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In a small prospective trial, a common complication of systemic juvenile idiopathic arthritis (sJIA) and its adult-onset counterpart were quickly brought under control with emapalumab (Gamifant), an inhibitor of interferon-gamma.

Among 14 patients with macrophage activation syndrome (MAS) that didn't respond to high-dose corticosteroids, 13 achieved remission with emapalumab in a median of 25 days, according to Fabrizio De Benedetti, MD, PhD, of Ospedale Pediatrico Bambino Gesu in Rome, and colleagues.

Results of the trial also demonstrated that interferon-gamma is indeed "an important driver of MAS secondary to sJIA" and of , the researchers .

MAS is one type of hemophagocytic lymphohistiocytosis (HLH) and is seen in a number of rheumatic diseases, most commonly in sJIA and its adult form. Some 10-20% of these individuals are estimated to develop MAS at some point, and the condition is . Steroids are the first-line treatment; for patients who don't respond, a number of other immunosuppressant-type drugs have been tried, although none had been tested in prospective trials, De Benedetti and colleagues explained.

Animal and lab studies have implicated interferon-gamma as key to MAS pathology, the researchers noted, thus suggesting that a drug to inhibit that cytokine might be helpful. Emapalumab is such an agent: It was for treating patients with primary HLH, and thus its use for secondary forms of HLH was plausible.

For the , De Benedetti and colleagues enrolled pediatric and young adult patients from the U.S., Britain, and Europe who met criteria for a diagnosis of MAS (based on ferritin, triglyceride, fibrinogen, and aspartate aminotransferase levels and platelet counts) and who had failed high-dose intravenous steroid therapy. Therapies other than cyclosporin and steroids were stopped on study entry; a study amendment also allowed anakinra (Kineret) on the condition that these agents had been started at least 3 days before the first emapalumab dose.

Remission by treatment week 8 was the trial's primary efficacy endpoint. It was defined as "resolution of clinical signs and symptoms" along with white blood cell and platelet counts in the normal range (or higher) and clinically significant improvements in other lab values.

Emapalumab was given at 6 mg/kg for the first dose, then at 3 mg/kg every 3 days through day 15, and at the same dose twice weekly to day 28. Treatment could be stopped early at clinicians' discretion if remission occurred, as long as three or more doses had been given.

Total serum levels of interferon-gamma didn't change markedly with treatment, but processes considered to result from its activity declined markedly. This was indicated by serum levels of the chemokine ligand CXCL9 and soluble interleukin-2 receptor, which both fell massively within 2-4 weeks of starting emapalumab. These markers indicated "neutralization of interferon-gamma activity," the researchers wrote.

As indicated earlier, all but one patient achieved remission by week 8. Two of these, however, lost remission status by the prespecified criteria when evaluated at week 8 because of a slight abnormality in one lab parameter. No patients died during the trial or out through 1 year of follow-up after enrollment. Most patients were able to reduce steroid doses substantially, from a median of 15.7 mg/kg/day (predisone equivalent) at baseline to 0.56 mg/kg/day at week 8. At the final 1-year follow-up, five patients had stopped steroids altogether.

Although adverse events were common -- 88 total events during the 8-week efficacy period and 37 more during longer follow-up -- only a few were rated as serious and just one as severe (nonfatal cardiopulmonary failure). Infections were common, however, and the investigators recommended that emapalumab treatment come with monitoring for viral infections, especially cytomegalovirus.

De Benedetti and colleagues determined that use of anakinra in five patients contributed little to the treatment's efficacy, as these patients had not responded to it prior to starting emapalumab. Also, two of the three patients not in remission at week 8 were also taking anakinra. The authors didn't comment on the extent to which cyclosporin, continued beyond day 10 in six patients, might have helped.

Limitations to the study included the small numbers of patients and lack of a control group. However, the researchers argued that a randomized trial would not be possible or ethical, given the lack of a proven treatment to serve as active comparator, and that a placebo control could not be supported either.

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