Prioritising referrals of individuals at-risk of RA: guidance based on results of a 10-year national primary care observational study

Abstract

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, in individuals with new MSK symptoms, the association between patient factors and risk of progression to IA, 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.

Results: Six thousand seven hundred eighty individuals were recruited: 3% were anti-CCP+, of whom 45% progressed to IA, predominantly rheumatoid arthritis. Anti-CCP+ participants with high antibody 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)]. In low-level anti-CCP+ individuals, 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 5640 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 development of IA within 12 months.

Conclusions: 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 indicated an increased likelihood of progression to IA. In patients with low anti-CCP level and no pain in the hands/feet, progression is unlikely. In anti-CCP- patients, those with hand or knee pain were at increased risk of progression. This study demonstrates that routinely available tests and joint symptoms provide useful discrimination that may be used to prioritise referrals to rheumatology and avoid a delayed diagnosis.

Trial registration: NCT, NCT02012764 . Registered 25 January 2007.

Keywords: ACPA; Anti-CCP; Autoantibodies; Epidemiology; Inflammatory arthritis; Joint pain; Primary care; Progression; Rheumatoid arthritis; Risk.

Conflict of interest statement

Kulveer Mankia reports personal fees from Abbvie, UCB and Lilly, outside the submitted work. Paul Emery reports consultant fees from BMS, AbbVie, MSD, Lilly, Novartis, Pfizer, Roche, and Samsung outside the submitted work. He also reports research grants from AbbVie, BMS and Lilly, outside the submitted work. Leticia Garcia-Montoya, Jacqueline L.Nam, Laurence Duquenne, Catalina Villota-Eraso, Andrea Di Matteo and Collette Hartley have no disclosures.

© 2022. The Author(s).

Figures

Fig. 1

Reasons for exclusion from analysis

Fig. 2

A Symptomatic joints at baseline in anti-CCP− and anti-CCP+ individuals. B Symptomatic joints at baseline in anti-CCP- and anti-CCP+ individuals who progressed to an IA. Symptomatic joints in > 50% of the subjects are highlighted in red

Fig. 3

Time for progression to IA according to anti-CCP titre and pain in hands/feet

Fig. 4

Proposed primary care anti-CCP positive pathway