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Rheumatoid arthritis — clinical trials landscape

TL;DR — RA trials have moved from proving cytokine blockade to comparing strategies, intercepting preclinical disease, tapering sustained remission, testing tissue-guided selection and addressing RA-ILD. Trial registries are operational records, not evidence of benefit; COMPLETED means follow-up ended, UNKNOWN usually means the record is not current, and TERMINATED requires reading the reason. ClinicalTrials.gov v2 API queries on 2026-08-31 verified every NCT ID below. Prevention now has long-term contrasts: APIPPRA/ALTO retained a diminishing 4.9-month arthritis-free-survival advantage at four years, TREAT EARLIER was null overall at five years but positive in a risk-enriched ACPA-negative subgroup, and StopRA hydroxychloroquine was null at 36 months (Cope 2026, PMID 41576971; Mulligen 2026, PMID 42392130; Deane 2026, PMID 40884017). RA-ILD and biomarker trials remain small and often observational.

Registry interpretation

Field Meaning Common mistake
Overall status Recruitment/follow-up state Treating “completed” as positive
Phase Regulatory development stage Applying phase labels to observational studies
Primary outcome Prespecified main endpoint Substituting a favorable secondary endpoint
Enrollment Planned or actual sample Ignoring updates and attrition
Results posted Registry results module Assuming publication exists
Last update Sponsor record maintenance Interpreting UNKNOWN as a biological result

Verified trial and cohort map

NCT ID Registry title/short label Status returned 2026-08-31 Domain
NCT02778906 ARIAA abatacept in ACPA-positive arthralgia COMPLETED Prevention
NCT02603146 StopRA hydroxychloroquine strategy TERMINATED Prevention
NCT00124449 Abatacept versus placebo to assess prevention COMPLETED Prevention/early disease
NCT02092467 Tofacitinib versus TNF inhibitor safety COMPLETED Comparative safety
NCT01402661 CorEvitas RA drug safety/effectiveness registry ENROLLING_BY_INVITATION Real-world safety
NCT00224562 RATIO infections/lymphoma with TNF antagonists UNKNOWN Pharmacovigilance
NCT04078191 Tilmanocept imaging versus synovial CD206 TERMINATED Tissue/imaging biomarker
NCT05379322 Synovial biopsy predicting biologic response WITHDRAWN Precision treatment
NCT06737952 Cellular/molecular synovial tissue analysis NOT_YET_RECRUITING Tissue atlas
NCT00001375 Pathogenesis of early inflammatory synovitis COMPLETED Mechanism
NCT00147966 ARISE rituximab synovial effects COMPLETED Pharmacodynamic biopsy
NCT01374971 RA treatment and biopsy assessing certolizumab COMPLETED Pharmacodynamic biopsy
NCT03084419 APRIL abatacept in RA-ILD UNKNOWN Lung treatment
NCT05246293 Tofacitinib for RA-ILD UNKNOWN Lung treatment
NCT03297775 RA patients at risk for ILD RECRUITING Lung prediction
NCT05855109 RA-ILD screening-tool development COMPLETED Lung screening
NCT03616158 Longitudinal RA lung disease progression UNKNOWN Lung natural history
NCT04136223 RA-ILD progression characterization UNKNOWN Lung natural history
NCT06189495 Genakumab in CTD-ILD RECRUITING Lung treatment
NCT02901886 Intensive smoking cessation in RA UNKNOWN Modifiable risk
NCT01706874 Periodontal prophylaxis and RA activity COMPLETED Mucosal intervention

Prevention evidence linked to registrations

ARIAA randomized ACPA-positive people with MRI inflammation and found abatacept improved subclinical inflammation and reduced/delayed clinical RA during observation (Rech 2024, PMID 38364841; NCT02778906). APIPPRA/ALTO used a related but distinct high-risk population: one year of abatacept delayed progression for up to four years, but the arthritis-free-survival difference diminished to 4.9 months (95% CI 0.1–9.6) and post-treatment disease activity and patient-reported outcomes did not differ (Cope 2026, PMID 41576971). StopRA found clinical RA in 30.4% with hydroxychloroquine and 32.9% with placebo at 36 months (difference −5.8 percentage points, 95% CI −33.6 to 22.0; p=0.52) (Deane 2026, PMID 40884017; NCT02603146). Not every major trial has an NCT registration; identifiers from other registries are not converted into guessed NCT IDs here.

