Table 2.

Prediction of future IA and RA in prospective studies of at-risk populations.

Publication, YearCountry /
Population
Study TypeNo. of Subjects and
Incident IA/RA
Key Findings
del Puente, 198815USA, Akimel O’Odham (Pima) peopleProspective cohort study2712 subjects; 70 (2.6%) with incident IA/RA after up to 19 yrs of follow-upThe highest rate of development of RA (48/1000 PYs) was in subjects with baseline RF titer of > 1:256.
Silman, 199216UKProspective cohort study370 unaffected FDRs from families with RA; 14 with incident RAIncident RA was highest in subjects with RF positivity.
van de Stadt, 201345The NetherlandsProspective study of individuals presenting to rheumatology clinics347 subjects with RF and/or ACPA positivity but no IA at baseline; 131 with incident IA/RA after a median of 12 mosA score was developed assigning 1 point for each of the following that were present: positive FDR status, no alcohol consumption (use of alcohol was protective), symptoms starting < 12 mos prior, intermittent symptoms, symptoms in upper and lower extremities, VAS of ≥ 50 mm, morning stiffness ≥ 60 mins, self-reported swelling in any joint; in addition, up to 4 points were assigned if both RF and ACPA were positive. In individuals with scores of ≥ 7, 74% developed IA/RA within 3 yrs.
de Hair, 201339The NetherlandsProspective study of ACPA+ and/or RF+ subjects55 subjects; 15 (27%) with incident IA after a median of 13 mosNonsmokers and those with normal body weight had the lowest rates of progression to IA/RA.
Ramos-Remus, 201576MexicoProspective study of unaffected FDRs of patients with RA819 FDRs; 17 (2.1%) with incident IA/RA over 5 yrsACPA positivity with or without concomitant RF positivity had PPVs of 58-64% for development of RA during follow-up.
Rakieh, 201534UKProspective study of ACPA+ (CCP2) subject with arthralgia referred to rheumatology clinics100 ACPA+ individuals; 50 with incident IA/RA after a median of 7.9 mosA score was developed assigning 1 point for each of the following: tender joints, morning stiffness > 30 mins, presence of the shared epitope, high levels of RF and/or ACPA, and the presence of US power Doppler findings in ≥ 1 joint. In individuals with the highest scores (≥ 2), > 41% developed IA/RA within 24 mos, and in individuals with scores of ≥ 4, 68% developed IA within 24 mos.
Burgers, 201774The Netherlands and SwedenProspective study of subjects with arthralgia178 subjects with arthralgia meeting EULAR criteria for CSA at baseline; 44 (18%) developed incident IA/RA after a median of 16 wksStudy to validate the EULAR definition for clinically suspect arthralgia.71 The presence of ≥ 3 of the following factors was ~84% sensitive and had a PPV of ~30% for IA/RA within 2 yrs: duration of onset of symptoms < 1 yr, symptoms in MCP joints, morning stiffness ≥ 60 mins, more severe morning symptoms, having an FDR with RA, and on examination, difficulty making a fist and tenderness with an MCP squeeze. However, PPV for IA was much less if the criteria were applied by a nonrheumatologist practitioner (PPV ~3%).
Tanner, 201978CanadaProspective cohort study of FDRs of patients with RA374 subjects; 10.9% were ACPA+ at baseline; 18 (4.8%) developed IA/RA after ~5 yrs of follow upACPA+/RF+ individuals at baseline developed IA at a higher rate/1000 PYs (97.1) than ACPA+/RF− (36.4), ACPA−/RF+ (7.2), and ACPA−/RF− (4.1). ACPA+/RF+ were just as likely to become autoantibody negative as developing IA after 5 yrs.
Gilbert, 202179SwitzerlandProspective cohort study of FDRs of patients with RA1458 subjects; ~5% were ACPA+ at baseline; ~17% were RF− IgM+As of 2021, 16 individuals had developed incident IA and were predominately ACPA+.
Bemis, 202177USAProspective cohort study of FDRs of patients with RA1780 subjects; 304 antibody + (17.1%) at baseline; 20 (15.3% of antibody +) developed IA after ~4.5 yrs of follow upACPA+/RF+ individuals at screening developed IA at a higher rate (38%) than ACPA+ alone (15%) and RF+ alone (9%). High level ACPA (ie, ≥ 2 × ULN) at screening was associated with the development of IA (HR 4.1).
Bergstedt, 202235USAProspective cohort study of ACPA+ individuals found through health-fair screening90 ACPA+ individuals; 26 (29%) developed IA after ~2 yrs of follow upThose who developed IA had a higher prevalence of SE (69% vs 38%). High level ACPA (≥ 2 × ULN) was higher in those who developed IA (85% vs 60%). Dual RF-IgA and RF-IgM+ was associated with IA (HR 2.9).
Duquenne, 202366UKProspective cohort study of individuals found through clinical referrals for joint symptoms455 ACPA+ (CCP2) subjects without baseline IA; 148 (~33%) developed clinical IA over a median follow-up of 223 wksDeveloped scoring systems to predict IA within 1 yr: A simple score used to triage referrals to secondary care, which included morning stiffness > 30 min, ACPA level, RF+, and elevated ESR. A score above the threshold had a PPV of ~28% for IA development within 1 yr. A comprehensive score used in secondary care which included age > 50 yrs, ever smoker, morning stiffness, ACPA level, RF+, SE+, ESR high, VAS global pain, HAQ score, US PD signal, US tenosynovitis+, US erosion+. A score above the threshold had a PPV of ~70% for IA development within 1 yr.
  • ACPA: anticitrullinated protein antibodies; CCP2: cyclic citrullinated peptide 2; CSA: clinically suspect arthralgia; ESR: erythrocyte sedimentation rate; EULAR: European Alliance of Associations for Rheumatology; FDR: first-degree relative; HAQ: Health Assessment Questionnaire; HR: hazard ratio; IA: inflammatory arthritis; MCP: metacarpophalangeal joints; PD: power doppler; PPV: positive predictive value; PY: person-year; RA: rheumatoid arthritis; RF: rheumatoid factor; SE: shared epitope; ULN: upper limit of normal; US: ultrasound; VAS: visual analog score.