Hypogammaglobulinaemia during rituximab treatment in multiple sclerosis: A Swedish cohort study

Abstract

Background and purpose: Mechanisms behind hypogammaglobulinaemia during rituximab treatment are poorly understood.

Methods: In this register-based multi-centre retrospective cohort study of multiple sclerosis (MS) patients in Sweden, 2745 patients from six participating Swedish MS centres were identified via the Swedish MS registry and included between 14 March 2008 and 25 January 2021. The exposure was treatment with at least one dose of rituximab for MS or clinically isolated syndrome, including data on treatment duration and doses. The degree of yearly decrease in immunoglobulin G (IgG) and immunoglobulin M (IgM) levels was evaluated.

Results: The mean decrease in IgG was 0.27 (95% confidence interval 0.17-0.36) g/L per year on rituximab treatment, slightly less in older patients, and without significant difference between sexes. IgG or IgM below the lower limit of normal (<6.7 or <0.27 g/L) was observed in 8.8% and 8.3% of patients, respectively, as nadir measurements. Six out of 2745 patients (0.2%) developed severe hypogammaglobulinaemia (IgG below 4.0 g/L) during the study period. Time on rituximab and accumulated dose were the main predictors for IgG decrease. Previous treatment with fingolimod and natalizumab, but not teriflunomide, dimethyl fumarate, interferons or glatiramer acetate, were significantly associated with lower baseline IgG levels by 0.80-1.03 g/L, compared with treatment-naïve patients. Switching from dimethyl fumarate or interferons was associated with an additional IgG decline of 0.14-0.19 g/L per year, compared to untreated.

Conclusions: Accumulated dose and time on rituximab treatment are associated with a modest but significant decline in immunoglobulin levels. Previous MS therapies may influence additional IgG decline.

Keywords: IgG decrease; IgM decrease; disease‐modifying therapy; hypogammaglobulinaemia; immunoglobulin decrease; multiple sclerosis; real‐world data; rituximab therapy.

FIGURE 1

Serum levels of IgG (a) and IgM (b) decline as a function of time on treatment with rituximab. The boxes display the median and interquartile (IQR) range at each time point. Whiskers denote 1.5 × IQR and dots indicate outliers or individual values outside this range. The dashed black line indicates the lower limit of normal (LLN) for IgG at our laboratory (6.7 g/L). The red dash‐dot line in (a) indicates the level of severe hypogammaglobulinaemia (<4 g/L) and in (b) LLN (0.27 g/L).

FIGURE 2

Individuals with higher baseline IgG (a) or IgM (b) tended rather to decline faster in IgG upon a similar rituximab challenge over time compared to individuals with lower baseline values. The boxes display the median and interquartile range (IQR) at each time point. Whiskers denote 1 . 5 × IQR and dots indicate outliers. The dashed black line indicates the lower limit of normal (LLN) for IgG at our laboratory (6.7 g/L). The red dash‐dot line in (a) indicates the level of severe hypogammaglobulinaemia (<4 g/L) and in (b) LLN (0.27 g/L).