Weathering the Cytokine Storm: Macrophage Activation Syndrome in Adults & Children

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“Macrophage activation syndrome [MAS] can be difficult to identify because it mimics other inflammatory states. However, early recognition and treatment are important to obtain the best outcomes for our patients because MAS can worsen quickly,” says Peter Nigrovic, MD, a rheumatologist at Boston Children’s Hospital, where he is chief of the Division of Immunology, and at Brigham and Women’s Hospital and leads the Center for Adults with Pediatric Rheumatic Illness. He also leads a basic and translational science lab that focuses on the mechanisms of inflammation in arthritis and systemic lupus erythematosus (SLE).

Dr. Peter Nigrovic

Dr. Nigrovic is the author of a review  that is part of a series on immunology for rheumatologists launched earlier this year in Arthritis & Rheumatology.¹ In this new installment, Dr. Nigrovic reviews MAS—a cytokine storm potentially leading to life-threatening multisystem end-organ dysfunction—in children and adults, focusing on MAS complications in Still’s disease.²

Practical Approach to MAS

“The goal of this review was to provide a practical approach to [the] diagnosis and treatment [of MAS], starting with basic lab tests easily available to everyone and then incorporating less familiar measurements, such as CXCL9 and interleukin (IL) 18,” Dr. Nigrovic explains. “I have sought to be very specific, including a treatment algorithm and drug dosing recommendations, recognizing that data remain very limited and so other approaches may also be reasonable.”

MAS, a state of immune hyperactivation, occurs in rheumatic diseases, most typically in Still’s disease, which includes systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease; SLE; Kawasaki disease; malignancy, especially leukemia and lymphoma; severe bacterial and viral illnesses; and inborn immunity errors.

“In patients exhibiting a high degree of systemic inflammation, MAS should be suspected early, especially in the context of Still’s disease or other conditions that pose a risk for MAS,” Dr. Nigrovic says. “Measuring ferritin is a good first step, but MAS is characterized by a broader pattern involving other clinical and laboratory features, so looking for other elements of this pattern is important. Sometimes, it makes sense to start treatment for MAS even before you are sure, [because] the ‘MAS vicious cycle’ of reciprocal immune cell activation can spiral out of control.”

Dr. Nigrovic introduces the review with a case study. He next discusses the hallmarks of MAS, which include severe systemic inflammation, usually with fever, together with elevated ferritin, a low platelet count and other markers of disseminated intravascular coagulation and transaminase elevation. Dr. Nigrovic reviews the latest data on the pathogenesis, diagnosis, treatment and prognosis of MAS. He discusses MAS of the central nervous system and Still’s disease-associated lung disease.

The review includes informative tables, detailed images and legends, and many references.

Case Study

The case study followed a 17-year-old male patient who presented with a three-week history of daily fever, spiking in the afternoons, along with a transient rash and arthralgias. Physical examination revealed a body temperature of 38.5ºC, a palpable spleen tip, and a macular and linear erythematous rash on his trunk.

Laboratory tests showed a white blood cell count of 15,000/μL, hemato­crit at 37%, platelets at 453,000/μL, an erythrocyte sedimentation rate (ESR) of 83 mm/h, C-reactive protein (CRP) at 8 mg/dL, and ferritin at 850 ng/mL. Aspartate transaminase (AST) and alanine transaminase (ALT) were normal. IL-18 was 36,000 pg/mL (normal <800 pg/mL) and CXCL9 was 230 pg/mL (normal <121 pg/mL).

While awaiting prior authorization for treatment with the recombinant IL-1 receptor antagonist anakinra, the patient received naproxen. His fevers somewhat improved, occurring every few days for two weeks, but then worsened. Re-evaluation of the patient revealed the following: body temperature 40ºC, hematocrit 31%, platelets 230,000/μL, ESR 45 mm/h, CRP 16 mg/dL, ferritin 43,000 ng/mL, AST 450 U/L, and ALT 430 U/L. IL-18 increased to 180,000 pg/mL and CXCL9 increased to 3,200 pg/mL.

The patient’s symptoms improved after treatment with pulse glucocorticoids and anakinra, and he was transitioned to the anti-IL-1β antibody canakinumab. He remains in clinical remission off glucocorticoids, with normal CRP, ferritin and CXCL9, an IL-18 of 8,300 pg/mL.

