Rituximab versus Mycophenolate Mofetil in Patients with Pemphigus Vulgaris.

BACKGROUND: Rituximab and mycophenolate mofetil are used to treat pemphigus vulgaris, but they have not been adequately compared in clinical trials. METHODS: In a randomized, controlled trial, we assigned patients with moderate-to-severe pemphigus vulgaris in a 1:1 ratio to receive intravenous rituximab (1000 mg on days 1, 15, 168, and 182) or oral mycophenolate mofetil (2 g per day), in addition to an oral glucocorticoid administered on the same tapering schedule in the two groups. The primary end point was sustained complete remission at week 52, defined as the healing of lesions with no new active lesions, as reflected by a Pemphigus Disease Area Index (PDAI) activity score of 0 (on a scale of 0 to 250, with higher scores indicating greater disease severity), for at least 16 weeks without the use of glucocorticoids. Secondary end points were the cumulative dose of glucocorticoids, the number of disease flares, and the change from baseline in the score on the Dermatology Life Quality Index (DLQI; scores range from 0 to 30, with higher scores indicating greater impairment). RESULTS: Of the 135 patients who underwent randomization, 67 were assigned to receive rituximab and 68 to receive mycophenolate mofetil. The primary outcome was assessed in the modified intention-to-treat population: 62 patients in the rituximab group and 63 in the mycophenolate mofetil group. The median PDAI activity scores at baseline were 22.7 in the rituximab group and 18.3 in the mycophenolate mofetil group. At week 52, sustained complete remission was observed in 25 patients (40%) in the rituximab group and in 6 (10%) in the mycophenolate mofetil group (difference, 31 percentage points; 95% confidence interval [CI], 15 to 45; P<0.001). The mean cumulative glucocorticoid dose during the 52-week treatment period was 3545 mg in the rituximab group and 5140 mg in the mycophenolate mofetil group (difference, -1595 mg; 95% CI, -2838 to -353; P<0.001). There were 6 disease flares in the rituximab group and 44 in the mycophenolate mofetil group (adjusted rate ratio, 0.12; 95% CI, 0.05 to 0.29; P<0.001). The mean change in DLQI score was -8.87 points and -6.00 points, respectively (difference, -2.87 points; 95% CI, -4.58 to -1.17; P = 0.001). Serious adverse events occurred in 15 of 67 patients (22%) in the rituximab group and in 10 of 68 (15%) in the mycophenolate mofetil group. CONCLUSIONS: Rituximab was superior to mycophenolate mofetil in producing sustained complete remission at 52 weeks in patients with pemphigus vulgaris. Rituximab resulted in a greater reduction in glucocorticoid use than mycophenolate mofetil, but more patients in the rituximab group had serious adverse events. Further trials are needed to determine the comparative efficacy and safety of rituximab and mycophenolate mofetil beyond 52 weeks of treatment. (Funded by F. Hoffmann-La Roche; PEMPHIX ClinicalTrials.gov number, NCT02383589.).

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).

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.

Rituximab pediatric drug development: Pharmacokinetic and pharmacodynamic modeling to inform regulatory approval for rituximab treatment in patients with granulomatosis with polyangiitis or microscopic polyangiitis.

Anti-neutrophil cytoplasmic antibody-associated vasculitides granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are rare, potentially organ- and life-threatening autoimmune conditions affecting adult and pediatric patients. An open-label phase II study was conducted to determine safe and effective dosing regimens of rituximab in pediatric patients with GPA/MPA. To determine the selection of an appropriate dose regimen in children for induction and maintenance, a population pharmacokinetic approach was used (nonlinear mixed-effect modeling), combining pediatric data with data from adults with GPA/MPA. The time course of B-cell depletion was assessed in both populations. The exposure-effect relationship was assessed by logistic regression. Twenty-five pediatric patients (80% female patients; age range, 6-17 years) were enrolled in the trial and received the induction regimen of intravenous rituximab 375 mg/m2 weekly for 4 weeks, which resulted in a similar exposure to that of adults. Based on pharmacokinetic modeling, a maintenance dosing regimen of 250 mg/m2 administered twice over 14 days followed by 250 mg/m2 every 6 months is expected to result in similar rituximab exposure as that of adults receiving the approved maintenance dose of 500 mg administered twice over 14 days followed by 500 mg every 6 months. The time course of B-cell depletion was similar between the pediatric and adult populations, supporting the similarities in response in both populations and allowing extrapolation to patients less than 6 years old. Using a partial extrapolation approach helped identify safe and effective dosing regimens of rituximab in pediatric patients with GPA/MPA and lead to regulatory approval.

