Comparing pre- and post-diagnosis presentations of multiple sclerosis and other inflammatory diseases in primary care: an agnostic study of French and British health records
Authors: Guinebretière Octave , Nedelec Thomas , Gantzer Laurène , Lekens Beranger , Durrleman Stanley , Louapre Celine 
Published: November 2022

ImportanceThe identification of a prodrome in multiple sclerosis (MS) is the key to early prevention and the targeting of new interventions.ObjectiveTo assess the associations between health conditions diagnosed in primary care and the risk of incident MS relative to other autoimmune inflammatory diseases.DesignA case-control study in the UK and France was conducted from Jan 1, 1996 to March 28, 2022 in the UK and from Jan 4, 1998 to March 28, 2022 in France.SettingData were obtained from electronic health records from the Health Improvement Network database.ParticipantsWe included all individuals with at least two years of history in the database and a recorded diagnosis of either MS, lupus or Crohn’s disease. Three controls matched for sex, age at index date and year at index date were randomly assigned to each individual with a diagnosis of MS.Main outcome measuresWe agnostically tested the associations between 113 different diagnoses and multiple sclerosis diagnosis during the five years before or the five years after the diagnosis of MS. Unadjusted odds ratios (ORs) and 95% CIs were estimated, andpvalues were corrected for multiple comparisons. We also stratified for sex, age at diagnosis, and year of diagnosis. A logistic regression analysis (adjusted for sex and age at diagnosis) was performed to compare MS patients with lupus and Crohn’s disease patients.ResultsThe study population consisted of patients with MS (UK: 15,808; and France: 4,366), Crohn’s disease (UK: 20,872; and France: 9,605) or lupus (UK: 5,296; and France: 2,041). We identified twelve health conditions as significantly positively associated with the risk of MS. After considering health conditions suggestive of demyelinating events as the first diagnosis of MS, five health conditions remained significantly associated with MS: depression (UK OR 1.22 [95%CI 1.11-1.34]), sexual dysfunction (1.47 [1.11-1.95]), constipation (1.5 [1.27-1.78]), cystitis (1.21 [1.05-1.39]), and urinary tract infections (1.38 [1.18-1.61]). However, none of these conditions was selectively associated with MS in comparisons with both lupus and Crohn’s disease. During the five years after MS diagnosis, all five health conditions identified here were still associated with MS.Conclusion and relevanceThe identified symptoms may be considered to be not only prodromal, but also early-stage symptoms, albeit not specific to MS.Key pointsQuestionWhat prediagnostic manifestations of multiples sclerosis (MS) occur in primary care settings and how do they differ from those of other autoimmune diseases?ResultsIn this agnostic study of 15,808 MS patients from the UK and 4,366 MS patients from France, we identified five health conditions as positively associated with the risk of MS when recorded in the five years preceding MS diagnosis. We show that most of these health conditions were also present in the early presentations of lupus and Crohn’s disease.MeaningOur findings suggest that the prodromal phase of MS is largely similar to the prediagnostic manifestations of other autoimmune diseases.