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

Marc Messner; Michael Unterhofer; Jonas Strauss; Sylvia Mink; Janne Cadamuro; Hannes Oberkofler; Wolfgang Hitzl; Peter Wipfler; Eugen Trinka; Tobias Moser

doi:10.1177/17562864251357275

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

Ther Adv Neurol Disord. 2025 Aug 4:18:17562864251357275. doi: 10.1177/17562864251357275. eCollection 2025.

Authors

Marc Messner¹, Michael Unterhofer¹, Jonas Strauss¹, Sylvia Mink², Janne Cadamuro³, Hannes Oberkofler³, Wolfgang Hitzl^{4

5}, Peter Wipfler¹, Eugen Trinka^{1

6}, Tobias Moser⁷

Affiliations

¹ Department of Neurology, Neurocritical Care, and Neurorehabilitation, Christian Doppler University Hospital, Paracelsus Medical University and Center for Cognitive Neuroscience, member of European Reference Network EpiCARE, Salzburg, Austria.
² Central Medical Laboratories, Feldkirch, Austria.
³ Department of Laboratory Medicine, Paracelsus Medical University, Salzburg, Austria.
⁴ Department of Ophthalmology and Optometry, Paracelsus Medical University, Salzburg, Austria.
⁵ Research Program Experimental Ophthalmology and Glaucoma Research, Paracelsus Medical University, Salzburg, Austria.
⁶ Neuroscience Institute, Christian Doppler University Hospital, Paracelsus Medical University and Center for Cognitive Neuroscience, Salzburg, Austria.
⁷ Department of Neurology, Neurocritical Care, and Neurorehabilitation, Christian Doppler University Hospital, Paracelsus Medical University and Center for Cognitive Neuroscience, member of European Reference Network EpiCARE, Ignaz-Harrer-Straße 79, Salzburg 5020, Austria.

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.