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Prioritising Referrals To Rheumatology For Individuals At-Risk of an Inflammatory Arthritis: Guidance Based on Results of a 10-Year National Primary Care Study

Background: Musculoskeletal (MSK) symptoms are among the commonest reasons for primary care assessments; however, few individuals will be diagnosed with an inflammatory arthritis (IA) within the following year. The purpose of this study was to investigate which of the factors available in primary care are associated with progression to IA in individuals with new MSK symptoms, in order to optimise primary care referrals to Rheumatology. 
 
Methods: Individuals ≥16 years old with new non-specific MSK symptoms and no clinical synovitis were recruited by primary care across the UK from July-2007 until May-2019. Those testing positive for the anti-CCP2 assay (anti-CCP+) were invited to Leeds for follow-up. Subjects with a negative result (anti-CCP-) were sent a 1-year questionnaire, and general practitioners were contacted to confirm whether the individual had been diagnosed with an IA by a rheumatologist. Predictors for progression were assessed using multivariable regression analysis. 
 
Findings: 6,780 individuals recruited: 3% were anti-CCP+, of whom 45% progressed to IA, predominantly rheumatoid arthritis. In anti-CCP+ participants, high anti-CCP levels had an odds ratio (OR) for progression to IA of 9∙42 [p<0∙001,95%CI(3∙13-28∙30)], hand pain OR 2∙74 [p=0∙043,95%CI(1∙03-7∙27)] and foot pain OR 4∙10 [p=0∙003,95%CI(1∙59-10∙54)]. Low-level anti-CCP+ antibodies and absence of pain in hands or feet had a negative predictive value of 96% for progression to IA. 
 
One-year follow-up data were available for 5,640 anti-CCP- individuals, of whom 53 were diagnosed with IA (0∙93%). Pain in hands, OR 2∙51 [p=0∙018,95%CI(1∙17-5∙39)] or knees, OR 3∙03 [p=0∙003,95%CI(1∙47-6∙25)] were associated with IA development within 12 months. 
 
Interpretation: This is the largest prospective primary care study of individuals at-risk of IA, and the first one to prospectively investigate the outcome of MSK symptoms in a large anti-CCP- cohort. High anti-CCP levels and pain in hands/feet had an increased likelihood of progression to IA. Individuals with low anti-CCP levels and no pain in hands/feet were unlikely to progress. In anti-CCP- patients, hand or knee pain associated increased risk of progression. This provides useful discrimination that may be used to prioritise referrals to Rheumatology and avoid a delayed diagnosis. 
 
Trial Registration: Trial registration number: NCT02012764 
 
Funding: The study sponsor (the University of Leeds) and the funding source [National Institute for Health Research (NIHR) Leeds Biomedical Research Centre] were involved in the trial design and patient recruitment. 
 
Declaration of Interest: Kulveer Mankia reports personal fees from Abbvie, UCB and Lilly, outside the submitted work. Paul Emery reports consultant fees from Pfizer, Abbvie, Amgen, MSD, Roche, Sanofi, BMS, Novartis, Lilly, Gilead, Samsung, Celltrion outside the submitted work. He also reports research grants from AbbVie, BMS and Samsung, outside the submitted work. Leticia Garcia-Montoya, Jacqueline L.Nam, Laurence Duquenne, Andrea Di Matteo, Catalina Villota-Eraso and Collette Hartley have no disclosures. 
 
Ethical Approval: Leeds West Research Ethics Committee (REC reference number 06/Q1205/169) Participants gave written informed consent to participate in the “CCP study”.