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Risk of Cervical Abnormalities for Women With Multiple Sclerosis Treated With Moderate-Efficacy and High-Efficacy
Francesca Bridge1, Julia Brotherton1, Jim Stankovich1
1From the Department of Neuroscience (F.B., J.S., P.G.S., O.G.S., M.M., H.B., V.G.J., A.V.D.W.), Central Clinical School, Monash University; Department of Neurology (F.B., O.G.S., M.M., L.R., H.B., V.G.J., A.V.D.W.), Alfred Health, Melbourne; Australian Centre for the Prevention of Cervical Cancer (formerly Victorian Cytology Service) (J.B.), Carlton South; Centre for Epidemiology and Biostatistics (J.B.), Melbourne School of Population and Global Health, University of Melbourne; Department of Neurosciences (O.G.S., K.B.), Eastern Health; MS Centre (K.B., T.K., A.-L.N., K.G., M.M., L.T.), Department of Neurology, Royal Melbourne Hospital; Eastern Health Clinical School (K.B., A.-L.N.), Monash University, Box Hill; CORe (T.K., A.-L.N.), Department of Medicine, University of Melbourne; Oncology and Dysplasia Unit (C.D.W.), Royal Women's Hospital, Parkville; and Department of Obstetrics and Gynaecology (C.D.W.), University of Melbourne, Australia.
Background And Objectives:
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).
Methods:
This is a multicenter cohort study with data collected from 1998 to 2019 in Victoria, Australia. Data linkage was performed using matching records from the MSBase Registry, the National Human Papillomavirus (HPV) Vaccination Program Register, and the Victorian Cervical Cytology Register. The primary outcome was the detection of any type of cervical abnormality as determined by cytology or histology. Survival methods were used to assess the time to cervical abnormality detection on cervical screening tests (CSTs). Crude and adjusted Cox proportional hazards models were used to determine time to and magnitude of association of DMTs with the risk of cervical abnormality. In a sensitivity analysis, we constructed standardized survival curves averaged over the same set of covariates to determine the commensurate population-average (marginal) causal effects.
Results:
We included 248 wwMS. The incidence of abnormal CSTs was lower (p < 0.001) for women not exposed to moderate-high-efficacy therapy (10.2 per 1,000 patient-years [95% confidence interval (CI) 5.5-14.9]), compared with those exposed (36.6 per 1,000 patient-years [95% CI 21.7-51.6]). Exposure to higher efficacy treatment was associated with a 3.79-fold increased hazard (95% CI 2.02-7.08, p < 0.001) of developing a cervical abnormality relative to those not exposed. When adjusted for vaccination status, smoking, hormonal contraceptive use, and socioeconomic status, the risk remained elevated at 3.79 (95% CI 1.99-7.21, p < 0.001). Marginal hazard ratios declined over time, ranging from 3.90 (95% CI 2.09-7.27) at 20 years of age to 2.06 (95% CI 1.14-3.73) at 70 years of age.
Discussion:
A greater than three-and-a-half-fold increased risk of cervical abnormalities was found after exposure to moderate-high-efficacy DMTs. This risk persisted despite adjusting for HPV vaccination status, hormonal contraception use, smoking, and socioeconomic status. If confirmed in future studies, we would advocate for wwMS exposed to moderate-high-efficacy DMTs to be treated in line with immune-deficient paradigm in cervical screening and HPV vaccination programs.
Classification Of Evidence:
This study provides Class III evidence that highly active MS therapy compared with less active therapy increases the risk of developing cervical abnormalities among women with MS.
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