Diagnosis & Treatment

An unusually direct connection exists “between the pathogenesis of MAS and the strategies used to diagnose and treat it,” Dr. Nigrovic writes. He highlights insights gained from primary hemophagocytic lymphohistiocytosis (HLH), “a set of rare inborn errors of immunity that present as MAS in infancy or early childhood, often from defects in cell-cell killing mediated by perforin, a protein expressed by CD8+ T cells, natural killer cells and other lineages.”

The vicious cycle of macrophage activation syndrome. Antigen-presenting cells (macrophages and dendritic cells) and lymphocytes (primarily CD8+ T cells) form a cytokine-generating vicious cycle driven by multiple activation pathways (red ar-rows). Under normal conditions, this positive feedback loop is stopped by inhibito-ry pathways (blue), including killing of activated antigen-presenting cells and lym-phocytes, regulatory T cells and elimination of triggers, such as viruses (not shown). In MAS, factors leading to uncontrolled activation of this vicious cycle (gray boxes) include genetic and acquired defects in cell-cell killing, excess stimula-tion (Still’s disease activity, infection, malignancy) and IL-2 theft by highly activated CD8+ T cells expressing the high-affinity IL-2 receptor α chain CD25.

The review covers several opportunities for diagnosing and monitoring MAS. Of those introduced in the case study, CXCL9 is a chemokine released in response to, and a reliable measure of, interferon-gamma (IFNγ) activity. IL-18 is a pro-inflammatory cytokine often elevated during inactive Still’s disease, more so during MAS. Meanwhile, levels of soluble CD25, which is shed by activated T cells, rise in MAS, but also with infectious, autoimmune and neoplastic conditions.

“Marked elevation of CD38+HLA-DR+ cycling lymphocytes is readily identified by flow cytometry and represents a hallmark of MAS,” Dr. Nigrovic writes. “Typically, the laboratory abnormalities of MAS emerge together, such that elevation in one value in the absence of others should trigger consideration of other entities.”

Treatment for MAS is reviewed in the 2022 ACR/EULAR consensus report.³ Key agents in routine use include glucocorticoids and anakinra, both discussed in the case study; Janus kinase inhibitors, such as ruxolitinib; calcineurin inhibitors tacrolimus and cyclosporine; monoclonal antibody emapalumab, which neutralizes IFNγ; and topo­isomerase II inhibitor etoposide.

The review includes a figure depicting an algorithm for treating MAS in suspected Still’s disease and a table detailing drug dosing and monitoring.

“Treatment of MAS is not standardized. Intensity of therapy is generally proportionate to illness severity,” Dr. Nigrovic explains. “It is important for the clinician not to be reassured if the patient appears relatively well, or to mistake ‘normal’ platelet count or falling ESR as evidence of improvement. Primary HLH is typically managed by hematology/oncology specialists using etoposide, but this agent is generally not indicated for MAS related to Still’s disease unless other options have failed.”

Final Thoughts

Dr. Nigrovic, who practices both pediatric and adult rheumatology, notes, “Here at Boston Children’s Hospital and at the Brigham and Women’s Hospital, we’ve had a surprising number of difficult MAS cases over the last few years that have posed real challenges for our inpatient teams. My goal for this review was to provide a guide to our adult and pediatric rheumatology fellows and attendings as they handle these very sick patients.

“I was fortunate to have many of our fellows volunteer to read the draft to ensure that it provides a clear path forward for them. I am especially grateful to my many expert colleagues, locally, nationally and internationally, who provided comments on part or all of the review,” he says.

“While these experts differ somewhat in how they treat MAS, I have tried to ensure that the review broadly reflects current practice, while providing the key references to the primary data to allow readers to make up their own minds and to best adjust treatment to the needs of each individual patient,” Dr. Nigrovic concludes.

Katie Robinson is a medical writer based in New York.

References

1. Bucala R, Solomon DH. Immunology for the rheumatologist: A&R introduces a new problem-based immunology review series with great educational potential. Arthritis Rheumatol. 2024 Jan;76(1):9–10.
2. Nigrovic, PA. Macrophage activation syndrome. Arthritis Rheumatol. Accepted author manuscript. 2024 Nov 3.
3. Shakoory B, Geerlinks A, Wilejto M, et al. The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Ann Rheum Dis. 2023;82(10):1271–1285.