Strategy and tapering trials

TICORA, FIN-RACo, SWEFOT, RETRO and TARA changed how clinicians use existing drugs: scheduled escalation, early combination, and cautious tapering (Grigor 2004, PMID 15262104; Korpela 2004, PMID 15248204; van Vollenhoven 2009, PMID 19665644; Tascilar 2021, PMID 38297524; van Mulligen 2020, PMID 32482645).

Question Best established answer Remaining trial need
Tight control or routine care? Tight control superior Delivery in low-resource systems
Initial MTX or immediate biologic? MTX strategy for most High-risk biomarker subgroup
Imaging-targeted escalation? No added routine benefit Targeted discordant cases
Taper in sustained remission? Possible, but flare common Biomarker-guided taper
Stop all DMARDs? Minority sustain drug-free remission Define durable immune reset

Precision-treatment trials

R4RA is the key published template: it used synovial biopsy to compare rituximab with tocilizumab after TNF failure (Humby 2021, PMID 33485455). The withdrawn NCT05379322 and terminated NCT04078191 illustrate feasibility and sponsor/operational fragility in tissue-guided programs.

RA-ILD trial deficit

The RA-ILD registry landscape is dominated by cohorts, screening tools and small studies. This reflects phenotype heterogeneity, slow outcomes, competing joint-treatment needs and safety. Trials need centralized HRCT review, prespecified progressive-fibrosis criteria, FVC/DLCO trajectories, exacerbations, survival, joint outcomes and infection.

Interpretation rule

A registry record establishes that a study was registered; only results reporting and peer-reviewed analysis can establish what happened and how confidently it should change practice.

Mechanism scoreboard: successes, failures, and live registry programs

Mechanism/program Evidence or live status What it tests
Vagus-nerve modulation Early human work showed suppression of ex-vivo TNF and improved disease activity (Koopman 2016, PMID 27382171). RESET-RA randomized 242 advanced-therapy inadequate responders: ACR20 was 35.2% active versus 24.2% sham at 3 months (p=0.0209); related serious events were 1.6% and perioperative (Tesser 2026, PMID 41429981). Whether bioelectronic anti-inflammatory control can provide a non-drug treatment with durable net benefit.
BTK inhibition BMS-986142 failed both coprimary endpoints: week-12 ACR20 42% at 200 mg versus 31% placebo, difference 11.8% (95% CI −3.6 to 27.2); the 350-mg arm stopped for liver enzymes and lack of benefit (Conaghan 2023, PMID 38251590). Strong target rationale does not guarantee adequate tissue pharmacology or clinical efficacy.
GM-CSF receptor blockade Mavrilimumab 150 mg produced week-24 ACR20 73.4% versus 24.7% placebo, with DAS28-CRP change −1.90 versus −0.68 (Burmester 2017, PMID 28213566). A positive phase II signal requiring confirmation against active modern comparators and longer pulmonary safety follow-up.
GM-CSF versus TNF A 138-patient phase IIb comparison was not powered for superiority and found overlapping response estimates (Weinblatt 2018, PMID 28941039). Why exploratory head-to-head trials cannot establish a class hierarchy.
Implanted vagus stimulator extension Active, not recruiting; 14 participants (NCT04862117). Long-term device safety and durability in RA.
Afimkibart after TNF/JAK failure Recruiting phase 2; planned n=160 (NCT07137598). A novel advanced-therapy option in a clinically refractory population.
BMS-986528 Recruiting phase 1/2; planned n=84 refractory RA (NCT07412704). Early safety, dose, and proof of mechanism.
Inebilizumab/blinatumomab master protocol Recruiting phase 2; planned n=220 across autoimmune cohorts (NCT06570798). Depth and modality of B-cell depletion.
JAK dose tapering Recruiting phase 4; planned n=308 across baricitinib, tofacitinib, upadacitinib and filgotinib (NCT06687551). Whether targeted synthetic DMARD exposure can be reduced without unacceptable flare.
NKX019 cellular therapy Recruiting phase 1/2; planned n=240 across immune-mediated diseases (NCT06733935). Allogeneic CD19-directed NK-cell therapy after lymphodepletion.
CC-97540 CAR-T Active, not recruiting phase 1; planned n=270 across severe refractory autoimmune diseases (NCT05869955). Feasibility and safety of deep immune reset, with RA-specific efficacy still uncertain.
Surovatamig Recruiting phase 1; planned n=48 with RA or SLE (NCT07201558). Safety, pharmacokinetics and pharmacodynamics of a new immune engager.
PF-08154225 Not yet recruiting phase 1/2; planned n=54 across SLE, RA, inflammatory myositis and systemic sclerosis, with RA eligible in parts 1a/1b (NCT07782450). Safety and pharmacodynamic characterization in an explicitly multi-disease, non-RA-powered program.
MK-1045 Recruiting phase 1; planned n=21 across SLE and RA (NCT07363590). Dose-escalation safety and tolerability; no efficacy inference is possible from registration.

