Delayed Identification of RA in Patients With Autoantibody Negativity

Rheumatoid factor – laboratory analysis performed on a blood sample that is extracted from a vein in the arm using a hypodermic needle and vacutainer.
Study authors noted an increase in time-to-referral for patients with rheumatoid arthritis with autoantibody negativity.

Patients with rheumatoid arthritis (RA) with autoantibody negativity were found to have a higher risk for delayed identification of their condition and consistent burden of severe disease, according to a letter published in the Annals of the Rheumatic Diseases.

Although early identification and treatment of RA can help slow disease progression and reduce joint damage, patients are not always referred to a rheumatologist within the recommended 12 weeks of symptom-onset. Furthermore, current RA classification criteria that are heavily weighted on autoantibodies may prevent early recognition of patients with seronegativity.

Authors of the current study examined changes over time in diagnostic delay and clinical presentation in patients with RA with autoantibody positivity and -negativity.

Patients with RA who were hospitalized to an early arthritis clinic between 2005 and 2017 were included in the study. Rheumatoid arthritis was determined using the 1987 American College of Rheumatology (ACR) criteria before December 2010 and the 2010 ACR/European Alliance of Associations for Rheumatology (EULAR) criteria thereafter. The time between symptom-onset and referral and clinical characteristics were compared across different time periods and between patients who tested negative vs positive for rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA).

A stable percentage of patients with autoantibody positivity (41%-44%) were referred within 12 weeks during the study period. The number of swollen joints and C-reactive protein levels at presentation decreased between the 2005 and 2007 and 2014 and 2017 time periods (-5.6 and -1.1 mg/dL, respectively), indicating that these patients presented with milder disease in recent years.

Patients who tested seronegative-positive were more likely to experience a delay in diagnosis. The percentage of patients referred within 12 weeks decreased from 37.9% between 2005 and 2007 to 25.6% between 2014 and 2017 (P =.08). Among patients with high disease activity, identification within 12 weeks decreased from 44.5% before 2010 to 31% after 2010 (P =.09). Study authors noted an improvement in inflammatory features, such as swollen joints, among these patients. However, patient-reported outcomes of pain and patient global assessment remained constant, suggesting that these patients were burdened by severe disease.

The study authors concluded, “Such changing phenotype of autoantibody-negative RA arises from a number of concomitant factors which have only partially been explored, including delayed referral from primary care, requirement of more severe inflammation to fulfil the RA criteria, and lower sensitivity of current classification tools. Interventions that specifically aid the early and accurate identification of autoantibody-negative patients with RA therefore appear an urgent need.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


De Stefano L, D’Onofrio B, Sakellariou G, Manzo A, Montecucco C, Bugatti S. Progressive increase in time to referral and persistently severe clinical presentation over the years in autoantibody-negative patients with rheumatoid arthritis in the setting of an early arthritis clinic. Ann Rheum Dis. Published online April 29, 2022. doi:10.1136/annrheumdis-2022-222264