Long-term impact of oral cladribine on humoral immunity in multiple sclerosis

Abstract

Background: Cladribine (CLAD), an immune reconstitution therapy for active multiple sclerosis (MS), can reduce intrathecal antibody production.

Objectives: In this study, we investigated the long-term impact of oral CLAD on protective antibody levels, essential for preventing infections and immune defense.

Design: Observational long-term study including a cohort of 15 CLAD-treated MS patients.

Methods: We longitudinally studied the humoral immunity to seven common pathogens (measles, mumps, varicella-zoster virus, diphtheria and tetanus toxin, rubella, hepatitis B virus (HBV)) and absolute immunoglobulin G (IgG) levels prior to CLAD treatment (baseline, BL; 12/2017-03/2020) and after an average of 73 months (long-term) follow-up to explore the impact on pre-existing IgG. At long-term, we assessed IgG response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to evaluate potential inhibitory effects on the formation of new immunity.

Results: We found no CLAD associated loss of humoral immunity over up to 7 years. Pathogen-specific IgG antibodies were present in 60%-100% and 67%-100% of patients at BL and long-term, respectively. We found no decline in absolute IgG levels 73 months after starting CLAD treatment. Patients who received subsequent anti-CD20 treatment had significantly lower SARS-CoV-2 antibody levels (p = 0.011) compared to the rest of the cohort, which developed adequate anti-SARS-CoV-2 IgG. One patient had a clinically silent tick-borne encephalitis (TBE) infection mounting appropriate IgG and IgM. No severe COVID-19 cases occurred, and no new safety concerns were identified.

Conclusion: These long-term data suggest that CLAD treatment does not impact preexisting humoral immunity or antibody production toward novel antigens. Our results support the positive long-term safety profile of the drug.

Keywords: B cells; COVID-19; SARS-CoV-2; coronavirus; disease-modifying therapies; immunization; immunoglobulins; vaccine titers.

Figure 1.

(a) Preexisting pathogen-specific IgG immunity to seven common pathogens was not altered by CLAD treatment after LT (mean 73 months) surveillance. (b) Pathogen-specific IgG levels to SARS-CoV-2 (anti-Spike IgG) assessed 73 months after CLAD initiation. Cohort divided into patients with (CLAD → subsequent anti-CD20 therapy; green dots) and without (CLAD therapy; blue dots) subsequent anti-CD20 treatment. Individuals with subsequent anti-CD20 depleting therapy (n = 5) mounted significantly fewer antibodies to SARS-CoV-2 (anti-Spike IgG). Dashed lines indicate cut-off values. Error bars represent 95% confidence intervals. (c) Absolute IgG blood levels remained stable despite immune reconstitution by CLAD. (d) Absolute IgG blood levels of five patients with consecutive anti-CD20 B cell depleting therapy remained stable during the follow-up period. Gray dotted lines represent the normal range of IgG levels. Error bars represent 95% confidence intervals with n = 15, for VZV n = 14. BAU, binding antibody units; BL, baseline; CLAD, cladribine; HBV, hepatitis B; IgG, immunoglobulin G; LT, long-term follow-up; mg/dl, milligrams per deciliter; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; Switch, start of consecutive anti-CD20 B cell depleting therapy; tox, toxin; VZV, Varicella-zoster virus.