Objectives To study infection rates in patients with low immunoglobulin (Ig) serum concentrations following administration of rituximab (RTX) in RA clinical trials.
Methods Pooled analysis of RA clinical trial data from patients who developed low IgM or IgG (defined as below lower limit of normal [LLN] for ≥4 mths [or 2 consecutive study visits]) after ≥1 RTX course. Igs were generally measured every 8-16 wks. Patients with low Ig were permitted to receive RTX re-treatment courses. Infection rates were assessed before and during/after low IgM/IgG. Low IgG/IgM at baseline screening (IgG <5.65 and IgM <0.55 mg/mL) were exclusion criteria for entry into the trials.
Results Of 3194 patients who had received up to 17 RTX courses over 9.5 yrs, 22.4% (n=717) developed low IgM and 3.5% (n=112) developed low IgG for ≥4 mths. All had measurable Ig levels. No increases in overall infection rates were observed in patients during/after low IgM/IgG vs before documentation of low Ig (Table). For IgG, serious infection (SIE) rates were similar before and during/after low IgG, but both were significantly higher than in patients who never developed low IgG. At baseline these patients were on average older, had longer disease duration, lower mean CD19+ count, lower mean IgG levels (8.4 vs 13.2 mg/mL) and had received more non-biologic DMARDs vs those who did not develop low IgG. Baseline oral steroid use was similar across sub-groups. For IgM, SIE rates were not significantly higher during/after low IgM vs before low IgM, and were similar to rates in patients who never developed low IgM. In patients with low IgG or IgM, the SIE profile was consistent with RTX clinical experience as most infections affected the lower respiratory tract. Analysis of SIE onset in relation to timing of low Ig was limited due to discrete protocol-defined time points for Ig assessments. Other limitations included low patient numbers in some subgroups and lack of placebo comparator.
Conclusions Following RTX treatment, low Ig concentrations (particularly IgM, less often IgG) were observed. Patients with low IgM had no increased risk of infection or SIE. For the small subgroup of patients with low IgG (112/3194 [3.5%]), a higher SIE rate was seen both before and during/after the development of low IgG, suggesting that these pts had a higher a priori risk of developing SIEs, possibly associated with demographic and/or clinical characteristics rather than with low IgG itself. Thus, for both Ig classes, SIE rates were similar before and during/after development of low Ig.
Disclosure of Interest R. van Vollenhoven Grant/Research support from: Abbott, GSK, Merck, Pfizer, Roche, UCB, Consultant for: Abbott, GSK, Merck, Pfizer, Roche, UCB, G. Silverman Consultant for: Roche, Genentech, Paid Instructor for: Roche, Genentech, Speakers Bureau: Roche, Genentech, C. Bingham Grant/Research support from: Roche, Genentech, Biogen/IDEC, Consultant for: Roche, Genentech, P. Durez Speakers Bureau: BMS, Pfizer, Merck, Abbott, Roche, UCB, P. Lehane Employee of: Roche Products Ltd, N. Tyson Shareholder of: Roche Products Ltd, Employee of: Roche Products Ltd, E. Fisheleva Employee of: Roche Products Ltd
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