Registry status, enrollment and presence/absence of posted results were retrieved on 2026-08-31 and are mutable. None of the 29 previously tracked records had changed overall status or gained/lost a posted-results module since the audited 2026-08-30 snapshot. Multi-disease protocols can list RA without providing an RA-powered cohort; phase 1 enrollment is not evidence of efficacy. The most informative landscape includes negative trials such as BMS-986142 alongside positive programs, because selective attention to surviving mechanisms exaggerates translation efficiency.

Evidence map

This map adds directly adjacent evidence used to bound interpretation. Inclusion means the record informs this topic or a tightly linked decision; it does not imply that every study supports every conclusion on the page.

Adjacent evidence Relevance to this page
Greenblatt HK, et al. Preclinical rheumatoid arthritis and rheumatoid arthritis prevention. Curr Opin Rheumatol. 2020;32:289-296. (PMID 32205569) Adjacent evidence from classification-and-diagnosis.md, genetics-environment-and-mucosal-origins.md, preclinical-autoimmunity-and-prevention.md
van Heemst J, et al. HLA and rheumatoid arthritis. Ann Med. 2014. (PMID 24813459) Adjacent evidence from biomarkers-and-tissue-precision.md, classification-and-diagnosis.md, difficult-to-treat-and-refractory-ra.md, genetics-environment-and-mucosal-origins.md, overview.md, preclinical-autoimmunity-and-prevention.md, synovial-immunobiology.md
Petrovská N, et al. The pre-clinical phase of rheumatoid arthritis: from risk factors to prevention. Semin Immunopathol. 2021. (PMID 33746022) Adjacent evidence from genetics-environment-and-mucosal-origins.md, preclinical-autoimmunity-and-prevention.md
Haville S, et al. Pre-RA: can early diagnosis lead to prevention? Best Pract Res Clin Rheumatol. 2022. (PMID 34991984) Adjacent evidence from genetics-environment-and-mucosal-origins.md, preclinical-autoimmunity-and-prevention.md
Dumoulin QA, et al. Development of RA after methotrexate in ACPA-negative clinically suspect arthralgia: four-year TREAT EARLIER data. Lancet Rheumatol. 2024. (PMID 39303731) Adjacent evidence from genetics-environment-and-mucosal-origins.md, preclinical-autoimmunity-and-prevention.md
Frazzei G, et al. Prevention of rheumatoid arthritis: a systematic literature review. Autoimmun Rev. 2023. (PMID 36280095) Adjacent evidence from genetics-environment-and-mucosal-origins.md, overview.md, preclinical-autoimmunity-and-prevention.md
Lucchino B, et al. Mucosa-environment interactions in the pathogenesis of rheumatoid arthritis. Cells. 2019. (PMID 31295951) Adjacent evidence from epidemiology-and-burden.md, genetics-environment-and-mucosal-origins.md, preclinical-autoimmunity-and-prevention.md
Möller B, et al. Infectious triggers in periodontitis and the gut in RA: association and causality. Front Oral Health. 2020. (PMID 32582191) Adjacent evidence from genetics-environment-and-mucosal-origins.md, preclinical-autoimmunity-and-prevention.md
Dedmon LE. The genetics of rheumatoid arthritis. Rheumatology. 2020. (PMID 32638005) Adjacent evidence from classification-and-diagnosis.md, epidemiology-and-burden.md, genetics-environment-and-mucosal-origins.md, overview.md, preclinical-autoimmunity-and-prevention.md
