A 61-y.o. woman with pulmonary sarcoid presented with 3 weeks of fever, malaise, and 15-lb weight loss. Social, travel, and family history was unremarkable.
Initial exam noted diffuse lymphadenopathy. Labs revealed leukopenia, anemia, transaminitis, and elevated inflammatory markers (ESR 50 mm/h, CRP 266 mg/L).
Contrast-enhanced CT showed enlarged axillary and retrocrural lymph nodes. Further testing evidenced: serum EBV IgG positive but PCR negative; ANA (1:1280); SS-A IgG >8; and markedly elevated ferritin and triglycerides. Serum soluble IL-2 receptor level was elevated. Bone marrow biopsy showed non-caseating granulomas. Liver and renal function began to rapidly worsen.
Clinically she was felt to have hemophagocytic lymphohistiocytosis (HLH). After discussion with family, our patient was initiated on tocilizumab, dexamethasone, and cyclosporine.
Inflammatory markers and organ function briefly improved, but then suddenly and dramatically deteriorated. She developed multi-organ failure requiring mechanical ventilation and hemodialysis. After six days of therapy, she expired. Autopsy revealed atypical lymphocyte-depleted Hodgkin’s lymphoma with involvement of the bone marrow, liver, lungs, and spleen.
Hemophagocytic lymphohistiocytosis (HLH; a.k.a. macrophage activation syndrome) is an uncommon life-threatening disorder characterized by inappropriate macrophage activation and resultant massive inflammatory response. While familial HLH is mainly a childhood disorder, adult hospitalists encounter secondary HLH driven by viral infection, malignancy, or rheumatologic disorders. Early recognition is essential as the disease often rapidly progresses. Unfortunately, there are no controlled treatment studies and current common treatment regimens for secondary HLH still yield a survival of only 55%. Most regimens are derived by extrapolation from existing familial HLH treatment protocols (i.e., HLH-94, HLH-04).
Tocilizumab, an anti-IL6 receptor monoclonal antibody, may potentially be useful in treating HLH. Massive “cytokine storm” is strongly implicated in HLH pathogenesis, with resultant uncontrolled NK- and cytotoxic- CD8(+)-T-cell activation. Reduction of IL-6 using tocilizumab theoretically may mitigate this inappropriate macrophage activation. A few cases report benefits from adding tocilizumab to usual therapy for HLH in patients with known autoimmune disease or malignancy. Paradoxically, HLH has also been observed during tocilizumab therapy for systemic-onset juvenile idiopathic arthritis. It is therefore possible that targeting a single cytokine may not be sufficient to control this hypercytokinemia. Nonetheless, cytokine-targeted therapy may enhance treatment for HLH, especially when medication toxicity precludes standard agents.
Tocilizumab may enhance treatment for secondary HLH by blocking cytokine overproduction. Standardized protocols incorporating tocilizumab are needed to further study this concept.
To cite this abstract:Quinn K, Gandiga P, Broome C, Whelton S. Use of Anti-Il6 Receptor Antibody (Tocilizumab) for Induction Therapy in Secondary Hemophagocytic Lymphohistiocytosis/macrophage Activation Syndrome (Hlh/mas). Abstract published at Hospital Medicine 2015, March 29-April 1, National Harbor, Md. Abstract 661. Journal of Hospital Medicine. 2015; 10 (suppl 2). https://www.shmabstracts.com/abstract/use-of-anti-il6-receptor-antibody-tocilizumab-for-induction-therapy-in-secondary-hemophagocytic-lymphohistiocytosismacrophage-activation-syndrome-hlhmas/. Accessed May 24, 2019.