limited, P. Lehane Employee of: Roche Products Limited