To evaluate the risk of cervical abnormality in women with multiple sclerosis (MS) exposed to high efficacy-disease modifying therapies (DMTs).
Methods
Multi-centre retrospective cohort study in Victoria, Australia utilising data collected from 1998–2019. Data linkage matched patient data across three registries: (1) MSBase Registry (2) National HPV Vaccination Program Register (NHVPR) (3) Victorian Cervical Cytology Register (VCCR). Primary outcome was detection of any type of cytological or histological cervical abnormality classified as low-grade or worse (>/= grade 1 cervical intraepithelial neoplasia) identified on cervical screening tests. Survival methods assessed time to cervical abnormality. Crude and adjusted Cox proportional hazards were used to determine the magnitude of association of exposure to high-efficacy DMTs with cervical abnormality.
Results
248 women with MS were included in the analysis. Cervical abnormality incidence was higher for women exposed to high-efficacy DMTs (36.6/1000 patient-years (95% CI 21.7 – 51.6)) than those unexposed to high efficacy therapy (10.2/1000 patient-years (95% CI 5.5–14.9), p<0.001). High-efficacy DMT exposure was associated with a 3.79-fold increased hazard (95% CI 2.02–7.08, p<0.001) of developing a cervical abnormality. This risk persisted despite adjusting for human papillomavirus (HPV) vaccination status, smoking, hormonal contraceptive use and socioeconomic status (HR 3.78, 95% CI 1.98–7.19, p<0.001).
Conclusions
A greater than 3.5-fold increased risk of cervical abnormality was detected after exposure to high-efficacy DMTs. This highlights the need for increased safety vigilance including patient-centred counselling and ensuring participation primary and secondary prevention strategies such as HPV vaccination and cervical screening programs for women with MS.
The aim of this work was to evaluate sex differences in the incidence of multiple sclerosis relapses; assess the relationship between sex and primary progressive disease course; and compare effects of age and disease duration on relapse incidence. Annualized relapse rates were calculated using the MSBase registry. Patients with incomplete data or <1 year of follow-up were excluded. Patients with primary progressive multiple sclerosis were only included in the sex ratio analysis. Relapse incidences over 40 years of multiple sclerosis or 70 years of age were compared between females and males with Andersen-Gill and Tweedie models. Female-to-male ratios stratified by annual relapse count were evaluated across disease duration and patient age and compared between relapse-onset and primary progressive multiple sclerosis. The study cohort consisted of 11 570 eligible patients with relapse-onset and 881 patients with primary progressive multiple sclerosis. Among the relapse-onset patients (82 552 patient-years), 48 362 relapses were recorded. Relapse frequency was 17.7% higher in females compared with males. Within the initial 5 years, the female-to-male ratio increased from 2.3:1 to 3.3:1 in patients with 0 versus ≥4 relapses per year, respectively. The magnitude of this sex effect increased at longer disease duration and older age (P < 10−12). However, the female-to-male ratio in patients with relapse-onset multiple sclerosis and zero relapses in any given year was double that of the patients with primary progressive multiple sclerosis. Patient age was a more important determinant of decline in relapse incidence than disease duration (P < 10−12). Females are predisposed to higher relapse activity than males. However, this difference does not explain the markedly lower female-to-male sex ratio in primary progressive multiple sclerosis. Decline in relapse activity over time is more closely related to patient age than disease duration.
Abstract Background Pregnancy in women with multiple sclerosis (MS) is associated with a reduction of long-term disability progression. The mechanism that drives this effect is unknown, but converging evidence suggests a role for epigenetic mechanisms altering immune and/or central nervous system function. Objectives We aimed to identify whole blood and immune cell-specific DNA methylation patterns associated with parity in relapse-onset multiple sclerosis. Methods We compared whole-blood methylation patterns between 96 matched pairs of nulligravida and parous females with MS (n=192). Parity was defined as at least one term or pre-term birth, and nulligravida was defined as no prior pregnancies. Methylation was measured with Illumina EPIC arrays, and data was pre-processed and statistically analysed using the ChAMP package. Cell-type proportions were estimated using the EpiDISH package, and cell-specific analysis conducted using linear regression. Gene-set enrichment analysis (GSEA) was performed with ToppGene API and GOmeth. Methylation age was calculated with the methyAge package. Methylation age acceleration (MAA) was calculated by regressing methylation age on chronological age. FDR<0.05 was used to assess significance. Results The median time from last pregnancy to blood collection was 16.66 years (range = 1.45 – 44.42 years). We identified 903 differentially methylated positions (DMPs) in whole blood; 365 were hypomethylated and 528 were hypermethylated in parous women. We further identified two differentially methylated regions (DMRs) in CRYGN on Chromosome 7 and an intergenic region on Chromosome 15. There were four and eight cell type specific DMPs in CD4+ and CD8+ cells, respectively. Differentially methylated genes were enriched in neuronal plasticity pathways. Parity was associated with reduced MAA by a mean of 1.44 to 2.27 years using the PhenoAge (p = 0.002) and GrimAge (p = 0.005) algorithms. Conclusion Whole-blood methylation patterns are associated with birth history in females with relapse-onset multiple sclerosis. We found enrichment of differentially methylated genes encoding neuronal processes and reduced MAA in parous women. These methylation changes could mediate the long-term benefit of pregnancy for disease progression in multiple sclerosis.
