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

Importance The identification of a prodrome in multiple sclerosis (MS) is the key to early prevention and the targeting of new interventions. Objective To assess the associations between health conditions diagnosed in primary care and the risk of incident MS relative to other autoimmune inflammatory diseases. Design A 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. Setting Data were obtained from electronic health records from the Health Improvement Network database. Participants We 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 measures We 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, and p values 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. Results The 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 relevance The identified symptoms may be considered to be not only prodromal, but also early-stage symptoms, albeit not specific to MS. Question What prediagnostic manifestations of multiples sclerosis (MS) occur in primary care settings and how do they differ from those of other autoimmune diseases? Results In 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. Meaning Our findings suggest that the prodromal phase of MS is largely similar to the prediagnostic manifestations of other autoimmune diseases. ### Competing Interest Statement CL has received consulting or travel fees from Biogen, Novartis, Roche, Sanofi, Teva and Merck Serono, none related to the present work. LG and BL are full time employees of Cegedim. ### Funding Statement The research leading to these results has received funding from the joint program in neurodegenerative diseases (JPND) ANR-21-JPW2-0002-01 (LeMeReND) and the program "Investissements d'avenir" ANR-10-IAIHU-06. This work was funded in part by the French government under management of Agence Nationale de la Recherche as part of the "Investissements d'avenir" program, reference ANR-19-P3IA-0001 (PRAIRIE 3IA Institute). Editorial support, in the form of medical writing and copyediting, was provided by Julie Sappa of Alex Edelman and Associates. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Approval was sorted before carrying out this study (and for the use of datasets). The study was a retrospective analysis of secondary anonymised patient data only. For the UK database, data is only available to researchers carrying out approved medical research. Ethical approval was granted by the NHS South-East Multicentre Research Ethics Committee in 2003 (ref: 03/01/073) for establishment of the THIN database, and it was updated in 2011. A further update and approval was granted in 2020 by the NHS South Central, Oxford C Research Ethics Committee (Ref: 20/SC/0011). For the French Database, several audits were conducted by CNIL (Commission Nationale de l'Informatique et des Libertes, the French authority responsible for the protection of personal data). Data are available from the GERS SAS for researchers who meet the criteria for access to confidential data. Researchers willing to replicate the results should address a request to the Cegedim company (info@the-health-improvement-network.co.uk). The study was approved by the THIN Scientific Research Committee (SRC) on 4th Feb 2022 (SRC reference 21-016). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data used in the preparation of the article are available from the Cegedim company upon reasonable request (info@the-health-improvement-network.co.uk).