Case Presentation: A 53 yo female presented with a subacute syndrome of intermittent fevers, fatigue, heliotrope rash, weight loss, fingertip necrosis, and nodular skin lesions. Skin biopsy was positive for septal and lobular granulomatous panniculitis. Serology was positive for antinuclear antibody (ANA) and anti-ribonucleoprotein (RNP), negative for other vasculitis and rheumatologic autoantibodies. She was diagnosed with mixed connective tissue disorder and started on immunosuppression with prednisone, hydroxychloroquine, and rituximab. Several weeks after initiating immunosuppression she was admitted to the hospital with new-onset high grade fevers to 103 and extensive ulcerative lesions on her back and legs. On admission she was noted to have pancytopenia, liver injury, acute renal failure, and inflammatory myositis. Viral workup was negative. CT chest revealed diffuse pulmonary nodules concerning for disseminated fungal infection and she was started on broad spectrum antibacterial and antifungal coverage. Bone marrow biopsy revealed hemophagocytosis. She was noted to meet criteria for HLH on the basis of fevers, splenomegaly, pancytopenia, ferritin > 40,000, fibrinogen < 150 and elevated soluble IL-2 receptor antibody level of 19,800. The patient was started on IVIG and was planned for anakinra when she developed acutely worsened mental status, hypotension, hypoxia, and hematochezia. Her WBC count fell to 0.4, hemoglobin to 6.4, and she became hypotensive to 80/50 on three vasopressors. Blood cultures drawn her during acute decompensation returned positive for E.coli within 6 hours. After a prolonged resuscitation the patient was transitioned to comfort care and died with family at the bedside.
Discussion: HLH is a disease of defective regulation of peripheral T-cell expansion and macrophage activation, most commonly seen in the setting of lymphoid cancers and viral infections. The pathophysiology of the predisposition to HLH seen in rheumatologic conditions has been attributed to an underlying intense systemic inflammatory reaction. However, several case series have suggested a temporal correlation between treatment for rheumatologic conditions (particularly anti-TNF alpha inhibitors and other biologics) and the acute development of HLH. Alterations in T-cell and macrophage-derived cytokine levels have been postulated to be the mechanism underlying the emergence of HLH in this setting. Our case suggests an alternative etiology for this correlation. This patient developed multi-organ failure suggestive of HLH only after the initiation of high dose immunosuppressive therapy, without receiving a biologic or anti-TNF drug. She did, however, develop disseminated pulmonary and dermatologic fungal infection (later speciated to aspergillus and pseudomonas) in the setting of profound immunosuppression. While rheumatologic conditions are clearly a predisposing factor in the development of HLH, several groups have proposed an alternative hypothesis that immunosuppression-induced infection is the proximal trigger for final dysregulation. Our case would support this, and emphasizes the importance of early treatment of infections in advanced rheumatologic disorders.
Conclusions: In rare cases, macrophage activation syndrome can be triggered by rheumatologic conditions, often emerging in the setting of biologic immunosuppression. Effective management demands both immunosuppression and simultaneous aggressive treatment of underlying infections.