A 5-year-old boy was recently diagnosed with systemic juvenile idiopathic arthritis (SJIA). He initially presented with rash, fever, joint pains, and a high ESR of 80, but has started on methotrexate and prednisolone, prescribed by his rheumatologist. He has been feeling better, with an improvement in his rash and arthritis, but in the past few days he has had onset of fevers and general malaise. In his pediatrician’s office, a fever to 39 degrees C is noted, but no obvious source of infection. Exam is otherwise unremarkable with no rash or arthritis. Recent laboratory evaluation revealed CBC with a WBC of 3.5, Hgb of 12.5, and PLT of 130. His ESR is normal at 5 mm/hr. After phone consultation with his rheumatologist, the child is sent to the Emergency Department for further evaluation where he is found to have an elevated ferritin, C-reactive protein, and a slightly enlarged spleen by ultrasound. He is admitted for treatment of macrophage activation syndrome (MAS).
Discussion: MAS is a life-threatening complication of a number of rheumatic illnesses including systemic lupus erythematosus, Kawasaki disease, and, most commonly, SJIA, where it is seen in 10% of cases. MAS is a sepsis-like systemic inflammation condition, resulting in multiorgan failure and potential death within days if not promptly recognized and treated. Clinical manifestations include fever, rash, hepato-splenomegaly, and lymphadenopathy. Patients develop a disseminated intravascular coagulopathy, with consumption of fibrinogen, much like what is often seen in infectious sepsis.
Because the ESR is primarily elevated due to increased fibrinogen produced during inflammation, in MAS, the ESR is paradoxically low due to the excessive consumption. Therefore, an elevated C-reactive protein in the face of a “normal ESR” should prompt concern for MAS. Other laboratory findings include cytopenia (as in the mild cytopenia seen in the above patient), elevated ferritin, and elevated ALT and AST. Since children with SJIA often initially present with elevated ESR, WBC, and platelets due to their systemic inflammation, “resolution” of these parameters has the potential to be confused with developing MAS. Thus, a patient still experiencing signs of inflammation, but whose ESR, WBC, and platelets are trending down to normal values should be considered for MAS rather than treatment response.
Figure 2: Example of a hemophagocyte (arrow) ingesting red blood cells, platelets, and lymphocytes from the spleen of a mouse with macrophage activation syndrome.
A pathologic hallmark of MAS is the finding of hemophagocytes on tissue biopsy, usually bone marrow. Hemophagocytes are macrophages ingesting other hematopoietic elements such as lymphocytes, red blood cells, or platelets (see Figure 2). Although these cells are considered a hallmark—indeed, the syndrome itself is named after these macrophages—it should be noted that hemophagocytes can been seen in other conditions, and they are not always seen in MAS, so they are neither specific nor sensitive. Nonetheless, in the correct clinical context, detection of hemophagocytes may aid in diagnosis.
Treatment of MAS requires rapid and aggressive immunosuppression, usually with some combination of intravenous “pulse” glucocorticoid, cyclosporine, and inhibition of the cytokine IL-1b using anakinra, a biologic that interferes with IL-1b activity. Frequent monitoring for disease progression, end organ damage, and medication toxicity is required. Despite best efforts, the mortality rate for MAS remains at least 10% and, depending on the population studied, can be much higher. For this reason, immediate referral to an emergency department for evaluation and likely inpatient observation is needed.
MAS-like syndromes may occur in many clinical contexts, including immunodeficiencies, EBV infections, and malignancies. Many times, MAS is the initial presentation of these diseases. As recognition of this condition increases, we are finding that perhaps MAS is not quite as rare as once thought. As prompt recognition and treatment is critical to outcome, primary care pediatricians can play a significant role in identifying and referring patients for care.
The fundamental causes of MAS remain unclear. Ongoing research in MAS in CHOP’s Division of Rheumatology is helping to identify these causes and suggest novel means of treatment. With the ever increasing arsenal of cytokine-specific immunsuppressive therapies, the possibility of “personalized medicine” approaches is growing by identifying patient-specific cytokines and immune cells that are activated, and blocking exactly those pathways. CHOP is leading the way in this effort, highlighted by some recent successes in specifically targeting novel cytokines we have identified as elevated in MAS patients.