The effect of cladribine on immunoglobulin levels compared to B cell targeting therapies in multiple sclerosis

Background: Cladribine is a useful therapeutic option in RRMS with moderate to high disease activity. Its oral formulation and tolerability make it a useful alternative to infusion therapies. Cladribine is known to deplete CD19+ B lymphocytes, but its effect on immunoglobulin subsets is unclear. Objective: To identify whether cladribine therapy in pwMS reduces immunoglobulin subset levels as a surrogate marker of infection risk. Methods: A ‘real-world’ retrospective analysis of 341 pwMS presenting to a single tertiary centre between March 2017 and July 2021. Differences in immunoglobulin levels between cladribine, other disease-modifying therapies and no active treatment were assessed using a univariate ANOVA. Results: Three hundred and forty-one patients had immunoglobulin levels assessed, with 29 patients treated with cladribine. The mean IgG, IgM and IgA levels on cladribine therapy were 10.44 ± 0.40, 0.99 ± 0.09 and 2.04 ± 0.18 g/L respectively. These were not significantly different from patients not on active treatment. There was a statistically significant reduction in IgG and IgM levels for patients treated with ocrelizumab (9.37 ± 0.19 and 0.68 ± 0.04 g/L) and natalizumab (8.72 ± 0.53 and 0.69 ± 0.12 g/L) compared to patients not on treatment. Conclusion: Cladribine therapy for RRMS was not associated with immunoglobulin subset deficiencies. This is contrasted to ocrelizumab and natalizumab which demonstrate significant reductions in both IgG and IgM levels.</p

DNA methylation changes in CD4+ T cells isolated from multiple sclerosis patients on dimethyl fumarate

Background: Dimethyl fumarate is an oral treatment for multiple sclerosis, whose mechanism of action is not fully understood. Objective: To investigate the effects of dimethyl fumarate on DNA methylation in the CD4+ T cells of multiple sclerosis patients. Methods: We performed Illumina EPIC arrays to investigate the DNA methylation profiles of CD4+ T cells derived from multiple sclerosis patients before and after dimethyl fumarate treatment. Results: Treatment with dimethyl fumarate resulted in 97% of differentially methylated positions showing hypermethylation. Four genes, SNORD1A, SHTN1, MZB1 and TNF had a differentially methylated region located within the transcriptional start site. Conclusion: This study investigates the effect of dimethyl fumarate on DNA methylation in multiple sclerosis patients.</p

Supplemental material for DNA methylation changes in CD4⁺ T cells isolated from multiple sclerosis patients on dimethyl fumarate

<p>Supplemental material for DNA methylation changes in CD4⁺ T cells isolated from multiple sclerosis patients on dimethyl fumarate by Vicki E Maltby, Rodney A Lea, Karen A Ribbons, Katherine A Sanders, Daniel Kennedy, Myintzu Min, Rodney J Scott and Jeannette Lechner-Scott in Multiple Sclerosis Journal – Experimental, Translational and Clinical</p

Silent lesions on MRI imaging - Shifting goal posts for treatment decisions in multiple sclerosis.

The current best practice suggests yearly magnetic resonance imaging (MRI) to monitor treatment response in multiple sclerosis (MS) patients. To evaluate the current practice of clinicians changing MS treatment based on subclinical new MRI lesions alone. Using MSBase, an international MS patient registry with MRI data, we analysed the probability of treatment change among patients with clinically silent new MRI lesions. A total of 8311 MRI brain scans of 4232 patients were identified. Around 26.9% (336/1247) MRIs with one new T2 lesion were followed by disease-modifying therapy (DMT) change, increasing to 50.2% (129/257) with six new T2 lesions. DMT change was twice as likely with new T1 contrast enhancing compared to new T2 lesions odds ratio (OR): 2.43, 95% confidence interval (CI): 2.00-2.96 vs OR: 1.26 (95% CI: 1.22-1.29). DMT change with new MRI lesions occurred most frequently with 'injectable' DMTs. The probability of switching therapy was greater only after high-efficacy therapies became available in 2007 (after, OR: 1.43, 95% CI: 1.28-1.59 vs before, OR: 0.98, 95% CI: 0.520-1.88). MS clinicians rely increasingly on MRI alone in their treatment decisions, utilizing low thresholds (1 new T2 lesion) for optimizing MS therapy. This signals a shift towards no evidence of disease activity (NEDA)-3 since high-efficacy therapies became available