Kadura S, et al. Rheumatoid arthritis-interstitial lung disease: manifestations, pathogenesis and management. Eur Respir Rev. 2021. (PMID 34168062) Adjacent evidence from classification-and-diagnosis.md, epidemiology-and-burden.md, extra-articular-and-comorbid-disease.md, genetics-environment-and-mucosal-origins.md, overview.md, preclinical-autoimmunity-and-prevention.md, ra-associated-interstitial-lung-disease.md, red-flags-and-safety-concerns.md
Kim Y, et al. Etiology and pathogenesis of rheumatoid arthritis-interstitial lung disease. 2023. (PMID 37833957) Adjacent evidence from extra-articular-and-comorbid-disease.md, genetics-environment-and-mucosal-origins.md, preclinical-autoimmunity-and-prevention.md, ra-associated-interstitial-lung-disease.md
Qi XY, et al. Gut microbiota in rheumatoid arthritis: mechanistic insights, biomarkers and translation. 2025. (PMID 40825448) Adjacent evidence from genetics-environment-and-mucosal-origins.md, preclinical-autoimmunity-and-prevention.md
Frade-Sosa B, et al. Neutrophils, neutrophil extracellular traps, and rheumatoid arthritis. 2023. (PMID 37867028) Adjacent evidence from genetics-environment-and-mucosal-origins.md, preclinical-autoimmunity-and-prevention.md
Aletaha D, et al. Precision medicine and management of rheumatoid arthritis. J Pers Med. 2020. (PMID 32276742) Adjacent evidence from genetics-environment-and-mucosal-origins.md, preclinical-autoimmunity-and-prevention.md
Bhamidipati K, et al. Precision medicine in rheumatoid arthritis. Nat Rev Rheumatol. 2022. (PMID 35248489) Adjacent evidence from biomarkers-and-tissue-precision.md, difficult-to-treat-and-refractory-ra.md, genetics-environment-and-mucosal-origins.md, preclinical-autoimmunity-and-prevention.md, synovial-immunobiology.md
Atzeni F, et al. Biomarkers in rheumatoid arthritis. Mediators Inflamm. 2017. (PMID 28825772) Adjacent evidence from biomarkers-and-tissue-precision.md, difficult-to-treat-and-refractory-ra.md, genetics-environment-and-mucosal-origins.md, preclinical-autoimmunity-and-prevention.md, synovial-immunobiology.md
Perera J, et al. Seropositive and seronegative RA phenotypes, biomarkers and synovium. 2024. (PMID 38727279) Adjacent evidence from biomarkers-and-tissue-precision.md, classification-and-diagnosis.md, difficult-to-treat-and-refractory-ra.md, genetics-environment-and-mucosal-origins.md, overview.md, preclinical-autoimmunity-and-prevention.md, synovial-immunobiology.md
de Pablo P, et al. Imaging tests predicting RA in unclassified arthritis. RMD Open. 2022. (PMID 34782180) Adjacent evidence from biomarkers-and-tissue-precision.md, classification-and-diagnosis.md, difficult-to-treat-and-refractory-ra.md, genetics-environment-and-mucosal-origins.md, overview.md, preclinical-autoimmunity-and-prevention.md, synovial-immunobiology.md
Mandl P, et al. Imaging for treat to target in RA. Rheumatology. 2019. (PMID 31518423) Adjacent evidence from biomarkers-and-tissue-precision.md, classification-and-diagnosis.md, conventional-dmards.md, difficult-to-treat-and-refractory-ra.md, epidemiology-and-burden.md, genetics-environment-and-mucosal-origins.md, guidelines.md, overview.md, preclinical-autoimmunity-and-prevention.md, synovial-immunobiology.md, treat-to-target-and-remission.md
He S, et al. Plasma protein biomarkers predating onset and treatment response in RA. 2025. (PMID 40691443) Adjacent evidence from biomarkers-and-tissue-precision.md, difficult-to-treat-and-refractory-ra.md, genetics-environment-and-mucosal-origins.md, preclinical-autoimmunity-and-prevention.md, synovial-immunobiology.md
Evidence-map records are listed in full below and were live-retrieved from PubMed in this build session.

