Macrophage activation syndrome (MAS) is an under-recognized complication of rheumatic illnesses that can progress quickly to multi-organ failure and death. A similar condition, known as secondary hemophagocytic lymphohistiocytosis (sHLH), has seen treatment options expand greatly in recent years. A new crop of clinical trials may produce additional agents over the next few years.
“I think pediatricians are a little more aware of MAS than internists and adult rheumatologists, in general, because there’s a familial form of the disease,” said Randy Cron, MD, PhD. “It is becoming increasingly recognized, particularly as a complication of diseases like lupus, systemic JIA, and a variety of other conditions.”
Oncologists have long treated sHLH/MAS with the chemotherapeutic agent etoposide. Etoposide works, Dr. Cron said, but it carries a significant number of serious side effects and complications. Newer cytokine-targeting agents such as anakinra, an interleukin-1 (IL-1) inhibitor, are generally effective and far less toxic than etoposide.
Dr. Cron will open a symposium on Therapeutic Approaches to Macrophage Activation Syndrome on Monday from 8:30 – 10 am in Room B216-B217, Building B of the Georgia World Congress Center. He is Professor of Pediatrics and of Medicine, Arthritis Foundation Alabama Chapter Endowed Chair in Pediatric Rheumatology, and Director of Pediatric Rheumatology at the University of Alabama at Birmingham.
MAS is almost always diagnosed in patients who have already been hospitalized, Dr. Cron noted. They are typically sicker than they should be based on available clinical information, almost always febrile, and almost always have elevated serum ferritin.
“If you are sick enough to be in the hospital and you have a fever, you’re worthy of having your serum ferritin checked,” he said. “Checking serum ferritin is cheap, fast, and readily accessible almost anywhere, including outside the developed world. Elevated serum ferritin and fever is a simple screen to get you thinking of MAS and doing a more thorough workup.”
MAS is not a diagnosis of exclusion and often develops in patients who have some other inflammatory condition, such as rheumatic illnesses (e.g., lupus), hematologic malignancies (e.g., leukemia), infections (e.g., Epstein-Barr virus), or some other immunologic insult. The immune system response to that insult triggers proinflammatory cytokine release that can lead to multiple organ failure if not halted early.
MAS is driven largely by pro-inflammatory cytokines, including members of the IL-1 family, such as IL-1β, IL-18, and IL-33.
Effective treatment can result from blocking different members of the IL-1 family as well as inhibition of the interferon-gamma (IFN-γ) pathway that has been implicated in both MAS and HLH, Dr. Cron said. Emapalumab, an anti-IFN-γ monoclonal antibody, was recently approved by the Food and Drug Administration to treat primary HLH in 2019. Clinical trials are currently under way with emapalumab in MAS/sHLH.
IL-1 blockade works extremely well for some patients, said Edward Behrens, MD, Chief of Rheumatology and Joseph Lee Hollander Chair in Pediatric Rheumatology at Children’s Hospital of Philadelphia. But not for all. He will discuss agents that block other members of the IL-1 family, focusing on IL-18 and IL-33.
Patients with some autoinflammatory disorders show partial response to IL-1 but respond better to blockade of IL-18. Animal studies suggest that IL-33 blockade may also be effective in MAS.
Fabrizio De Benedetti, MD, PhD, Head of Pediatric Rheumatology at Ospedale Pediatrico Bambino Gesu, in Rome, Italy, will explore the clinical implications of the latest findings in IFN-γ and in IL-6 blockade for MAS/sHLH. IL-6 blockade using tocilizumab has been effective in treating cytokine release syndrome, a disorder that resembles MAS.
Just recognizing MAS remains a substantial concern, Dr. Cron said. If MAS isn’t recognized, it won’t be treated appropriately, he said. And because MAS can progress rapidly to multiple organ failure and death, early diagnosis and treatment results in better outcomes.
“We may ultimately know which therapy will be most appropriate for individual patients, but at this point, treatment is still largely trial and error,” he said. “It’s good to have multiple treatment options, but the first step in treatment is still recognizing what is going on. Unless you identify MAS and treat it early, you will miss an opportunity to save lives.”