Age-related adverse events of disease-modifying treatments for multiple sclerosis: A meta-regression

Abstract

Objective: To verify the hypothesis of an age-dependent increase of infections and neoplasms in patients with multiple sclerosis (MS) under disease-modifying treatments (DMTs) with different mechanisms of action. Methods: We extracted relevant data from 45 randomized clinical trials (RCTs) on currently licensed DMTs. We fitted inverse-variance weighted meta-regressions with random-effects models to estimate whether age and/or mechanism of action (immunomodulatory, sequestrating, and depletive) of currently licensed DMTs influenced the difference between experimental arm and control arm in the incidence of specific adverse events, namely, overall infections, opportunistic infections, and neoplasms. Results: A higher incidence of overall infections was observed in RCTs with depletive DMTs (event-rate ratio = 1.25, p < 0.001). Herpetic infections were more frequently observed in RCTs with both depletive (event-rate ratio = 3.51, p < 0.001) and, to a lesser extent, sequestrating DMTs (event-rate ratio = 1.52, p = 0.078). The interaction of age with depletive DMTs was associated with higher incidence of neoplasms ( p = 0.017), especially above 45 years of age. Discussion: Our study supports a detrimental effect of age on the safety profile of depletive DMTs, with an increased incidence of neoplasms especially over 45 years of age. We failed to demonstrate an age-related increased incidence of infections, possibly due to latency in their occurrence.

Identification of the Immunological Changes Appearing in the CSF During the Early Immunosenescence Process Occurring in Multiple Sclerosis

“…The M- phenotype is twice as frequent as the M+ phenotype in MS. Thus, the reduction of pro-inflammatory adaptive immune cells shown by these patients may account for the changes in adaptive immune response described for aged MS patients ( 38 ), and M+ status may protect from opportunistic infections in older patients ( 39 , 40 ).…”

Evolution of Disease Modifying Therapy Benefits and Risks: An Argument for De-escalation as a Treatment Paradigm for Patients With Multiple Sclerosis

“…In addition, malignancy and other agent-specific adverse events are reported in some cases ( 6 , 7 ). In a meta-regression of 45 trials utilizing DMTs with a variety of mechanisms, depletive DMTs (ocrelizumab and alemtuzumab) were associated with higher incidence of neoplasms, with an effect in those >45 years ( 41 ). While there was initial concern based on phase III trial data that ocrelizumab may lead to increased rates of breast cancer, this has not been demonstrated in an analysis of 11 clinical trials and post-marketing surveillance ( 27 ).…”

Molecular Mechanisms of Immunosenescene and Inflammaging: Relevance to the Immunopathogenesis and Treatment of Multiple Sclerosis

“…Since DMTs directly act on the immune system, there has always been a major concern about risk for cancer and infections (191,310). While some found initially a slightly increased risk for cancer (e.g., urogenital, breast, CNS cancers, lymphomas, melanomas) (311,312), the overall risk considering all current DMTs is not increased [reviewed by (313)], although a higher incidence of neoplasm with depletive DMTs (alemtuzumab, cladribine, ocrelizumab) was found by a meta-regression analysis, especially after the age of 45 years (314). Switching from DMTs, especially more than twice, was also a risk factor for cancer (311).…”