How much of the increased infection risk from higher rituximab doses is mediated by hypogammaglobulinemia in patients with multiple sclerosis?
Annette Langer-Gould1, Bonnie Li2, Jessica Smith2, Edlin Gonzales2, Stanley Xu2
1Neurology, Los Angeles Medical Center, Southern California Permanente Medical Group, 2Research & Evaluation, Southern California Permanente Medical Group
Objective:
To estimate to what extent increased infection risk from more rituximab exposure is mediated by hypogammaglobulinemia in multiple sclerosis (MS) patients.
Background:
Prolonged treatment with B-cell depleting therapies increase the risk of hypogammaglobulinemia and infections. These relationships are poorly understood.
Design/Methods:

We conducted a retrospective cohort study utilizing the electronic medical record among Kaiser Permanente Southern California members who met MS diagnostic criteria and were treated with at least two rituximab infusions, 2008-2020. Multivariable Andersen-Gill hazards models were used to assess risk of recurrent outpatient (≥4/year) or serious/hospitalized infections and linear regression to examine correlates of IgG values.

Results:

We identified 2477 MS patients who were treated with rituximab for a median of 2.0 years (IQR=1.0-3.0). 405 patients (16.4%) developed recurrent outpatient infections, 153 (6.2%) serious infections and 249 (10.1%) IgG <700 mg/dL. Higher cumulative rituximab dose (>4g) was correlated with lower IgG levels (Beta=-57.0, p<0.0001, ref≤2g) and, in models mutually adjusted for hypogammaglobulinemia, both were independently associated with an increased risk of serious (>4g, aHR=1.57, 95%CI=1.08-2.28, p=.018; IgG<500, aHR=2.90, 95%CI=1.52-5.54, p=0.001) and outpatient infections (>4g, aHR=2.09, 95%CI=1.64-2.66, p<.0001; IgG<500 aHR=2.48, 95%CI=1.64-3.75, p<.0001; ref=IgG≥700). Mediation analyses showed that hypogammaglobulinemia accounted for 12.6% 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 infections (aHR=5.86, p<.0001), obesity (aHR=1.38, p=.0017) and chronic obstructive pulmonary disease (aHR=1.88, p=.0001) for outpatient infections.  Black (16.6% of population) or Asian (2.8%) race or Hispanic (31.0%) ethnicity was correlated with significantly higher IgG levels (Betas=260.7, 252.7, 67.3, respectively, p’s<.0001, ref=white) but had no independent influence on infection risks.

Conclusions:

Higher cumulative rituximab doses increase the risk of infections primarily via mechanisms independent of hypogammaglobulinemia. Important factors that influence these relationships include selected comorbidities, race and ethnicity, advanced physical disability, and age.

10.1212/WNL.0000000000202546