Published: Oct 2, 2013 | Updated: Oct 2, 2013

By Nancy Walsh

Full Story:  http://www.medpagetoday.com/Rheumatology/Arthritis/42007

High-dose fish oil added to a “treat to target” regiman of conventional disease-modifying treatment in early rheumatoid arthritis (RA) was associated with improved outcomes, a randomized study found.

Among patients receiving fish oil in conjunction with triple therapy with methotrexate, sulfasalazine, and hydroxychloroquine, the likelihood of treatment failure at 1 year was lower than for those given triple therapy alone (hazard ratio 0.28, 95% CI 0.12-0.63,P=0.002), according to Susanna M. Proudman, MD, of the University of Adelaide in Australia, and colleagues.

In addition, the rate of remission was significantly greater in the fish oil group than among controls (HR 2.17, 95% CI 1.07-4.42, P=0.03), the researchers reported online in Annals of the Rheumatic Diseases.

“In addition to benefits of fish oil for articular disease in RA, there may be benefits for the increased cardiovascular risk of RA, which include increased risk of cardiovascular mortality, including an almost two-fold increased risk of sudden cardiac death,” the researchers observed.

Previous studies and meta-analyses  suggested that fish oil, which contains the omega-3 fatty acids eicosapentaenoic (EPA) acid and docosahexaenoic acid (DHA), could have symptomatic benefits for patients with RA.

However, those earlier studies have minimal relevance to contemporary RA management, because patients in those trials had longstanding disease and the dosages of disease-modifying anti-rheumatic drugs (DMARDs) were kept constant through the trials.

Contemporary treatment, however, focuses on starting treatment early, within the first year of symptom onset, and adjusting treatment to meet the specific target of low disease activity or remission.

Proudman and colleagues enrolled 140 patients with early RA, randomly assigning them to receive high-dose (5.5 g/day) or low-dose (0.4 g/day) fish oil (EPA plus DHA). The low-dose group represented controls, as that dosage has not been associated with clinical effects in previous studies.

The initial triple regimen consisted of methotrexate (Trexall), 10 mg per week, sulfasalazine (Azulfidine) 500 mg per day, and hydroxychloroquine (Plaquenil), 200 mg twice per day.

Dosages could be increased in a structured fashion if the swollen joint count remained at two or higher, if the erythrocyte sedimentation rate or C-reactive protein level remained elevated, or if pain, fatigue, or early morning stiffness persisted.

The use of nonsteroidal anti-inflammatory drugs (NSAIDs) and oral corticosteroids was discouraged.

Treatment failure was defined as the need to add leflunomide (Arava) to the triple regimen.

At 1 year, 10.5% of patients taking fish oil and 32.1% of controls had begun taking leflunomide.

The failure rate remained significantly lower for the fish oil group after adjustment for smoking, baseline anti-cyclic citrullinated peptide, and shared epitope (HR 0.24, 95% CI 0.10-0.54, P=0.0006).

The remission rate also was significantly greater after adjusting for those factors (HR 2.09, 95% CI 1.02-4.30, P=0.04).

Only one patient, who was in the control group, had begun taking a biologic agent at 1 year.

Activities of daily living, as measured on the modified Health Assessment Questionnaire, improved “substantially” in both groups. There was no difference in the number of patients who required steroids during the trial, and mean methotrexate doses didn’t differ between the groups.

At baseline, 38% of the fish oil group and 34% of controls were taking NSAIDS, but by 1 year, only one patient, in the control group, was still doing so.

The proportion of patients with serious adverse events was similar in the two groups, at 11.6% of the fish oil group and 3.8% of controls (P=0.13).

While serious adverse events occurred more often in the fish oil group, “there was no pattern suggesting a linkage with fish oil use,” the researchers observed.

A number of cardiac events were reported by a single patient who had ischemic heart disease and atrial fibrillation, and an intracerebral hemorrhage occurred in a patient with uncontrolled hypertension who was being treated with clopidogrel and had stopped taking the fish oil 5 months earlier.

“The study design has allowed the effects of fish oil to be assessed in the context of modern DMARD treatment for RA,” Proudman and colleagues noted.

That fish oil would provide benefits in RA is biologically plausible, they explained, because of the ability of the omega-3 fatty acids to inhibit the release of inflammatory mediators and peptides, including prostaglandin E2 and leukotriene B4, as well as tumor necrosis factor alpha — all of which are targets of current treatments.

They also pointed out that only one patient had progressed to biologic treatment by 1 year, which suggested a potential for cost-saving with fish oil and conventional triple therapy, in that it may “at least delay progression to biologic therapy.”

“That the protocol, with only minor adjustments, has remained standard practice within our busy clinic after completion of the trial, further underlines its applicability to real practice settings,” they concluded.