Open questions

  • Which registry statuses represent genuinely active RA studies after direct sponsor confirmation?
  • Can prevention trials demonstrate sustained drug-free benefit, not only delay? (Rech 2024, PMID 38364841)
  • Will tissue-guided trials improve outcomes enough to justify biopsy burden? (Rivellese 2022, PMID 35589854)
  • Can pragmatic trials compare entire treatment sequences rather than single drugs?
  • What international platform can recruit adequately powered RA-ILD trials?

References

  1. Cope AP, et al. Long-term outcomes of abatacept in individuals at risk of developing rheumatoid arthritis (ALTO): a randomised, double-blind, placebo-controlled trial. Lancet Rheumatol. 2026;8:e171-e180. PMID 41576971
  2. Mulligen EV, et al. Long-term durability of a time-limited methotrexate intervention in patients with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative arthralgia at increased risk for rheumatoid arthritis (TREAT EARLIER): 5-year data from a double-blind, randomised, placebo-controlled trial. Lancet Rheumatol. 2026;8:e638-e649. PMID 42392130
  3. Deane KD, et al. A Phase 2 Trial of Hydroxychloroquine in Individuals at Risk for Rheumatoid Arthritis. Arthritis Rheumatol. 2026;78:809-820. PMID 40884017
  4. Rech J, et al. Abatacept inhibits inflammation and onset of rheumatoid arthritis in individuals at high risk (ARIAA): a randomised, international, multicentre, double-blind, placebo-controlled trial. Lancet. 2024;403:850-859. PMID 38364841
  5. Grigor C, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;364:263-9. PMID 15262104
  6. Korpela M, et al. Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease-modifying antirheumatic drugs: five-year experience from the FIN-RACo study. Arthritis Rheum. 2004;50:2072-81. PMID 15248204
  7. van Vollenhoven RF, et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial. Lancet. 2009;374:459-66. PMID 19665644
  8. Tascilar K, et al. Treatment tapering and stopping in patients with rheumatoid arthritis in stable remission (RETRO): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Rheumatol. 2021;3:e767-e777. PMID 38297524
  9. van Mulligen E, et al. Tapering towards DMARD-free remission in established rheumatoid arthritis: 2-year results of the TARA trial. Ann Rheum Dis. 2020;79:1174-1181. PMID 32482645
  10. Humby F, et al. Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial. Lancet. 2021;397:305-317. PMID 33485455
  11. Koopman FA, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2016;113:8284-9. PMID 27382171
  12. Tesser JRP, et al. Vagus nerve-mediated neuroimmune modulation for rheumatoid arthritis: a pivotal randomized controlled trial. Nat Med. 2026;32:369-378. PMID 41429981
  13. Conaghan PG, et al. Evaluation of BMS-986142, a reversible Bruton's tyrosine kinase inhibitor, for the treatment of rheumatoid arthritis: a phase 2, randomised, double-blind, dose-ranging, placebo-controlled, adaptive design study. Lancet Rheumatol. 2023;5:e263-e273. PMID 38251590
  14. Burmester GR, et al. A randomised phase IIb study of mavrilimumab, a novel GM-CSF receptor alpha monoclonal antibody, in the treatment of rheumatoid arthritis. Ann Rheum Dis. 2017;76:1020-1030. PMID 28213566
  15. Weinblatt ME, et al. A Randomized Phase IIb Study of Mavrilimumab and Golimumab in Rheumatoid Arthritis. Arthritis Rheumatol. 2018;70:49-59. PMID 28941039
