Box 2.

Summary of published trials to prevent/delay incident clinical RA in at-risk populations^*

Study	Inclusion criteria	Study design and intervention	Primary outcome	Major findings
Bos et al 2010	RF and/or ACPA positive shared epitope positive; arthralgia	RCT; dexamethasone 100 mg IM x 2 doses vs placebo	Incident clinical IA	17/83 (21%) developed IA after a median follow-up of 26 months; no difference between arms (dexamethasone 21% vs placebo 20%); Dexamethasone use associated with decreased autoantibody levels
Gerlag et al 2019 (PRAIRI)	RF and ACPA positive; CRP >0.6 mg/L; arthralgia	RCT; rituximab 1000 mg x 1 dose (and steroid) vs placebo	Incident clinical IA	30/81 (37%) developed IA after a mean follow-up of 29 months; no significant difference in overall rates of IA between arms (rituximab 14/41 (34%), placebo 14/40 (40%)); rituximab associated with delay of onset of IA
van Boheemen et al 2021 (StapRA)	RF and ACPA positive or ACPA >3x ULN; arthralgia	RCT; atorvastatin 40 mg/day x 3 years vs placebo	Incident clinical IA	15/62 (24%) developed IA after a median follow-up of 14 months; no significant difference between arms (atorvastatin 9/31 (29%) vs placebo 6/31 (19%)
Krijbolder et al 2022 (TREAT EARLIER)	Arthralgia and MRI evidence of joint inflammation but without clinical swollen joint; RF/ACPA not required for inclusion although 33% of participants were RF and/or ACPA positive	RCT; methylprednisolone 120 mg x 1 dose and methotrexate up to 25 mg/week x 1 year vs placebo; 1-year post-drug follow-up	RA by 2010 criteria present at 2 time points 2 weeks apart	44/236 (~19%) developed RA over the 2 years of the trial; no significant differences between arms (methotrexate 23/119 (19%), placebo 21/117 (18%); decreased measures of physical function, pain and MRI inflammation in MTX treated group. The highest rate of RA development was within ACPA+ individuals (27/54=50%), although there was no significant difference in rates between arms at 2 years.
Hahn et al 2022 (VITAL)	Individuals without cancer or cardiovascular disease	RCT; omega-3 fatty acid (1000 mg/day) and/or vitamin D (2000 IU/day) vs placebo x 5 years	Incident autoimmune disease (including RA) by chart review	Vitamin D supplementation for five years, with or without omega-3 fatty acids, reduced aggregate incidence of autoimmune disease, including RA, by ~22%.
Rech et al 2024 (ARIAA)	ACPA positive and MRI evidence of joint inflammation	RCT; abatacept 125 mg SQ weekly x 6 months vs placebo; 12-month post-drug follow-up	MRI inflammatory parameter improvement; clinical RA	At 18 months there was significant MRI improvement in abatacept arm compared to placebo (28/49 (57%) vs 14/49 (29%)). At 18 months there was also significantly less progression to clinical RA in abatacept arm compared to placebo (17/49 (35%) vs 28/49 (57%)).
Deane et al 2022 (StopRA)**	ACPA >=2x ULN	RCT; hydroxychloroquine 200–400 mg/day x 1 year versus placebo; 2 years post-drug follow-up	RA by 2010 criteria	In preliminary analyses, 43/144 (~30%) developed RA over the 3 years of the study; no significant differences between arms (24/71 (34%), placebo 26/73 (36%); trial halted and final analyses pending
Cope et al 2024 (APIPPRA)	ACPA+RF positive or ACPA >=3x normal and arthralgia	RCT; abatacept 125 mg weekly injection x 1 year versus placebo; 1-year post-drug follow-up	RA by 2010 criteria	At 2 years, 65/213 (~31%) of participants developed RA by 2010 criteria; 25% in abatacept arm and 37% in placebo arm. This resulted in differences in mean arthritis-free survival time between arms of ~99 days (p=0.002). In exploratory analyses, the highest risk for progression was individuals with multiple positive autoantibodies; this group also had the best response to abatacept.

^*While the inclusion criteria varied across studies, across the studies the participants could not have clinical RA at baseline defined as the presence on physical examination of a swollen joint consistent with synovitis.

^**The results from StopRAhave only been presented in abstract form.

Abbreviations: RA=rheumatoid arthritis; ACPA=antibodies to citrullinated protein antigens; RF=rheumatoid factor; RCT=randomized controlled trial; ULN=upper limit of normal; SQ=subcutaneous; MRI magnetic resonance imaging; MTX=methotrexate; IM=intramuscular; IA=inflammatory arthritis; IU=international units