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Peer-reviewedCC BY 4.0RMD Open

Frequency and predictors of disease progression in contemporary ACPA-negative undifferentiated arthritis in a treated-to-target early arthritis clinic

  • Ludovico De Stefano1,2
  • Elena Manna1,2,3
  • Clelia Zampaglione1,2
  • Federica Sabatelli1,2
  • Emmanuele Guadalupi1,2
  • Garifallia Sakellariou1,4
  • Antonio Manzo1,2
  • Carlomaurizio Montecucco1
  • Serena Bugatti1,2
4 affiliations
  1. 1Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
  2. 2Division of Rheumatology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
  3. 3S.C. Reumatologia, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
  4. 4Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy
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Abstract

Objectives: Since the introduction of the 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology (EULAR) criteria, undifferentiated arthritis (UA) has become predominantly seronegative and heterogeneous, with poorly defined predictors of persistence. We assessed rheumatoid arthritis (RA) development and treatment intensification in contemporary anticitrullinated protein antibodies (ACPA)-negative UA managed under a standardised treat-to-target protocol.

Methods: Consecutive ACPA-negative patients with UA enrolled in the Pavia Early Arthritis Clinic (2011–2019) were analysed. UA was defined as clinical synovitis not fulfilling 1987 or 2010 RA criteria and without alternative diagnosis at baseline or within 6 months. All patients started hydroxychloroquine; escalation was driven by persistent disease activity. Outcomes over 24 months were RA development and the composite outcome of RA development or treatment intensification.

Results: Among 402 patients, arthritis was predominantly hand-restricted (75.1%), less often combined hand/large-joint (19.2%) or isolated large-joint (5.7%). RA developed in 13.1% of the patients, whereas 38.1% developed RA or required treatment intensification. Combined hand and large-joint arthritis independently predicted RA development (adjusted OR 2.68, 95% CI 1.29 to 5.57) and the composite outcome (adjusted OR 3.32, 95% CI 1.77 to 6.24). C reactive protein (CRP) elevation and pain burden were associated with treatment intensification. Classification tree analysis identified large-joint involvement as the first discriminator; together with the no-large-joint/CRP >0.5 mg/dL branch, it captured 64% of events, with positive predictive value 48% and negative predictive value 72%.

Conclusions: In contemporary ACPA-negative UA, progression is driven by anatomical joint distribution rather than generic disease activity. Combined hand/large-joint involvement identifies a high-risk phenotype, while CRP refines risk in clinically milder branches.

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Cite

BibTeXRIS
BibTeX
@article{stefano2026frequency,
  title = {{Frequency and predictors of disease progression in contemporary ACPA-negative undifferentiated arthritis in a treated-to-target early arthritis clinic}},
  author = {Ludovico De Stefano and Elena Manna and Clelia Zampaglione and Federica Sabatelli and Emmanuele Guadalupi and Garifallia Sakellariou and Antonio Manzo and Carlomaurizio Montecucco and Serena Bugatti},
  journal = {RMD Open},
  year = {2026},
  month = oct,
  doi = {10.1136/rmdopen-2026-007443},
  url = {https://doi.org/10.1136/rmdopen-2026-007443},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Frequency and predictors of disease progression in contemporary ACPA-negative undifferentiated arthritis in a treated-to-target early arthritis clinic
AU  - Ludovico De Stefano
AU  - Elena Manna
AU  - Clelia Zampaglione
AU  - Federica Sabatelli
AU  - Emmanuele Guadalupi
AU  - Garifallia Sakellariou
AU  - Antonio Manzo
AU  - Carlomaurizio Montecucco
AU  - Serena Bugatti
PY  - 2026
DA  - 2026/10/27
JO  - RMD Open
DO  - 10.1136/rmdopen-2026-007443
UR  - https://doi.org/10.1136/rmdopen-2026-007443
AB  - Objectives: Since the introduction of the 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology (EULAR) criteria, undifferentiated arthritis (UA) has become predominantly seronegative and heterogeneous, with poorly defined predictors of persistence. We assessed rheumatoid arthritis (RA) development and treatment intensification in contemporary anticitrullinated protein antibodies (ACPA)-negative UA managed under a standardised treat-to-target protocol.  Methods: Consecutive ACPA-negative patients with UA enrolled in the Pavia Early Arthritis Clinic (2011–2019) were analysed. UA was defined as clinical synovitis not fulfilling 1987 or 2010 RA criteria and without alternative diagnosis at baseline or within 6 months. All patients started hydroxychloroquine; escalation was driven by persistent disease activity. Outcomes over 24 months were RA development and the composite outcome of RA development or treatment intensification.  Results: Among 402 patients, arthritis was predominantly hand-restricted (75.1%), less often combined hand/large-joint (19.2%) or isolated large-joint (5.7%). RA developed in 13.1% of the patients, whereas 38.1% developed RA or required treatment intensification. Combined hand and large-joint arthritis independently predicted RA development (adjusted OR 2.68, 95% CI 1.29 to 5.57) and the composite outcome (adjusted OR 3.32, 95% CI 1.77 to 6.24). C reactive protein (CRP) elevation and pain burden were associated with treatment intensification. Classification tree analysis identified large-joint involvement as the first discriminator; together with the no-large-joint/CRP >0.5 mg/dL branch, it captured 64% of events, with positive predictive value 48% and negative predictive value 72%.  Conclusions: In contemporary ACPA-negative UA, progression is driven by anatomical joint distribution rather than generic disease activity. Combined hand/large-joint involvement identifies a high-risk phenotype, while CRP refines risk in clinically milder branches.
SN  - 2056-5933
ER  -