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Starting therapy early more than doubled the likelihood that patients with seronegative rheumatoid arthritis (RA) would respond to treatment with a disease-modifying anti-rheumatic drug (DMARD), analysis of data from a French cohort found.

On a multivariate analysis, the only factor that was associated with a good or moderate response to DMARD treatment at 1 year was starting treatment within 3 months of symptom onset, with an odds ratio of 2.41 (95% CI 1.07-5.42, P=0.03), according to Cédric Lukas, MD, of Montpellier University, and colleagues.

This finding supported what for their entire cohort -- seropositive and seronegative alike -- that an early start to treatment was crucial to response in RA. "We confirmed that seronegative RA does not greatly differ from overall RA in terms of both therapeutic response and structural and functional prognosis and, most importantly, that the usual and consensually recommended concepts of therapeutic management should not be applied differently in these patients," they wrote in .

Seronegative RA, or the absence of rheumatoid factor (RF) and/or anticitrullinated protein antibodies (ACPA), has typically been considered a distinct entity with a less severe course and more favorable outcome than seropositive disease. It also can be challenging to diagnose, and first-line treatment with methotrexate is less often promptly initiated despite guideline recommendations. Moreover, the influence of autoantibodies on treatment response has been unclear.

Therefore, Lukas and colleagues looked at 1-year outcomes among 172 seronegative patients in their ESPOIR cohort, to identify factors that were associated with good or moderate responses (vs no response) according to the criteria of the European League Against Rheumatism (EULAR). These criteria reflect the change over time in the Disease Activity Score in 28 joints (DAS28).

Patients' mean age was 50, and 80% were women. Mean tender joint count was 11.7, swollen joint count was 9.0, and the majority were classified as having high disease activity, with mean baseline score being 5.5 on the DAS28. During the first year after diagnosis, 57% of patients were prescribed methotrexate, 21.5% were given hydroxychloroquine, 12.8% received sulfasalazine, and 7% were given leflunomide. Only a small minority received treatment with other agents including biologics.

At 1 year, 66% of patients had a good or moderate EULAR response. On a univariate analysis, good or moderate responses were associated with a baseline swollen joint count of seven or more, treatment initiation within 3 months of the onset of synovitis, erythrocyte sedimentation rate, C-reactive protein level, and a Health Assessment Questionnaire Disability Index (HAQ-DI) of ≥1. Only early treatment remained significant in the multivariate analysis.

There were no significant differences in responses at 1 year when the use of methotrexate and/or leflunomide was compared with the use of other second-line agents such as hydroxychloroquine.

The researchers then considered predictors of functional disability and radiographic changes at year 1.

They found that predictors of functional disability, defined as a HAQ-DI >0.5, included a HAQ-DI >1 at baseline (OR 6.59, 95% CI 3.29-13.2, P<0.001) and active smoking (OR 2.59, 95% CI 1-6.69, P=0.05). Factors that were protective were female sex (OR 0.28, 95% CI 0.10-0.79, P=0.02), and baseline erythrocyte sedimentation rate >15 (OR 0.45, 95% CI 0.20-0.98, P=0.05).

For structural progression, they found that 10% of patients had an increase of at least 1 point on the total Sharp score at year 1 and 6% had a progression of ≥5 points. On a multivariate analysis, the presence of erosions at baseline was associated with an increased likelihood of radiographic progression of at least 1 point, while the risk was lower for patients with ≥10 tender joints at baseline.

The only factor that was associated with progression of 5 points on the Sharp score was the presence of erosions at baseline (OR 5.42, 95% CI 1.14-25.7, P=0.03).

The risk of structural progression being strongest among patients who already had visible erosions on radiographs of the hands and feet "confirms that despite the overall better expected prognosis with seronegative versus seropositive RA, in particular [ACPA] positivity, careful and complete examination of every patient is crucial, before the appropriate and optimal therapeutic management can be determined," the researchers wrote.

They concluded that despite the overall less severe prognosis associated with seronegative disease, the impact of early intervention was significant, "with the concept of the 'window of opportunity' being confirmed in this sub-population, pleading for an early start of a DMARD, ideally within 3 months after symptom onset."

A limitation of the analysis was that only patients who were prescribed a DMARD were included.

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