The impact of disease-modifying therapies on immunoglobulin blood levels in patients with multiple sclerosis: a retrospective cross-sectional study

Abstract

Background: Although disease-modifying therapies (DMTs) in multiple sclerosis (MS) are known to target the immune system, mechanisms of action, efficacy, safety, and tolerability profiles differ. The long-term impact of DMTs on the immune system and its relation to infectious complications is still poorly understood.

Objectives: To analyze the effect of DMTs on serum immunoglobulin (Ig) levels under consideration of patient demographics and therapy duration.

Design: We included 483 patients on DMTs, 69 patients without DMTs, and 51 controls in this retrospective cross-sectional study.

Methods: IgG, IgM, and IgG subclass 1-4 levels of patients with MS under treatment with DMTs were compared with treatment naive MS patients and controls by multivariate linear regression. Further, Ig levels stratified by DMTs were analyzed regarding therapy duration.

Results: MS patients treated with fingolimod (FG), natalizumab, and B-cell depleting therapies (BCDT) demonstrated significantly lower IgG and IgM levels than healthy controls after a median treatment of 37, 31, and 23 months, respectively (p < 0.05). Treatment with dimethyl fumarate (DMF) and teriflunomide was associated with lower IgG, but not IgM levels. DMF and BCDT were also associated with lower IgG1 levels, while FG led to a reduction of IgG2. Treatment with interferon-beta (IFN) and glatiramer acetate (GA) had no impact on Ig levels. Analysis of subgroups by linear regression also showed a time-dependent decrease of Igs levels in patients treated with BCDT with a median annual reduction of IgG of 3.2% and IgM of 6.2%.

Conclusion: Treatment with DMTs, except GA and IFN, was associated with a decrease in Ig levels. DMTs differed in the extent of decreasing Ig levels but also in their differential effects on Ig subclasses. Monitoring of Ig levels should be considered in patients on long-term treatment with DMTs, particularly those on BCDT, to identify patients at risk of low immunoglobulin levels.

Keywords: disease-modifying therapy; hypogammaglobulinemia; immunoglobulins; multiple sclerosis.

Figure 1.

IgG (a) and IgM (b) levels in mg/dl are presented by therapy group in a violin plot, allowing for presentation of data distribution. *Statistical significance compared to controls (see Table 2) BCDT, B-cell depleting therapy, DMF, dimethyl fumarate; DMT, therapy naive patients; FG, fingolimod; GA, glatiramer acetate; IFN, interferon-beta; NZ, natalizumab; TFM, teriflunomide.

Figure 2.

Scatterplots of Ig levels over time under B-cell depleting therapy (BCDT) [a] IgG and [b] IgM. Ig levels (mg/dl) in patients under treatment with BCDT were analyzed by multivariate linear regression in regard to therapy duration and displayed in a scatterplot. The Pearson correlation coefficient r is shown for both IgG and IgM. (a) Analysis of IgG. Estimate: 0.032; p-value: < 0.001 (b): Analysis of IgM: Estimate: 0.062; p-value: < 0.001.

Figure 3.

Ig level reduction relative to controls in percent by therapy group Ig levels (IgG, IgM, and IgG subclasses) are demonstrated as variation from controls in percent and divided by therapy group. *Statistical significance compared to controls (see Table 2 and Table 3) BCDT, B-cell depleting therapy; DMF, dimethyl fumarate; FG, fingolimod; GA, glatiramer acetate; IFN, interferon-beta; NZ, natalizumab; TFM, teriflunomide.