Multiple Sclerosis, Rituximab, Hypogammaglobulinemia, and Risk of Infections

Abstract

Background and objectives: B-cell-depleting therapies increase the risk of infections and hypogammaglobulinemia. These relationships are poorly understood. The objectives of these analyses were to estimate how much of this rituximab-associated infection risk is mediated by hypogammaglobulinemia and to identify other modifiable risk factors in persons with multiple sclerosis (pwMS).

Methods: We conducted a retrospective cohort study of rituximab-treated pwMS from January 1, 2008, to December 31, 2020, in Kaiser Permanente Southern California. Cumulative rituximab dose was defined as ≤2, >2 and ≤4, or >4 g. Serious infections were defined as infections requiring or prolonging hospitalizations, and recurrent outpatient infections as seeking care for ≥3 within 12 months. Exposures, outcomes, and covariates were collected from the electronic health record. Adjusted hazard ratios (aHRs) were estimated using Andersen-Gill hazards models, and generalized estimating equations were used to examine correlates of IgG values. Cross-sectional causal mediation analyses of rituximab and hypogammaglobulinemia were conducted.

Results: We identified 2,482 pwMS who were treated with rituximab for a median of 2.4 years (interquartile range = 1.3-3.9). The average age at rituximab initiation was 43.0 years, 71.9% were female, 49.7% were White, non-Hispanic patients, and 29.6% had advanced disability (requiring walker or worse). Seven hundred patients (28.2%) developed recurrent outpatient infections, 155 (6.2%) developed serious infections, and only 248 (10.0%) had immunoglobulin G (IgG) < 700 mg/dL. Higher cumulative rituximab dose (>4 g) was correlated with lower IgG levels (Beta = -58.8, p < 0.0001, ref ≤2 g) and, in models mutually adjusted for hypogammaglobulinemia, both were independently associated with an increased risk of serious (>4 g, aHR = 1.56, 95% CI 1.09-2.24; IgG < 500, aHR = 2.98, 95% CI 1.56-5.72) and outpatient infections (>4 g, aHR = 1.73, 95% CI 1.44-2.06; IgG < 500 aHR = 2.06, 95% CI 1.52-2.80; ref = IgG ≥ 700). Hypogammaglobulinemia explained at most 17.9% (95% CI -47.2-119%) of serious infection risk associated with higher cumulative rituximab exposure but was not significant for outpatient infections. Other independent modifiable risk factors were advanced physical disability for serious (aHR = 5.51, 95% CI 3.71-8.18) and outpatient infections (aHR = 1.24, 95% CI 1.06-1.44) and COPD (aHR = 1.68, 95% CI 1.34-2.11) and obesity (aHR = 1.25, 95% CI 1.09-1.45) for outpatient infections.

Discussion: Higher cumulative rituximab doses increase the risk of infections even in this population where 90% of patients maintained normal IgG levels. Clinicians should strive to use minimally effective doses of rituximab and other B-cell-depleting therapies and consider important comorbidities to minimize risks of infections.

Figure 1. Cohort Assembly for Main Effects and Mediation Analyses

Kaiser Permanente Southern California (KPSC) members who met multiple sclerosis (MS) diagnostic (dx) criteria and received at least 1 dose of rituximab (RTX) for MS were included in main analyses. To be able to assess the effect of race and ethnicity on immunoglobulin levels and infection risk, patients with mixed or native American/Alaskan native race were excluded due to small sample. AG = Andersen-Gill; ICD = International Classification of Diseases; GEEs = generalized estimation equations.

Figure 2. Infection Risk in Rituximab-Treated Persons With MS Mediated by Serum IgG Levels

Depicted is the hypothetical model of causal pathway in rituximab-treated persons with MS (pwMS) and serious or recurrent outpatient infections (A). The average direct effect (ADE) is the effect of higher cumulative rituximab (RTX) doses (>2 g) on infection risk not mediated by hypogammaglobulinemia (<700 mg/dL). The average causal mediation effect (ACME) is the estimated indirect effect of rituximab mediated through hypogammaglobulinemia, and the total effect represents the direct and indirect effects. Serious infections and recurrent outpatient infections were modeled separately. Depicted in (B) are the results of the mediation analysis in rituximab-treated pwMS and the risk of serious infections. While the ACME at 0.0037 (95% CI 0.0005–0.0100) was statistically significant (p = 0.022), indicating that a proportion of the increased risk of serious infections with higher rituximab doses (greater than 2 g) is mediated by drug-induced hypogammaglobulinemia, it accounts for very little of the total effect (0.021, 95% CI −0.002 to 0.040). By contrast, the ADE at 0.017 (95% CI −0.005 to 0.040) was quite similar to the total effect indicating that most of the effect of rituximab on serious infection risk is not mediated by hypogammaglobulinemia. This is consistent with a relatively small estimated proportion mediated of 17.9% (95% CI −47.2 to 119). IgG = immunoglobulin G.

Figure 3. Patient Flow Through Rituximab Dosing Schedules After Treatment Initiation

Depicted is the total number of patients on various rituximab dosing schedules throughout the study period. Induction doses and maintenance doses and frequencies are indicated by color and labeled in the diagram. The most common induction doses were 500 mg (n = 887, 35.7%) and 1,000 mg (n = 875, 35.3%). The most common maintenance dose during the first year after first rituximab infusion was 500 mg every 6 months (q6mo in hot pink; n = 842, 41.3% of the 2,040 patients who received at least 1 infusion that year). During year 2, use of 500 mg q12 months (q12mo in brown, n = 559, 39.3%) was slightly higher than 500 mg q6mo (n = 424, 30.6%), and over time, 500 mg q12mo was the most common dosing schedule used (65.4% by year 6). The total number of patients receiving at least 1 dose of rituximab in a particular year declined with each year of follow-up (n = 565 in year 4, n = 182 in year 6) reflecting primarily year of treatment initiation and follow-up time rather than treatment discontinuation.

Figure 4. IgG Levels per Patient at Baseline and After Rituximab Initiation

Depicted is the total number of patients with normal IgG levels ≥1,000 mg/dL, in red and ≥700 and <1,000 mg/dL in blue) and low levels (<700 and ≥500 in green, <500 not visible) or a value was not obtained (not done, nd) because no infusion was planned during that year at baseline (before rituximab initiation) and after completing years 2, 4, and 6 of treatment. Decline in IgG levels began after treatment initiation and continued decline with longer duration of rituximab use, but even in patients who completed 4 years (n = 565) and 6 years (n = 182) of treatment, most of them had normal IgG levels (84.8% year 4 and 79.7% year 6). IgG = immunoglobulin G.