Is Seronegative Rheumatoid Arthritis True Rheumatoid Arthritis?

A Nationwide Cohort Study

Kirsi Paalanen; Kari Puolakka; Elena Nikiphorou; Pekka Hannonen; Tuulikki Sokka


Rheumatology. 2021;60(5):2391-2395. 

In This Article

Abstract and Introduction


Objectives: The classification of seronegative arthritides can be challenging. Our aim was to examine the incidence of SpA diagnosis among patients initially diagnosed as seronegative RA.

Methods: Using nationwide Finnish registers from social insurance institutions, we identified all adult patients who were diagnosed with incident seronegative RA [International Classification of Diseases (ICD)-10 code M06] from 1 January 2000 to 31 December 2014. The patients whose diagnoses subsequently changed to the ICD-10 codes of SpA (M07, M45, M46, K50 and K51) were identified in the national care register, until 31 December 2016.

Results: A total of 9784 adult seronegative RA patients were identified. Of these, 564 patients had their diagnosis subsequently changed to SpA: 275 (48.7%) patients with PsA, 245 (43.4%) patients with axial SpA and 44 (7.8%) patients with diagnoses related to IBD. The cumulative incidence of SpA diagnoses in 15 years was 10.4% (95% CI 8.9, 12.1) and 8.1% (95% CI 7.1, 9.3) in men and women, respectively.

Conclusion: This study calls for vigilance in seronegative RA patients, especially those with more atypical presentations, since the diagnosis could change. The possibility of SpA diagnosis should be considered and specifically looked for, as this could impact on management and response to treatment.


Seronegative RA has long been recognized as a phenotype of RA without the presence of RF, and more recently ACPAs. However, seropositive and seronegative RA seem to 'behave' differently during the course of illness and in various ways.[1]

Published studies support disparate disease mechanisms in seropositive vs seronegative RA, with different genetic and environmental risk factors.[2–4] Some studies implicate that seronegative patients may present with more severe clinical manifestations at baseline than seropositive patients, and in fact the current classification criteria require high disease activity in seronegative cases.[5,6] On the other hand, in studies involving both early RA and undifferentiated arthritis (UA) patients, seronegative patients seem to have better prognosis in spite of higher disease activity at disease onset.[5,7] Concerning the risk of radiographic progression, several studies report it to be lower in seronegative patients, including a long-term follow-up study of RA patients over 15–20 years.[7–9] The findings concerning the treatment outcomes between seronegative and seropositive patients vary across the studies reviewed.[6,10,11] Despite the aetiopathological and clinical differences between seronegative and seropositive RA patients, both clinical RA trials and real-life cohort studies have included up to a third seronegative patients.[9,12]

Due to the heterogeneous nature of seronegative arthritides it is impossible predict the prognosis of these patients at disease onset. Some patients may require intense and long-standing therapy with DMARDs, but many do not develop chronic or destructive inflammatory disease in the long run. Since there is no differential diagnostic test available for this heterogeneous group of arthritides, it is imperative that these patients are followed up closely, observing disease course and evolution to enable stricter classification.

Our previous study indicated that during a 10-year follow-up, a majority of the patients in a clinical cohort who were originally diagnosed as seronegative RA could be classified with a more specific rheumatic disease, including a quarter of patients who were reclassified as SpA cases.[1] In the current study we aimed to evaluate the nationwide incidence of new SpA diagnoses among patients initially diagnosed as seronegative RA in Finland by using national registry data.