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An investigational antibody drug called MAS825 that inhibits interleukins 1β and 18 (IL-1β, IL-18) appeared extraordinarily effective for treating macrophage activation syndrome (MAS) in two patients with systemic juvenile idiopathic arthritis (sJIA), researchers reported.

One was a young adult Italian man; the other was a 10-year-old Brazilian girl. Both developed MAS that failed to respond to conventional treatment with high-dose corticosteroids and cyclosporine. "Compassionate use" of MAS825 brought rapid reduction in clinical symptoms and inflammatory biomarkers which has lasted 18 months in the man's case and 10 months for the girl, according to Roberta Caorsi, MD, of IRCCS Istituto Giannina Gaslini in Genoa, Italy, and colleagues.

Control of their underlying sJIA was also dramatically improved, the group . "In light of the pivotal role of IL-1β and IL-18 in sJIA, MAS and ILD [interstitial lung disease], MAS825 might represent a possible valid and safe option in the treatment of drug-resistant sJIA, especially in the presence of high serum IL-18 levels," Caorsi and colleagues wrote.

MAS is a affecting virtually the entire body, the researchers explained. Typically onset is sudden and is marked by high fever, major reductions in blood cell counts, bleeding events, liver dysfunction, and neurological symptoms. Although MAS can occur in many rheumatologic conditions, it's especially common in sJIA and also adult-onset Still's disease. Something like 10% of sJIA cases develop MAS at some point, according to the Arthritis Foundation.

has highlighted IL-18 as a biomarker and probable mediator for MAS, along with IL-1β and certain other cytokines. Thus, when Caorsi and colleagues were searching treatment alternatives for their two patients, they thought that MAS825 would be worth a try. The drug is currently under development by Novartis for a as well as ; the company also tested it for COVID-19 pneumonia early in the pandemic but .

Case Details

The young man, now 20 years old, was first diagnosed with sJIA at age 2 that was only partly controlled with standard drugs including corticosteroids and conventional anti-rheumatic drugs (methotrexate and others) and a series of biologic agents including adalimumab (Humira), anakinra (Kineret), and tocilizumab (Actemra), and others too.

In March 2022, he contracted COVID-19 with initially mild symptoms. After a few days, however, signs of MAS appeared. He began treatment with the standard regimen of high-dose methylprednisone and cyclosporine, with anakinra. Baricitinib (Olumiant) was eventually introduced as well. Symptoms and MAS biomarkers persisted and evolved, leading his clinicians to initiate the complement inhibitor eculizumab (Soliris) with plasmapheresis, which initially helped significantly.

But MAS biomarkers remained at high levels and the man also developed a range of severe side effects related to the immunosuppressant treatment -- enough to appear worse than MAS.

In June 2022, MAS825 infusions were started at 700 mg biweekly, "leading to rapid clinical and laboratory MAS parameter improvement, enabling significant glucocorticoid tapering, baricitinib withdrawal, and discharge," Caorsi and colleagues wrote. "After 18 months, the patient is still on biweekly MAS825 treatment, combined with [methotrexate], cyclosporine, and low-dose glucocorticoids (prednisone 15 mg/day), with complete control of systemic features." The man still had some arthritic joints requiring intra-articular steroid injections, but systemic features were otherwise controlled, and thus far he has had no adverse effects attributed to MAS825.

The 10-year-old girl was diagnosed with sJIA at age 1. Like the man, she underwent a variety of anti-rheumatic treatments with only partial success. She was also vulnerable to infection, perhaps because of treatments, which (also like the man) eventually produced side effects such as osteoporosis.

MAS developed in the girl following a severe case of otitis media. Among the symptoms was low oxygen saturation, such that she was put on supplemental oxygen. She was then given MAS825 biweekly at 10 mg/kg, leading to "rapid improvement of clinical and laboratory parameters, allowing progressive glucocorticoid tapering and oxygen supplementation withdrawal," Caorsi and colleagues reported. Eventually, cyclosporine was stopped. Currently the girl is on MAS825 and prednisone at 2.5 mg/day, along with a reduced dosage of antihypertensive medication.

Caorsi and colleagues noted that the need for biweekly intravenous infusions is a "limitation for the use of the drug in daily clinical practice"; a subcutaneous version would be much better but Novartis hasn't produced one yet.

"In light of [our] experience and other literature evidence," the researchers concluded, "we strongly advocate for a therapeutic trial to provide more robust evidence on the possible role of the bispecific anti-IL-1 and IL-18 inhibition strategy, especially in a subgroup of sJIA and Still's disease patients with high serum IL-18 levels."

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