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To the Editor: Idiopathic multicentric Castleman disease (iMCD) is a rare, life-threatening cytokine storm disorder of unknown etiology.1 Patients experience generalized lymphadenopathy, systemic inflammation, and multi-organ failure due to excess interleukin-6 (IL-6) and other cytokines.2 The most severe form of iMCD involves thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, and organomegaly (iMCD-TAFRO). Prognosis is poor; 25–35% of patients die within five years.3 IL-6 inhibition with siltuximab, which is the only FDA-approved therapy for iMCD, is effective in 40–50% of patients,4 leaving anti-IL-6-refractory patients with few therapeutic options. Improved understanding of iMCD-TAFRO pathogenesis is urgently needed to identify new treatments.

of patients die within five years.3 IL-6 inhibition with siltuximab, which is the only FDA-approved therapy for iMCD, is effective in 40–50% of patients,4 leaving anti-IL-6-refractory patients with few therapeutic options. Improved understanding of iMCD-TAFRO pathogenesis is urgently needed to identify new treatments. To identify novel, targetable pathways in iMCD-TAFRO, we analyzed patient biospecimens using proteomic, transcriptomic, in vitro modeling, and computational techniques. Serum proteomics comparing iMCD-TAFRO patients (n=26) to healthy controls (n=15) identified increased tumor necrosis factor (TNF) signaling in iMCD-TAFRO (Fig.1A; Fig. S1 in Supplementary Appendix). Single-cell RNA sequencing of peripheral blood mononuclear cells revealed that CD4+ T cells, particularly naïve CD4+ T cells, from iMCD-TAFRO patients had markedly increased expression of TNF (Fig.1B). In vitro studies confirmed these findings. Upon stimulation with PMA/I, over two-fold more naïve CD4+ T cells from iMCD-TAFRO patients (43%) produced TNF compared to healthy controls (17%) (Fig.1C and Fig. S2). These results implicate TNF signaling in iMCD pathogenesis and suggest that it may be a therapeutic target. In parallel, we pioneered a novel machine learning (ML) approach to generate predictive scores for the likelihood of every FDA-approved drug to treat every disease. Adalimumab, a TNF inhibitor approved for multiple autoimmune disorders, was the top predicted treatment for iMCD following IL-6 inhibitors and interestingly, CD4 T-cell inhibition was identified in the potential mechanism (Fig. S3).5

redictive scores for the likelihood of every FDA-approved drug to treat every disease. Adalimumab, a TNF inhibitor approved for multiple autoimmune disorders, was the top predicted treatment for iMCD following IL-6 inhibitors and interestingly, CD4 T-cell inhibition was identified in the potential mechanism (Fig. S3).5 We administered adalimumab to a highly treatment-refractory iMCD-TAFRO patient who was preparing for hospice care after experiencing multiple flares and relapsing on numerous treatments including Bruton’s tyrosine kinase (BTK) inhibition most recently (Fig.1D–E). Remarkably, the addition of adalimumab induced a sustained remission lasting 22 months to date, representing his longest remission since diagnosis. We employed multiple strategies to identify TNF signaling as a novel, targetable mechanism in iMCD-TAFRO. This study also highlights the potential of this novel translational approach—combining high-throughput ‘omics data with in vitro studies and ML models—to rapidly identify and prioritize new treatment strategies for rare diseases. Further studies are warranted to evaluate TNF inhibition in larger cohorts of iMCD patients.