Autoantibodies in the preclinical phase of RA
| Author, Year | Cohort | Cases (n) | Progression to arthritis (%) | Median duration from study entry to diagnosis of arthritis, months (IQR) | Median duration of follow-up, months (IQR) | Measured factors | Main result |
| de Bois et al, 199632 | Arthralgia (secondary care) | 52† | 10 (21) | NP | 12 | Presence of IgM-RF | RF predicts development of RA; PPV 50%, NPV 100%. |
| Bos et al, 201022 | ACPA+ and/or RF+ arthralgia (secondary care) | 147 | 29 (20) | 11 (5–17) | 28 (19–39) | Presence and level of IgM-RF and ACPA | Factors associated with arthritis development: –within all patients: ACPA (HR 6.0, 95% CI 1.8 to 20), but not RF –within ACPA+ patients: RF (HR 3.0, 95% CI 1.4 to 6.9) and high ACPA levels (HR 1.7, 95% CI 1.1 to 2.5). PPV for arthritis development within 2 years: ACPA-RF+ 6%, ACPA+RF− 16%, ACPA+RF+ 40%. |
| van de Stadt et al, 201128 | ACPA+ and/or RF+ arthralgia (secondary care) | 244 | 69 (28) | 11 (5–20) | 36 (18–60) | Reactivity of ACPA to five citrullinated peptides | Cox regression analysis within ACPA+ patients showed a trend between arthritis development and recognition of 2–5 peptides versus 0–1 peptides (HR 1.7, 95% CI 0.9 to 3.2). |
| Shi et al, 201333 | ACPA+ and/or RF+ arthralgia (secondary care) | 340 | 129 (38) | 12 (6–24) | 36 (20–52) | Presence and level of anti-CarP IgG antibodies | Anti-CarP antibodies, but not anti-CarP levels, predicted progression to RA, independent of ACPA and RF (HR 1.6, 95% CI 1.1 to 2.3). PPV for arthritis development: ACPA+ anti-CarP− 40%, ACPA+anti-CarP+ 58%. |
| Van de Stadt et al, 201323 | ACPA+ and/or RF+ arthralgia (secondary care) | 374 | 131 (35) | 12 (6–23) | 32 (13–48) | Presence and level of IgM-RF and ACPA | ACPA was associated with progression to arthritis when compared with RF+ACPA− patients: ACPA low + RF hour 2.7, 95% CI 1.3 to 5.6, ACPA high + RF hour 4.9, 95% CI 2.5 to 9.6, ACPA+RF+ hour 6.9, 95% CI 3.7 to 13.1. |
| de Hair et al, 201429 | ACPA+ and/or RF+ individuals at risk for RA (secondary care and public fairs) | 55‡ | 15 (27) | 13 (6–27) | 24 (14–47) | Presence and level of IgG ACPA and reactivity to 10 citrullinated peptides | Total number of citrullinated peptides recognised by ACPA was associated with arthritis development (HR 1.2, 95% CI 1.0 to 1.4). Proportion of ACPA+ patients and ACPA level was not different in patients with and without progression to arthritis. |
| Rakieh et al, 201527 | ACPA+ persons with aspecific musculoskeletal symptoms (primary and secondary care) | 100 | 50 (50) | 7.9 (0.1–52) | 20 (0.1–69) | IgM-RF and ACPA levels | A measurement combining high level of RF and/or ACPA was not associated with arthritis development (HR 1.5, 95% CI 0.5 to 4.5, independent of tenderness of small joints, morning stiffness, PD signal and SE). |
| Rombouts et al, 201531 | ACPA+ arthralgia (secondary care) | 183§ | 105 (57) | 12 (6–24) | 35 (21–52) | Fc glycosylation pattern of ACPA-IgG1 and total IgG1 | ACPA display decreased Fc galactosylation and increased fucosylation prior to the onset of RA. |
| Janssen et al, 201630 | ACPA+ and/or RF+ arthralgia (secondary care) | 34 | 14 (41) | 17 (5–35) | 40 (24–43) | Total Ig-RF and IgG-ACPA levels and ACPA reactivity to four citrullinated peptides | Within those who developed RA, ACPA and RF levels were not increased at time of diagnosis compared with 6 months before diagnosis. Patients with progression to arthritis had a broader IgG ACPA repertoire and more IgA reactivity for Fib1. |
| van Steenbergen et al, 201624 | Clinically suspect arthralgia (secondary care) | 150* | 30 (20) | 1.7 (0.8–4.1) | 17 (9–24) | IgM-RF and ACPA presence | In univariable analyses both ACPA and RF were associated with arthritis development (ACPA: HR 10, 95% CI 4.9 to 21; RF: HR 6.9, 95% CI 3.3 to 14). PPV for arthritis development within 1 year: ACPA 63%. |
| Nam et al, 201625 | Persons with aspecific musculoskeletal symptoms (primary care) | 2028 | 47 (2.3) | ACPA+ 1.8 (1.0–4.3) ACPA− 5.1 (2.9–14) | ACPA+ 12 (1.5–28) ACPA− 14 (13-22) | ACPA presence | RR for developing RA within 12 months in ACPA+ group was 67 (95% CI 32 to 138) and for IA it was 46 (95% CI 25 to 82). PPV of ACPA for development of RA was 42% and of IA 47%. |
| Ten Brinck et al, 201726 | Clinically suspect arthralgia (secondary care) | 241 | 44 (18) | 3.6 (1.2–4.8) | 103 (81–114) | IgM-RF, ACPA, anti-CarP presence and ACPA and IgM-RF level | ACPA, RF and anti-CarP were associated with arthritis development, but only ACPA was independently associated (HR 5.3, 95% CI 2.0 to 14). RF levels but not ACPA levels were associated with progression to arthritis. PPV for arthritis development within 2 years: ACPA-RF+ 38%, ACPA+RF− 50%, ACPA+RF+ 67%. |
Patients in refs 22 23 28 29 31 33 and in refs 24 26 are derived from the same cohort. Studies depicted in grey have provided absolute risks.*One patient who developed gout during follow-up was excluded from analyses.
†Five patients were lost to follow-up. In this study there was no correction for the presence of ACPA.
‡IgM-RF-positive and/or ACPA-positive individuals with arthralgia (n=34) or with a first-degree relative with RA with or without arthralgia (n=16). Information on family history of RA was missing for five patients in whom no arthritis developed.
§Patients in this study were selected based on high ACPA serum level (median 419 U/mL, IQR 131.0–1216.0).
ACPA, anticitrullinated protein antibodies; anti-CarP, anticarbamylated protein; IA, inflammatory arthritis; NP, not provided; NPV, negative predictive value; PD, power Doppler; PPV, positive predictive value; RA, rheumatoid arthritis; RF, rheumatoid factor.