Background/Purpose:

Evidence supports a therapeutic window of opportunity in early rheumatoid arthritis (RA), during which DMARD therapy most effectively improves clinical outcomes. The 2010 ACR/EULAR classification criteria for RA require that seronegative (i.e., RF- and ACPA-) patients have more joint involvement at diagnosis than patients who are seropositive (i.e., RF+ and/or ACPA+). We hypothesized that seronegative patients experience a delay in diagnosis and, thus, a delay in treatment initiation when compared with seropositive patients, potentially causing them to miss the therapeutic window of opportunity.

Methods:

A retrospective study was performed of a population-based cohort of patients with incident RA between 2009-2013 who fulfilled either the 1987 or 2010 classification criteria. A trained nurse abstractor unaware of the hypothesis collected data from the complete medical records. Patients were classified as either seronegative or seropositive as above. Time to fulfillment of both 1987 and 2010 classification criteria, first treatment with DMARD, and first remission were calculated from the time of first documented joint swelling. Health Assessment Questionnaire (HAQ), Disease Activity Score 28 (DAS28-CRP), and Simplified Disease Activity Index (SDAI) were compared between the groups. Remission was defined according to the 2011 ACR/EULAR Boolean-based definition.

Results:

156 patients were included; 113 were seropositive and 43 seronegative. Age, sex, smoking status, and obesity did not differ between groups. Median time from first documented joint swelling to fulfillment of the 1987 (100 vs. 3 days, p=0.003) and 2010 (58 vs. 0 days, p=0.011) criteria was significantly longer in seronegative than seropositive patients. The median time from first documented joint swelling to first DMARD was also significantly longer in seronegative patients (129.5 vs. 16 days, p=0.003). Methotrexate was the first DMARD for 97 patients (62%), with no significant differences between groups.

Patients were followed for a median of 4.9 years, during which disease activity measures were available for a median of 7 visits per patient, with no significant differences between groups. Time to first biologic DMARD was similar between the groups. Seronegative patients experienced persistently higher DAS28-CRP (mean difference: 0.46, p=0.027), SDAI (mean difference: 4.9, p=0.009), and HAQ disability index (mean difference: 0.25, p=0.020) over time, adjusting for age, sex and time from fulfillment of 2010 criteria. Time to first remission was later in seronegative than seropositive patients (hazard ratio: 0.47, 95% CI 0.24, 0.94). At 5 years after fulfilment of 2010 criteria, fewer seronegative than seropositive patients achieved ≥1 remission (32 vs. 50%, p=0.034).

Conclusion:

Patients with seronegative RA experience delay in diagnosis, according to both the 1987 and 2010 classification criteria, and delay in initiation of DMARD therapy. Patients with seronegative RA also experience persistently higher disease activity and delayed remission, suggesting that these patients miss the therapeutic window of opportunity more frequently than patients with seropositive RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/delay-of-diagnosis-and-treatment-in-seronegative-rheumatoid-arthritis-missing-the-window-of-opportunity/