Abstract Multiple sclerosis (MS) is a leading cause of neurological disability in adults. Heterogeneity in MS clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international MS Registry, MSBase. We assembled a cohort of deeply phenotyped individuals with relapse-onset MS. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined MS severity phenotypes in 1,813 individuals. Our results did not identify any variants of moderate to large effect sizes that met genome-wide significance thresholds. However, we demonstrate that clinical outcomes in relapse-onset MS are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62,000 variants and demographic variables available at MS disease onset, we could predict severity with an area under the receiver operator curve (AUROC) of 0.87 (95% CI 0.83 – 0.91). This approach, if externally validated, could quickly prove useful for clinical stratification at MS onset. Further, we find evidence to support central nervous system and mitochondrial involvement in determining MS severity.
The impact of immunomodulatory therapies on the risk of cervical pre-cancer and invasive cancer development is important for the health and safety of women with multiple sclerosis (wwMS). We investigate the risk of cervical abnormalities in wwMS treated with disease-modifying therapies (DMTs).
The TAM family of receptor protein tyrosine kinases comprises three known members, namely Tyro3, Axl, and Mer. These receptors are widely expressed in the nervous system, including by oligodendrocytes, the cell type responsible for myelinating the CNS. We examined the potential role of the TAM family and of their principle cognate ligand, Gas6 (growth arrest gene 6), in modulating the phenotype of the cuprizone model of demyelination. We found that the expression profiles of Axl , Mer , and Gas6 mRNA were increased in the corpus callosum in a temporal profile correlating with the increased migration and proliferation of microglia/macrophages in this model. In contrast, expression of Tyro3 decreased, correlating with the loss of oligodendrocytes. Gas6 both promoted in vitro survival of oligodendrocytes (39.3 ± 3.1 vs 11.8 ± 2.4%) and modulated markers of activation in purified cultures of microglia (tumor necrosis factor α mRNA expression was reduced ∼48%). In Gas6 −/− mice subjected to cuprizone-challenge, demyelination was greater than in control mice, within the rostral region of the corpus callosum, as assessed by luxol fast blue staining (myelination reduced by 36%) and by ultrastructural analysis. An increased loss of Gst-π (glutathione S -transferase-π)-positive oligodendrocytes was also identified throughout the corpus callosum of Gas6 −/− mice. Microglial marker expression (ionized calcium-binding adapter molecule 1) was increased in Gas6 −/− mice but was restricted to the rostral corpus callosum. Therefore, TAM receptor activation and regulation can independently influence both oligodendrocyte survival and the microglial response after CNS damage.
Introduction Long-term exposure of women with Multiple sclerosis (MS, wwMS) to immunomodulatory or immunosuppressive treatments may increase the risk of cervical dysplasia. However, little is known about cervical dysplasia risk and Human Papillomavirus (HPV)-vaccine coverage in wwMS. Methods Adult wwMS were recruited from two tertiary MS clinics. To explore the association between MS treatments (DMTs) and abnormal cervical screening tests (CSTs), we linked individual data from MSBase, the Victorian Cervical Screening Registry, and National HPV vaccination program registry (NHPVPR). Results To date, we have recruited 208 wwMS of whom 102 had complete data (vaccination status, cervical screening tests, MSBase data) and no previous history of abnormal CST at MS onset for this interim analysis. The average age was 33.8 (18 to 59 yrs) and most (n=58, 88%) were unvaccinated. 19 wwMS (19%) had an abnormal CST after MS onset (incidence rate 20.6 cases/1000 person-years, 95% confidence interval 12.4–32.1) over average 9.0 years of follow-up. 57 wwMS were treated with lower-efficacy therapies (56%), 73 with a high-efficacy therapy (72%), and 44 were exposed to both. Eight abnormal CSTs were detected before starting high-efficacy therapy (rate 12.6, 95% CI (5.4–24.8)) and 11 were detected after starting high-efficacy therapy (rate 38.6, 95% CI (19.3–69.0), p=0.022. Conclusion We provide preliminary data that high efficacy DMTs may increase the risk of abnormal CSTs over time. A larger cohort and inclusion of additional cervical dysplasia risk factors are required to fully elucidate risk in wwMS.
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