Evaluation of Serious Infection in Pediatric Patients with Low Immunoglobulin Levels Receiving Rituximab for Granulomatosis with Polyangiitis or Microscopic Polyangiitis.

INTRODUCTION: The aim of this work was to assess the impact of prolonged low immunoglobulin (IgG or IgM) serum concentrations on the potential cumulative serious infection (SI) risk in pediatric patients following rituximab treatment for granulomatosis with polyangiitis or microscopic polyangiitis (GPA/MPA) in PePRS. METHODS: Patients aged ≥ 2 to < 18 years received four weekly intravenous rituximab infusions of 375 mg/m2 and concomitant glucocorticoid taper. After 6 months, patients could receive further rituximab and/or other immunosuppressants per investigator discretion. Immunoglobulin levels and SIs were assessed throughout the 4.5-year observation period. Prolonged low IgG or IgM was defined as below the lower limit of normal age-specific reference range for ≥ 4 months. RESULTS: A total of 25 patients were included, of whom 19 (76%) had GPA and six (24%) had MPA; 18 (72%) had newly diagnosed disease and seven (28%) had relapsing disease. All 25 patients completed the rituximab induction regimen; 24 completed ≥ 18 months of follow-up. At month 18, eighteen patients (72%) had prolonged low IgG; 19 (76%), prolonged low IgM; and 15 (60%), both. Seven patients (28%) had nine SIs; one occurred during or after prolonged low IgG only, two during or after prolonged low IgM only, and six during or after concurrent prolonged low IgG and IgM. No patients died or discontinued the study due to SI. All patients had complete and sustained peripheral B-cell depletion for ≥ 6 months. CONCLUSIONS: The majority of pediatric patients who received rituximab for GPA/MPA with prolonged low immunoglobulin levels did not experience SIs. In patients with SIs, these events were manageable, and the number of SIs did not increase over time or with multiple rituximab treatments. These observations are consistent with the rituximab safety profile in adults with GPA/MPA. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01750697.

Phase IIa Global Study Evaluating Rituximab for the Treatment of Pediatric Patients With Granulomatosis With Polyangiitis or Microscopic Polyangiitis.

OBJECTIVE: To assess the safety, tolerability, pharmacokinetics, and efficacy of rituximab (RTX) in pediatric patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). METHODS: The Pediatric Polyangiitis Rituximab Study was a phase IIa, international, open-label, single-arm study. During the initial 6-month remission-induction phase, patients received intravenous infusions of RTX (375 mg/m2 body surface area) and glucocorticoids once per week for 4 weeks. During the follow-up period, patients could receive further treatment, including RTX, for GPA or MPA. The safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy outcomes with RTX were evaluated. RESULTS: Twenty-five pediatric patients with new-onset or relapsing disease were enrolled at 11 centers (19 with GPA [76%] and 6 with MPA [24%]). The median age was 14 years (range 6-17 years). All patients completed the remission-induction phase. During the overall study period (≤4.5 years), patients received between 4 and 28 infusions of RTX. All patients experienced ≥1 adverse event (AE), mostly grade 1 or grade 2 primarily infusion-related reactions. Seven patients experienced 10 serious AEs, and 17 patients experienced 31 infection-related AEs. No deaths were reported. RTX clearance correlated with body surface area. The body surface area-adjusted RTX dosing regimen resulted in similar exposure in both pediatric and adult patients with GPA or MPA. Remission, according to the Pediatric Vasculitis Activity Score, was achieved in 56%, 92%, and 100% of patients by months 6, 12, and 18, respectively. CONCLUSION: In pediatric patients with GPA or MPA, RTX is well tolerated and effective, with an overall safety profile comparable to that observed in adult patients with GPA or MPA who receive treatment with RTX. RTX is associated with a positive risk/benefit profile in pediatric patients with active GPA or MPA.

