RA Therapy: Study Supports Early Treatment Window

Neil Osterweil

January 14, 2015

In rheumatology, as in rocket science, there appears to be a launch window that can a make a critical difference in outcomes.

A study of more than 1200 patients treated with disease-modifying antirheumatic drugs (DMARDs) suggests that patients started on therapy within a few months of symptom onset will have more durable DMARD-free remissions than patients for whom therapy was delayed.

The curve of the relationship is nonlinear, indicating the presence of a "window of opportunity" for ameliorating joint erosion, dampening inflammation, and reducing the need for orthopedic surgery, report Jessica A. B. van Nies, MD, from the Department of Rheumatology, Leiden University Medical Center, the Netherlands, and colleagues.

"This study is the first providing strongly suggestive evidence that a confined period in which rheumatoid arthritis (RA) is more susceptible to treatment [exists]. Further proof might be obtained by performing clinical trials in patients with symptoms of very recent onset randomising for direct or delayed treatment. However, given the present knowledge this may be considered unethical," the authors write in their article, published online January 5 in the Annals of the Rheumatic Diseases.

"It seems that the window is not very broad, and in practice, it is hard to get people in[to] your practice and diagnosed in the first 5 months after symptom onset," said coauthor Annette H. M. van der Helm-van Mil, MD, also from the Department of Rheumatology, Leiden University Medical Center, to Medscape Medical News.

The findings suggest that treatment delayed is efficacy denied, because "then the optimal timing of intervention may have passed. I think that the implication is that we should optimize strategies to have patients early at our clinic," she said.

The investigators noted that several other studies have found worse outcomes for patients with RA with long disease or symptom duration before they are started on DMARDs, including more severe joint destruction, more orthopedic surgeries, lower likelihood of having a DMARD-free sustained remission, and higher RA-related mortality,

However, whether there is an optimal treatment window or, as in many disease states, the doctrine of the earlier the better to start treatment holds true was unclear, the authors write. This uncertainty prompted them to explore in a scientific fashion the shape of the association between treatment onset and duration of DMARD-free remissions.

Longitudinal Cohorts

The authors looked at data on patients in two longitudinal observation cohorts: 738 patients who were enrolled in the Leiden Early Arthritis Clinic (EAC) cohort and 553 who were enrolled in the Evaluation et Suivi de Polyarthrites Indifférenciées Récentes (ESPOIR) cohort in Nîmes, France.

They plotted log-hazard ratios to evaluate the relationship between pretreatment symptom duration and DMARD-free sustained remission over the course of 5 years of follow-up.

The median symptom duration at the time of inclusion into the cohort was 18.7 weeks for patients in the EAC and 21.3 weeks for those in ESPOIR. In EAC, 76.3% of patients and in ESPOIR 67.0% of patients started treatment on methotrexate. Most of the remaining patients in each cohort were started on either sulfasalazine or hydroxychloroquine.

During a 5-year follow-up, 11.5% of patients in EAC and 5.4% in ESPOIR had DMARD-free sustained remissions, which was the primary study outcome.

"We observed a non-linear association; the log-hazard on DMARD-free sustained remission decreased after a certain symptom duration. These data suggest that a confined period in which the disease is more susceptible to treatment is present indeed," the investigators write.

But just how long, or how short, that confined period is was less clear. When the authors created time-dependent receiver-operating characteristic (ROC) curves with DMARD-free sustained remission as the outcome, they found that in both cohorts, the area under the curve was relatively low (0.61 in EAC and 0.59 in EPSOIR), reducing the certainty about the optimum time window for starting treatment, the authors write.

The symptom duration period that was able to best discriminate patients with DMARD-free remissions from those with persistent disease was 14.9 weeks in the EAC cohort. The symptom duration with the best combination of sensitivity and specificity was 19.1 weeks in the ESPOIR cohort. The curves plotting the log-HR against symptom duration began to flatten out around 15 to 20 weeks after the onset of symptoms.

"It cannot be concluded that the window 'is closed' after this period, but the data of the present cohorts clearly showed that the hazard on remission was less after this period, and so possibly it 'starts to close' at this point in time. In other words, we do not suggest that DMARD treatment after a certain window is futile, but that initiating a DMARD in this particular window might yield a better outcome. In case a patient is identified after this period has passed, DMARD therapy should certainly not be withheld," they write.

A rheumatologist who was not involved in the study told Medscape Medical News that the findings are in line with her clinical experience.

"More than 'the earlier the better,' they're saying that if you start treatment in that window of time, between 3 and 5 months, then I think your outcomes will be much better," said Prabha Ranganathan, MD, associate professor of medicine in the Division of Rheumatology at Washington University in St. Louis, Missouri.

The study was supported by grants from the Netherlands Organization for Scientific Research, Dutch Arthritis Foundation, and EuroTEAM consortium. The authors and Dr Ranganathan have disclosed no relevant financial relationships.

Ann Rheum Dis. Published online January 5, 2015. Abstract

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