PAD4 Positivity & Response to Treatment Escalation
Dr. Darrah et al. retrospectively analyzed data from a previous clinical trial, the RA Comparison of Active Therapies in Patients with Active Disease Despite Methotrexate Therapy (RACAT) trial. The 282 participants were failing methotrexate monotherapy and were escalated to receive either 1) methotrexate and etanercept or 2) methotrexate, sulfasalazine and hydroxychloroquine. That study demonstrated both arms were relatively effective in quieting disease activity.8
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In the current paper, Dr. Darrah and colleagues analyzed those same patient outcomes with respect to original PAD4-antibody positivity at initiation of treatment escalation using the Disease Activity Score 28 (DAS28) joint assessment and the Sharp/van der Heijde scoring method. Their hypothesis was patients with PAD4 antibodies at baseline would show more progression in their disease with either of these treatments.1
“The results were completely opposite of what we expected, in that the patients actually did better,” says Dr. Darrah. Those patients positive for PAD4 antibodies had longer disease duration and more joint damage seen via radiography, although not in disease activity as measured by the DAS28. But in both unadjusted analyses and multivariable generalized estimating equation models, the patients positive for PAD4 antibodies showed greater improvements in DAS28 and less radiographic progression compared to PAD4-negative patients, regardless of how their treatment changed.
“Even though they came into the study with really severe joint disease, once they were initiated on a more aggressive therapy, they did better than patients who didn’t have the antibody,” says Dr. Darrah. “I think it suggests these patients might potentially benefit from more rapid treatment escalation earlier in the disease course.”1
Dr. Darrah notes that patients with PAD4 antibodies don’t tend to have more elevated markers of inflammation (like C-reactive protein or erythrocyte sedimentation rate) or more swollen and tender joints, although they have more erosive disease seen via X-ray. But these worsening X-ray changes take time to appear. If further work bears out the idea that PAD4-positive patients respond better to more aggressive therapy, the test might help clinicians initiate such therapy earlier, before irreversible joint damage becomes visible via X-ray.
V. Michael Holers, MD, the Scoville Professor of Rheumatology at the University of Colorado School of Medicine, Aurora, notes when the measurement of PAD autoantibodies becomes available as a clinical test, it may be useful in helping make therapeutic decisions. But he cautions, “It’s still a very early period investigation, largely using retrospective cohorts, so you’d have to replicate and validate and confirm clinical utility in other cohorts and in a prospective study design.”
Dr. Darrah also acknowledges that we do not know how the findings might generalize to patients who are methotrexate naive or to other RA subpopulations. She and her colleagues are studying how baseline PAD4 antibody status affects treatment response to drugs with other mechanisms of action.
Dr. Darrah notes the study raises important questions, such as why these patients hadn’t had their treatment escalated earlier. “It’s great that we can reduce their disease activity and slow down their erosive disease,” she says. “We’d like to understand why the PAD4-antibody-positive patients are progressing the way that they are and see if there might be a therapeutic window where we can treat them before they accumulate that severe joint damage—and actually prevent it.”