Study of the Association Between Menarche and Disease Course in Pediatric Multiple Sclerosis.

Background and objectives: Sex steroid hormones have been demonstrated to affect the immune system in multiple sclerosis (MS), and puberty may trigger MS activity. We aimed to evaluate the association between menarche and disease course in pediatric MS through comparison of relapse rates across premenarche, perimenarche, and postmenarche periods.

Methods: This is a retrospective analysis of a prospectively followed female cohort with pediatric-onset MS in the US Network of Pediatric MS Centers database. Perimenarche was considered the period from 1 year before to 1 year after the estimated menarche date based on menarche integer age. Relapses were collected prospectively. Negative binomial and repeated-measures Cox regression models were used to assess the association of pubertal development stage with relapse rate, adjusted for race, body mass index, and disease-modifying therapy (DMT).

Results: Of 736 participants (all female; mean onset age 14.4 ± 2.8 years; mean menarche age 11.6 ± 1.4 years), onset was in premenarche in 73, perimenarche in 112 (± 1 year of menarche), and postmenarche in 551. The median time of MS onset was 2.8 years after menarche. Most (86%) were exposed to DMT in follow-up. In adjusted negative binomial analysis, the annualized relapse rate during premenarche was 0.43, perimenarche was 0.65, and postmenarche was 0.43 (premenarche rate ratio [RR] 1.00 (95% CI 0.70-1.43) and perimenarche RR 1.52 (95% CI 1.16-1.99), compared with reference of postmenarche, p = 0.0049. In adjusted repeated-events Cox regression analysis, there was increased hazard to relapse in perimenarche and postmenarche compared with premenarche (perimenarche hazard ratio [HR] 1.78 [95% CI 1.17-2.70] and postmenarche HR 1.67 [95% CI 1.12-2.50], compared with reference of premenarche, p = 0.025). In this analysis, use of oral and infusion DMTs significantly lowered the relapse hazard compared with periods of no DMT use (injectable HR 0.98 [95% CI 0.83-1.15], oral HR 0.48 [95% CI 0.37-0.61], and infusion HR 0.24 [95% CI 0.18-0.31], compared with no DMT, p < 0.001).

Discussion: Onset of puberty may be a time of increase in disease activity and may require consideration of a change in therapeutic approach. Menarche age was used as a surrogate for puberty, and future studies measuring sex steroid hormones may be informative.