Can a multivariable prediction model identify anti-CCP positive individuals at risk of rheumatoid arthritis among those with non-specific musculoskeletal symptoms in primary care?
Problem
A phase of immunologically imminent rheumatoid arthritis (RA) precedes the onset of clinical rheumatoid arthritis (RA), characterised by increased circulating anti-cyclic citrullinated peptide (anti-CCP) antibodies. Early identification in the pre-clinical phase of RA in primary care (PC), through targeted anti-CCP testing, could prompt secondary care referral for earlier diagnosis, achieving better long-term outcomes.
This study aimed to develop a model identifying those likely to be anti-CCP positive amongst people presenting to PC with non-specific musculoskeletal symptoms.
Approach
Participants were recruited across the UK between 2014 and 2020 to the Leeds ‘Co-ordinated Programme to Prevent Arthritis’, a prospective, observational cohort study. Participants were aged ≥18 years who presented to PC with non-specific musculoskeletal symptoms and no history of clinical synovitis.
Fifteen baseline predictors were considered: age; gender; smoking status; first degree relative (FDR) with RA; and patient reported pain in: neck; back; shoulders; elbows hips; wrists; thumbs; hand and/or fingers; knees; ankles; foot and/or toes. Participants were followed-up at 12 months to determine if they had developed RA.
Analysis was performed in R. Variable selection was carried out via LASSO logistic regression. Model performance was assessed using area under the receiver operating characteristic curve (ROC AUC), decision curve analysis was utilised to assess clinical utility. Internal validation was carried out via 200 bootstrap re-samples with replacement to estimate corrected model fit estimates.
Findings
Analysis included 6879 participants; 203 (2.95%) were anti-CCP positive. Thirteen predictors were retained (age and ankles omitted); scores for each predictor were: sex (male) [+3], FDR with RA [+3], smoking (ever) [+2], pain in back [-3], neck [-2], knee [-1], wrist [+4], foot/toes [+3], hand/fingers [+3], shoulder [+3], thumb [+1]. With a score of ≥11 (≥4% risk) for anti-CCP testing the ROC AUC was 0.65 (95% CI (0.61-0.69), corrected AUC=0.49). Choosing a threshold of 4% suggested that benefit of testing one anti-CCP positive patient is 24 times larger than the harm of testing one anti-CCP negative patient. Sensitivity and specificity were 38.42 and 81.88 and positive- and negative-predicted values were 6.06 and 97.76. The net benefit was 0.0040 (corrected=0.0026). This threshold resulted in 19% being tested, corresponding to 39% of all anti-CCP positive participants. Twelve-month follow-up data was available for 2480 participants, of those who would be tested using our model, 6.68% developed RA, compared with 1.94% if everyone was tested. Out of those tested who were anti-CCP positive 56.85% developed RA (amongst anti-CCP negative participants, 1.23% developed RA).
Consequences
Targeted use of anti-CCP testing in PC may prompt earlier identification of people at risk of RA. A qualitative intervention development study with three sequential phases (IDEAS in Primary Care model; abstract submitted) has been undertaken to support clinicians using this prediction model, alongside heath economic modelling to explore potential cost-effectiveness.