Long-term changes of the peripheral immune repertoire after switching from sequestering disease-modifying treatments in Multiple Sclerosis: a single-center cohort study

Introduction: Multiple sclerosis is a chronic, demyelinating, immune-mediated disease of the central nervous system. It is clinically characterized by focal attacks, resulting in variable neurological manifestations according to localization of demyelinating plaques. It affects females more than males with a heterogeneous geographical distribution and peak of presentation at 30 years old. MS has a multifactorial origin, including genetic predisposition, environmental factors, and immunological dysregulation. Diagnosis is based on McDonald criteria and it is supported by clinical manifestations, neuroimaging (MRI), cerebrospinal fluid analysis, and electrophysiological studies. Treatment includes therapy for acute relapses, symptomatic therapy, and disease-modifying treatments (DMTs). Background: The main mechanisms of actions exploited by DMTs involve suppression, modulation or reconstitution of the immune system. The long-term impact of these drugs on the peripheral immune repertoire has not been thoroughly studied in the past, both in terms of laboratory changes and in terms of clinical correlation with disease activity and adverse events. Objectives: The present clinical study aims at investigating long-term changes in the peripheral immune system following interruption of sequestering DMTs, i.e. fingolimod and natalizumab, and switch to other high efficacy DMTs. Methods: This retrospective observational study focused on patients from a single center in Turin (Italy) who had switched from fingolimod or natalizumab to ocrelizumab or who had switched from fingolimod to natalizumab; comparison was made between these cohorts of patients and those undergoing treatment with ocrelizumab or natalizumab but who had switched from moderate efficacy DMTs or were treatment-naïve. Lymphocytes were tested every 6 months for up to 48 months, both as total number and as subpopulations. Infections and disease activity were recorded over the same period, with the help of anamnestic data from visits and of hospital records. Results: 389 MS patients were included (200 ocrelizumab, 189 natalizumab). After adjusting for baseline variables, fingolimod-switched patients currently in therapy with ocrelizumab showed reduced total lymphocytes up to 36 months post-switch, reduced CD3+ lymphocytes, and CD4+ lymphocytes (p<0.0001) up to 48 months post-switch (in particular, a lower percentage of naïve CD4+ was detected) and increased odds of total, CD3+, CD4+ lymphopenia. Fingolimod- switched patients currently in therapy with natalizumab presented reduced total lymphocytes, up to 12 months post-switch. Natalizumab-switched patients currently in therapy with ocrelizumab presented increased values of CD3+ lymphocytes up to 36 months post-switch (p=0.020) and of CD4+ and CD8+ lymphocytes up to 24 months post-switch. Infectious risk was not significantly different in subgroups according to prior treatment. Conclusion: Long-term residual effects of exposure of sequestering DMTs on the peripheral immune repertoire were observed to persist after drug interruption and switch to another high-efficacy DMT. Effects are more prominent in patients who had switched from fingolimod compared to natalizumab. Further studies will be needed to deepen knowledge on this topic.