Understanding Macrophage Activation Syndrome

“A massive inflammatory response that overwhelms the whole body.” That’s how doctors describe macrophage activation syndrome (MAS) – an uncommon but potentially life-threatening complication of systemic juvenile idiopathic arthritis (SJIA). Although it can occur with lupus and other rheumatic diseases, MAS mainly affects kids with SJIA.

About 10 percent of them will develop full blown MAS, usually when their disease is most active, according to Alexei Grom, MD, a pediatric rheumatologist at Cincinnati Children’s Hospital Medical Center and a leading authority on MAS. For other children, MAS symptoms, such as a high, constant fever, changes in alertness, easy bruising and an enlarged liver, may be the first sign they have SJIA.

The immune system has two parts – the innate system launches a generalized response to invading organisms and the adaptive system launches specific antibodies to fight specific organisms. MAS is due to an overactive innate immune system. Normally, several types of immune cells work together to fight infections in a coordinated and orderly way. The macrophages destroy viruses and bacteria. The T-lymphocytes send signals to gather and control macrophages. In MAS, this process gets out of control. The immune system can’t eliminate infectious cells, so it produces more and macrophages and T-lymphocytes. They flood the body with inflammatory cytokines, which can damage any organ, including the heart, liver, spleen and kidneys.

Just what causes the immune system to behave abnormally isn’t completely clear. Dr. Grom says about half of MAS cases are triggered by infections. Others can be caused by a disease flare, when symptoms worsen, or by certain drugs, including those used to treat SJIA such as NSAIDs and biologics. Often, there are no known triggers, although evidence suggests certain gene mutations may play a role. 

There’s no sure way to know if or when a child will develop MAS and no known way to prevent it. Simply controlling SJIA is no guarantee it won’t happen. But because MAS can come on very quickly – and can be fatal if not treated promptly – rapid diagnosis is crucial.

“Families should watch for any change in a child’s level of alertness, listlessness, confusion or loss of appetite,” says Daniel Lovell, MD, associate director of rheumatology at Cincinnati Children’s Hospital. “These are also common signs of a viral infection, but if kids don’t perk up, look more lethargic than usual or have seizures, then we need to be called immediately or they should go to the emergency department.” 

The goal in treating MAS is to reduce body-wide inflammation as quickly as possible and prevent organ damage. The standard treatment is high doses of intravenous prednisone for three to five days. Depending on how a child responds, doctors may add cyclosporine, a drug that suppresses the immune system. For some patients, cyclosporine reduces symptoms within 12 to 24 hours.

“[This combination] produces a very good response in the majority of patients, but for those who continue to have MAS, we need to consider using the chemotherapy drug etoposide,” Dr. Grom says. “As for biologics, the jury is still out. Some studies have found them effective and an equal number of studies have found them to be ineffective or to actually trigger MAS. For example, there are a few reports of dramatic improvements with anakinra (Kineret), but many patients also develop MAS while taking it.”

Today, MAS is diagnosed sooner than in the past, and kids are more likely to receive appropriate treatment. The result is that many recover and have less organ damage. Still, MAS is a life-threatening condition that can come back, even when effectively treated. Although it’s unusual for a child to have it more than once, families should always be alert for MAS symptoms, Dr. Lovell says.