A total of 6780 individuals were recruited from 312 primary care practices throughout the UK. Among these, 193 (2.84%) had a positive anti-CCP test and 6587 tested negative (97.15%). The final data set consisted of 151 anti-CCP+ individuals (out of whom 116 physically attended CAH for periodic assessments) and 5640 anti-CCP− subjects. Figure 1 shows reasons for exclusion from the analysis.
Anti-CCP positive individuals
Mean age was 52 (18–83) years, and the majority were female (62%). Of the 151 anti-CCP+, 65% (98/151) were anti-CCP+ high level and 35% (53/151) were anti-CCP+ low level (Table 1).
Half of all anti-CCP+ individuals reported a family history of RA (53%), and most of them (63%) were either previous or current smokers. Forty-five percent of anti-CCP+ individuals (68/151) progressed to IA, and 84% did so in less than 12 months. The mean time of progression was 45 weeks [range 2–494 weeks; median 17 weeks (IQR 8.25–43.00)], and the mean time of follow-up was 105 weeks (range 2–560 weeks). Of the 68 progressors, 63 met the 2010 ACR/EULAR criteria for RA , 2 were diagnosed with polymyositis, 2 with undifferentiated IA and 1 with spondyloarthritis. Figure 2 shows the most frequently reported symptomatic joints at baseline.
Subjects were classified into two groups according to their anti-CCP level (Table 1). The majority of low-level individuals were women; their mean age was lower and they had a lower progression rate. There were no significant differences between the groups regarding smoking status and family history of RA; however, smoking exposure was higher among anti-CCP+ high level males (70%) compared with anti-CCP+ high level females (60%). The most striking difference was the proportion of progressors: 62% among the anti-CCP+ high level individuals vs 13% among the low-level ones (P < 0.001).
In a multivariable model, high anti-CCP+ level [odds ratio (OR) 9.42; 95% confidence interval (CI) (3.13–28.30), P < 0.001], hand pain [OR 2.74; 95% CI (1.03–7.27), P = 0.043] and foot pain [OR 4.10; 95% CI (1.59–10.54), P = 0.003] were predictive of disease progression (Table 2).
In fact, absence of hand and foot pain had a negative predictive value (NPV) of 85.4% [95% CI (72.1–92.9), P = 0.001] for the development of IA. If the subject also had low anti-CCP+ level, the NPV increased to 95.8 % [95% CI (78.6% to 99.3%), P = 0.001]. For individuals with pain in either hands or feet and a high anti-CCP level, the positive predictive value (PPV) was 69.1% [95% CI (63.9% to 73.9%), P < 0.001].
The rate of progression to IA also varied depending on the presence of pain in hands/feet and the anti-CCP level (Fig. 3). Patients with a low anti-CCP level and no pain in hands/feet had the lowest progression rate, followed by those with low level and pain in hands/feet [hazard ratio (HR) 5.63; 95% CI (0.69–45.95), P = 0.107], individuals with a high anti-CCP level but no pain in hands/feet [HR 6.65; 95% CI (0.77–57.13), P = 0.084] and finally those with a high anti-CCP level and pain in hands/feet [HR 23.53; 95% CI (3.21–172.34), P = 0.002].
Patients without pain in hands/feet (7/68) had a slower progression to IA [mean 125 weeks, (SD 175.01), median 40 weeks (IQR 16–185)] compared with progressors with pain in these joints (61/68) [mean 36.87 weeks (SD 64.29), median 14 weeks (IQR 7.50–38)].
Regardless of the anti-CCP level, all the anti-CCP+ progressors without pain in either hands or feet (7/68) had other additional risk factors: smoking exposure (7/7) and/or family history of RA (6/7).
Additional univariable and multivariable analyses were performed to assess potential association between baseline MSK diagnosis (carpal tunnel syndrome, rotator cuff pathology, trigger finger, tennis elbow and osteoarthritis) and the development of IA; however, none of them was statistically significant (Supplementary Table 1).
Finally, there were no differences in the proportion of progressors between the anti-CCP+ participants who were regularly attending clinic at CAH and those who remained under GP care [43% (50/116) and 51% (18/35) of progressors respectively, P = 0.386].
Anti-CCP negative individuals
Mean age of anti-CCP negative individuals was 52 (16–91, SD 14.7) years, and 72% were female. Thirty eight percent reported having a FDR with RA and 38% were either current or former smokers. A total of 5678 individuals returned their 12-month questionnaires, of whom 239 reported progression to IA (4.2%). The disease status of 38/239 individuals could not be confirmed by a GP; therefore, only 201/239 were included in the analysis. Of these 201, GPs discounted IA in 148 participants and confirmed IA in 53, representing 0.93% (53/5640) of progressors among all anti-CCP negative individuals.
Twenty one of these 53 progressors were diagnosed with RA; 13 with spondyloarthritis, 11 with polymyalgia rheumatica (requiring DMARDs for joint swelling), 3 with polymyositis, 3 with systemic lupus erythematosus and 2 with systemic sclerosis. Only progression (yes/no) to IA within the first 12 months was recorded, and therefore, no data are available regarding the mean time of progression.
Figure 2 shows the most symptomatic joints at baseline. Progressors had a higher percentage of symptomatic joints and a higher number of other MSK diagnoses such as carpal tunnel syndrome (CTS), rotator cuff pathology and osteoarthritis (Supplementary Table 2).
Multivariable analysis (Table 3) showed that hand [OR 2.17; 95% CI (1.17–5.39), P = 0.018] and knee pain [OR 2.65; 95% CI (1.47–6.25), P = 0.003] were associated with the development of IA within the following 12 months. Older age showed only a slightly higher risk for IA [OR 1.04; 95% CI (1.02–1.07), P < 0.001].
RA was the most frequent diagnosis among the anti-CCP− progressors, and univariable analysis showed that pain in hands [OR 5.21; 95% CI (1.53–7.69), P = 0.008], thumbs [OR 2.87; 95% CI (1.19–6.93), P = 0.019], older age [OR 1.04; 95% CI (1.01–1.07), P = 0.026] and CTS [OR 3.49; 95% CI (1.40–8.67), P = 0.007] were associated with a higher risk of progression to RA (Supplementary Table 3). Multivariable analysis could not be performed to assess predictors of RA in anti-CCP− individuals due to the low number of patients per variable.
Based on the results of the study, Fig. 4 has been elaborated to provide clear guidance for primary care physicians attending patients with a new non-specific MSK complaint, who test positive for anti-CCP antibodies.