Case Report: Recurrent hemophagocytic lymphohistiocytosis in a patient with an NLRP12 variant and an autoinflammatory phenotype treated with combination IL-1 blockade and JAK inhibition

NLRP12-associated autoinflammatory disease (NLRP12-AID), also termed familial cold autoinflammatory syndrome type 2, is a rare autosomal dominant disorder attributed to variants in NLRP12, which encodes a negative regulator of nuclear factor (NF)-κB signaling and inflammasome activation. Hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) is a life-threatening complication only rarely described in NLRP12-AID, and evidence to guide management of refractory or recurrent disease is minimal. We report a 20-year-old man carrying an NLRP12 variant of uncertain clinical significance (c.1349C>T, p.Pro450Leu) with a longstanding systemic autoinflammatory phenotype who developed an initial episode of HLH/MAS followed by a suspected recurrence within 3 months. The first episode presented as vasopressor-dependent shock with biopsy-confirmed hemophagocytosis and responded to pulse methylprednisolone and high-dose anakinra, after which he was transitioned to canakinumab. Six weeks after discharge, he was readmitted with recurrent fever, hyperferritinemia, and severe hepatic injury. Reinstitution of maximum-dose anakinra and repeat pulse corticosteroids was followed by persistently elevated inflammatory markers over the subsequent 10 days; canakinumab dose escalation was planned but was administered later, on hospital day 34. Addition of the Janus kinase (JAK) 1/2 inhibitor baricitinib, prompted by emerging case-based evidence and multidisciplinary expert consultation, was followed by progressive decreases in ferritin and hepatic enzymes over 3 weeks; subsequent follow-up included infection and febrile neutropenia during combination immunosuppression. He was discharged on combination canakinumab, baricitinib, colchicine, and a corticosteroid taper. This report details the indication, timing, and observed response following addition of JAK inhibition for suspected recurrent HLH/MAS in a patient with an NLRP12 variant and an autoinflammatory phenotype.