Background/Purpose: This study analyzed infection rates in patients (pts) with low immunoglobulin (Ig) serum concentrations following rituximab (RTX) treatment in RA clinical trials.

Methods: Pooled analysis of clinical trial data from the All-Exposure population (all pts exposed to at least one/part of a RTX infusion) who developed low IgM or IgG (defined as below lower limit of normal [LLN] for ≥4 mth [or 2 consecutive study visits]) after ≥1 RTX course. Low IgG/IgM at baseline screening (IgG <5.65 and IgM <0.55 mg/mL) were exclusion criteria for trial entry. Igs were generally measured every 8–16 wks. Pts with low Ig were permitted to receive RTX retreatment. Infection rates were assessed before and during/after low IgM/IgG and compared with pts who never developed low Ig and the All-Exposure population. Pts received IV methylprednisolone prior to RTX infusions and concomitant MTX. In addition, stable background doses of oral corticosteroids (≤10 mg/day prednisone or equivalent) and NSAIDs were permitted throughout.

Results: Of 3194 pts who received ≤17 RTX courses over 9.5 yrs, 22.4% (n=717) developed low IgM and 3.5% (n=112) low IgG for ≥4 mth. All had measurable Ig levels. No increases in overall infection rates were observed in pts 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 pts who never developed low IgG. At baseline these pts were on average older, had longer disease duration, lower mean CD19+ count, lower mean IgG levels (8.4 vs 13.2 mg/mL), higher mean anti-CCP levels, and had received more non-biologic DMARDs vs those who did not develop low IgG. Baseline oral steroid use was similar across subgroups and all pts received 100 mg IV corticosteroid prior to RTX infusion. For IgM, SIE rates were not significantly higher during/after low IgM vs before low IgM, and were similar to rates in pts who never developed low IgM. In pts 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 pt numbers in some subgroups and lack of placebo comparator.

Infection rate in pts with low Ig

	Pts with IgG			Pts with IgM
	Before (n=112)	During/after (n=112)	Pts who never had IgG	Before (n=717)	During/after (n=717)	Pts who never had IgM (n=2477)
Total PY	223	307	11432	1171	2084	8707
Infections, n	325	262	9179	1264	1699	6803
Rate/100PY (95% CI)	146 (131–162)	85 (76–96)	80 (79–82)	108 (102–114)	82 (78–86)	78 (76–80)
SIE, n	18	28	425	34	98	339
Rate/100PY (95% CI)	8.0 (5.08–12.80)	9.13 (6.30–13.22)	3.72 (3.38–4.09)	2.9 (2.07–4.06)	4.70 (3.86–5.73)	3.89 (3.50–4.33)
*below LLN for ≥4 mth

Conclusion: Following RTX treatment, low Ig concentrations (particularly IgM, less often IgG) were observed. Pts with low IgM had no increased risk of infection or SIE. For the small subgroup of pts 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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/infection-risk-in-patients-with-low-immunoglobulins-following-rituximab-treatment-in-rheumatoid-arthritis/