  16. Greenblatt HK, et al. Preclinical rheumatoid arthritis and rheumatoid arthritis prevention. Curr Opin Rheumatol. 2020;32:289-296. PMID 32205569
  17. van Heemst J, et al. HLA and rheumatoid arthritis: how do they connect?. Ann Med. 2014;46:304-10. PMID 24813459
  18. Petrovská N, et al. The pre-clinical phase of rheumatoid arthritis: From risk factors to prevention of arthritis. Autoimmun Rev. 2021;20:102797. PMID 33746022
  19. Haville S, et al. Pre-RA: Can early diagnosis lead to prevention?. Best Pract Res Clin Rheumatol. 2022;36:101737. PMID 34991984
  20. Dumoulin QA, et al. Development of rheumatoid arthritis after methotrexate in anticitrullinated protein antibody-negative people with clinically suspect arthralgia at risk of rheumatoid arthritis: 4-year data from the TREAT EARLIER trial. Lancet Rheumatol. 2024;6:e827-e836. PMID 39303731
  21. Frazzei G, et al. Prevention of rheumatoid arthritis: A systematic literature review of preventive strategies in at-risk individuals. Autoimmun Rev. 2023;22:103217. PMID 36280095
  22. Lucchino B, et al. Mucosa-Environment Interactions in the Pathogenesis of Rheumatoid Arthritis. Cells. 2019;8:700. PMID 31295951
  23. Möller B, et al. Infectious Triggers in Periodontitis and the Gut in Rheumatoid Arthritis (RA): A Complex Story About Association and Causality. Front Immunol. 2020;11:1108. PMID 32582191
  24. Dedmon LE, et al. The genetics of rheumatoid arthritis. Rheumatology (Oxford). 2020;59:2661-2670. PMID 32638005
  25. Kadura S, et al. Rheumatoid arthritis-interstitial lung disease: manifestations and current concepts in pathogenesis and management. Eur Respir Rev. 2021;30:210011. PMID 34168062
  26. Kim Y, et al. Etiology and Pathogenesis of Rheumatoid Arthritis-Interstitial Lung Disease. Int J Mol Sci. 2023;24:14509. PMID 37833957
  27. Qi XY, et al. Gut microbiota in rheumatoid arthritis: Mechanistic insights, clinical biomarkers, and translational perspectives. Autoimmun Rev. 2025;24:103912. PMID 40825448
  28. Frade-Sosa B, et al. Neutrophils, neutrophil extracellular traps, and rheumatoid arthritis: An updated review for clinicians. Reumatol Clin (Engl Ed). 2023;19:515-526. PMID 37867028
  29. Aletaha D, et al. Precision medicine and management of rheumatoid arthritis. J Autoimmun. 2020;110:102405. PMID 32276742
  30. Bhamidipati K, et al. Precision medicine in rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2022;36:101742. PMID 35248489
  31. Atzeni F, et al. Biomarkers in Rheumatoid Arthritis. Isr Med Assoc J. 2017;19:512-516. PMID 28825772
  32. Perera J, et al. Clinical Phenotypes, Serological Biomarkers, and Synovial Features Defining Seropositive and Seronegative Rheumatoid Arthritis: A Literature Review. Cells. 2024;13:743. PMID 38727279
  33. de Pablo P, et al. Systematic review of imaging tests to predict the development of rheumatoid arthritis in people with unclassified arthritis. Semin Arthritis Rheum. 2022;52:151919. PMID 34782180
  34. Mandl P, et al. The role of ultrasound and magnetic resonance imaging for treat to target in rheumatoid arthritis and psoriatic arthritis. Rheumatology (Oxford). 2019;58:2091-2098. PMID 31518423
  35. He S, et al. A longitudinal cohort study uncovers plasma protein biomarkers predating clinical onset and treatment response of rheumatoid arthritis. Nat Commun. 2025;16:6692. PMID 40691443
  36. Rivellese F, et al. Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial. Nat Med. 2022;28:1256-1268. PMID 35589854