Macrophage Activation Syndrome (MAS) in a patient with history of Juvenile Idiopathic Arthritis (JIA): A Guideline Driven Clinical Approach

Summary: Background Hemophagocytic Lymphohistiocytosis (HLH) and MAS are life-threatening systemic hyper-inflammatory syndromes. MAS typically arises as a complication of rheumatic diseases like JIA or Systemic Lupus Erythematosus (SLE). The current, broader HLH definition includes MAS among the causes of ‘secondary’ HLH. HLH/MAS can occur in any age group, and typically develops in the setting of infectious, malignant or rheumatological diseases, or less commonly as a manifestation of underlying genetic inborn errors of immunity (IEI) that predispose to hyperinflammation. Case This is a 41-year-old female with history of JIA and SLE who presented with 1 week of fevers (Tmax 104F) with associated fatigue, and myalgias. She had been told by her Rheumatologist that her JIA had “burned out” at age 30 without recurrence of symptoms or other manifestations of rheumatic/connective tissue disease. Two years prior to presentation, the patient developed “lupus-like” features including fatigue, arthritis, photosensitivity, low complements, elevated dsDNA. She was managed with various medications in the past including Imuran, Mycophenolate Mofetil (MMF), and Methotrexate (MTX), Benlysta, and Baracitinib. Most recently she was taking monotherapy with prednisone 20mg daily and planned to start Saphnelo outpatient. Prior to admission, her dose of prednisone was increased to 60mg daily due to persistent fevers. Patient was admitted and vitals significant for fever with Tmax of 103F with other vitals stable. On exam patient found to be comfortable, with chronic deformities of hands and feet related to JIA, and a faint erythematous rash of bilateral arms. Labs were significant for Pancytopenia of WBC 1.2 (ANC 1.00), Hgb 8.5, Plt 112, Transaminitis of AST 108, ALT 48, elevated Alk Phos 160, fibrinogen 236, elevated CRP 10.6, ESR 25, hypocomplementemia of C3/C4 at 63 and 6 respectively, positive DsDNA of 14, Ferritin elevation of 1565, and elevated LDH 479. Blood cultures were negative x5 days, and respiratory viral panel negative on admission. CT Chest/Abdomen/Pelvis showed mild hepatosplenomegaly, nonspecific right upper lobe small ground glass opacity and subpleural reticulation, possible infectious/inflammatory etiology. TTE was performed to rule out occult infection and was negative for vegetation. Bone marrow (BM) biopsy performed and showed recovering BM, no abnormal findings. She was placed on broad spectrum antibiotics for empiric coverage, although infectious workup remained negative throughout hospital course. There was suspicion for possible MAS and patient was started on Methylprednisolone 500mg x3 days followed by 60mg prednisone daily, Anakinra 100mg BID, and IVIG 1g/kg/day x4 days. After initiation of treatment, fevers resolved, CRP improved from 10.6 to 3, ESR improved from 25 to 11, Ferritin improved from 2956 to 2811, and WBC improved from 0.6 (ANC 0.31) to 1.9 (ANC 0.98). Two days into treatment, patient refused Anakinra due to painful injection, resulting in fevers to 103F, Ferritin elevation to 8114, CRP elevation to 10.9, and WBC worsened to 1.4. Given clinical changes, a shared decision to re-initiate and increase Anakinra to 100mg TID was made. Two days later the patient’s fevers resolved with improvement in WBC to 2.6 (ANC 1.69), Ferritin 3821, CRP 3.3, and prednisone was changed to 40mg daily. Discussion The patient maintained significant control of inflammation while on steroids, IVIG, and Anakinra. When Anakinra was temporarily discontinued, her fevers quickly returned, and she had marked increase in Ferritin, CRP, and worsening CBC. Once Anakinra was resumed, her fevers resolved, and both her inflammatory markers and CBC continued to improve. In a patient with history of JIA and SLE presenting with unexplained fevers, pancytopenia, elevated liver enzymes, elevated ferritin (>1000), elevated acute phase reactants (ESR and CRP), fibrinogen of 236 (considered low in evaluation of MAS), new rash, hepatosplenomegaly, elevated LDH, elevation of sIL-2r of 1936 (a serologic test for HLH), and an H score of 282 (> 99% probability of HLH), a diagnosis of MAS secondary to SLE (HLH in the setting of a rheumatologic disorder) was made using the HLH 2004 Diagnostic Criteria. Conclusion Combining the HLH 2004 Diagnostic Criteria along with the HScore can provide an estimation of an individual’s risk of having HLH. Further research and discussion would be beneficial in optimizing the current guidelines for diagnosis and treatment of HLH/MAS.