Long-Term Safety of Rituximab in Granulomatosis With Polyangiitis and in Microscopic Polyangiitis.

OBJECTIVE: The present study was undertaken to conduct a phase IV, open-label, prospective study to characterize the long-term safety of rituximab in a 4-year observational registry of adult patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) within the US. METHODS: Patients initiating treatment with rituximab were evaluated every 6 months for up to 4 years. Outcomes included the incidence of serious adverse events (SAEs), infusion-related reactions (IRRs), and SAEs of specific interest, including serious infections, serious cardiac events, serious vascular events, and malignancies. RESULTS: Overall, 97 patients (72 with GPA and 25 with MPA) received rituximab through a median of 8 (range 1-28) infusions and were followed up for a median of 3.94 years (range 0.05-4.32 years). The estimated incidence rates (95% confidence interval [95% CI]) of serious infections, serious cardiac events, and serious vascular events were 7.11 (4.55-10.58), 5.03 (2.93-8.06), and 2.37 (1.02-4.67) per 100 patient-years (PYs), respectively. No IRRs or SAEs occurred within 24 hours of an infusion of rituximab. None of the 9 deaths reported (crude mortality rate 2.67 [95% CI 1.22-5.06] per 100 PYs) were considered to be related to use of rituximab. CONCLUSION: The safety profile of long-term treatment with rituximab in patients with GPA or MPA was consistent with that of rituximab administered for shorter durations and with rituximab's known safety profile in other autoimmune diseases for which it has received regulatory approval. These findings provide clinicians with long-term, practice-level safety data for rituximab in the treatment of GPA or MPA.

Risk of Malignancies in Patients with Rheumatoid Arthritis Treated with Rituximab: Analyses of Global Postmarketing Safety Data and Long-Term Clinical Trial Data.

INTRODUCTION: Patients with rheumatoid arthritis (RA) are at an increased risk of developing malignancies, but it is unclear whether this increased risk is the result of disease pathobiology or immunosuppressant treatments for RA. This analysis evaluated the potential risk of malignancy in patients with RA treated with rituximab (MabThera®/Rituxan®) a CD20+ B-cell depleting agent manufactured by F. Hoffmann-La Roche Ltd. METHODS: Malignancy rates were obtained from the rituximab global company safety database for adverse event reporting and from the rituximab global clinical trial program for RA consisting of eight randomized clinical trials, two long-term open-label extensions, and one open-label prospective study. Global company safety database searches were performed using the standard Medical Dictionary for Regulatory Activities (MedDRA) queries "Malignant tumors wide" and "Skin malignant tumors wide" up to April 30, 2017. Age- and sex-specific comparator values from the general population were obtained from the US National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: For the 409,706 patients with RA in the rituximab global company safety database since first market approval in 2006, 1739 cumulative malignant events were reported, with an overall malignancy reporting rate of approximately 4.2 events per 1000 patients. No evidence of increased risk of malignancy, of any organ-specific type, was found following rituximab treatment. The rate of malignancies from rituximab-treated patients in RA clinical trials was 7.4 per 1000 patient-years. This is within the expected range, with no evidence for increased risk over time or with additional rituximab courses. CONCLUSIONS: Analyses of the global postmarketing safety database and long-term clinical trial data showed no evidence of an increased risk of malignancy of any type following rituximab treatment in patients with RA. FUNDING: F. Hoffmann-La Roche Ltd.

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.