Emapalumab induces remission of macrophage activation syndrome


According to a phase 2 study, remission of macrophage activation syndrome (MAS) secondary to systemic juvenile idiopathic arthritis (sJIA) or adult-onset Still’s disease (AOSD) was achieved in patients taking emapalumab who failed high-dose glucocorticoids.

Juvenile Idiopathic Arthritis color line icon | Image Credit: © Backwoodsdesign - © Backwoodsdesign - stock.adobe.com.

Juvenile Idiopathic Arthritis color line icon | Image Credit: © Backwoodsdesign - © Backwoodsdesign - stock.adobe.com.

Emapalumab, a fully human anti-interferon-γ (IFNγ), demonstrated efficacy for inducing remission of macrophage activation syndrome (MAS) secondary to systemic juvenile idiopathic arthritis (sJIA) or adult-onset Still’s disease (AOSD) in patients who failed standard care with high-dose glucocorticoids, with or without anakinra (Kineret; Sobi) and/or cyclosporin, according to a recent study. 

MAS, a form of secondary hemophagocytic lymphohistiocytosis (HLH) that occurs as a life-threatening complication of rheumatic diseases, is most frequent in sJIA and AOSD, affecting approximately 10% to 20% of patients. According to study authors, sJIA and AOSD are considered the same disease but are named differently because of onset below or above 16 years, respectively. Study authors designated the term sJIA/AOSD to collectively identify these patients.

According to the study, IFNγ is present and pathogenic in animal models of MAS. In sJIA/AOSD, high IFNγ activity demonstrated by high serum levels of C-X-C motif chemokine ligand 9 (CXCL9), a chemokine selectively induced by IFNγ, is associated with the onset and severity of MAS.

Emapalumab was studied in a phase 2, open-label, single-arm trial (NCT03311854) that was conducted at 5 sites in France, Italy, Spain, the United Kingdom, and the United States. Screening, a 28-day treatment period, and a short-term 4-week follow-up made up the study, while data were collected up to 12 months in a long-term follow-up study (NCT02069899). The study objective was to confirm adequacy of the emapalumab dosing regimen related to IFNγ activity.

The initial dose of emapalumab was 6 mg/kg on day 0, then 3 mg/kg every 3 days until day 15, and twice per week until day 28.

The efficacy outcome of emapalumab was MAS remission by week 8, defined as, “resolution of clinical signs and symptoms according to the physician global assessment (visual analogue scale ≤1/10) and white blood cell and platelet count above lower limit of normal, lactate dehydrogenase (LDH), alanine aminotransferase and aspartate aminotransferase below 1.5 times upper limit of normal (ULN), fibrinogen >100 mg/dL and ferritin levels decreased by at least 80% or below 2000 ng/mL, whichever was lower,” according to authors.

All 14 patients that received emapalumab completed the study and entered long-term follow-up. Thirteen patients had sJIA onset before 16 years, while the other had AOSD with onset at 16 years and 9 months. Presumption of sJIA, that was later confirmed, was observed in 4 patients, and 6 patients had a of 19 total MAS episodes, and were treated with high-dose glucocorticoids, with the addition of anakinra and/or ciclosporin in approximately half, according to the study.

CXCL9 concentrations were markedly elevated in all patients at baseline, indicating high IFNγ activity. IFNγ concentrations varied across the patients. At day 3, IFNγ concentrations reflected IFNγ production at baseline. No correlation between total IFNγ at day 3 and CXCL9 levels at baseline was observed.

Authors stated, “emapalumab administration led to a rapid decrease in serum CXCL9 levels, indicating [neutralization] of IFNγ activity and therefore the appropriateness of the selected dosing regimen.” Indication of decreasing IFNγ production over time was observed after patients with elevated total IFNγ at day 3 showed a decrease in IFNγ concentrations over time. In the absence of high IFNγ production during the long-term follow-up period, emapalumab showed a slow linear terminal elimination phase (half-life of 24 days), like that in healthy subjects, authors stated. Total IFNγ, CXCL9 and soluble IL-2 receptor levels were close to or within normal range.

MAS activity and MAS laboratory parameters rapidly improved during emapalumab administration while glucocorticoids were tapered. By week 8, the efficacy outcome, 13 of 14 patients (93%) achieved MAS remission with a median time of 25 days after emapalumab initiation. The earliest remission was achieved at day 9. During long-term follow-up, 13 patients did not have MAS episodes. A MAS episode was observed in 1 patient 11 months after stopping emapalumab, when it was undetectable in serum.

At the conclusion of the long-term follow-up, 10 patients met the MAS remission criteria. Four patients did not meet these criteria because of a mild abnormality in 1 laboratory value (n = 1), MAS activity at 1.5 cm (n = 1), missing data (n = 1), or absence of data resulting from the patient missing the 12-month visit. After the initiation of emapalumab, 88 adverse events were reported in 13 patients. All events were mild or moderate in intensity except 2 (1 cardiopulmonary failure, 1 neutropenia), neither related to emapalumab.

Authors concluded, “results of this study show that [neutralization] of IFNγ with emapalumab is a therapeutic option for patients with severe MAS who have failed standard of care with high-dose glucocorticoids.”


De Benedetti F, Grom AA, Brogan PA, et al. Efficacy and safety of emapalumab in macrophage activation syndrome. Annals of the Rheumatic Diseases. Published online March 31, 2023. doi: 10.1136/ard-2022-223739

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