Blood advances | 2021
Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease.
Abstract
Idiopathic multicentric Castleman disease (iMCD) is a poorly-understood hematologic disorder involving cytokine-induced polyclonal lymphoproliferation, systemic inflammation, and potentially-fatal multi-organ failure. Though the etiology of iMCD is unknown, interleukin-6 (IL-6) is an established disease driver in approximately one-third of patients. Anti-IL-6 therapy, siltuximab, is the only FDA-approved treatment. Few options exist for siltuximab non-responders, and no validated tests are available to predict likelihood of response. We procured and analyzed the largest-to-date cohort of iMCD samples, which enabled classification of iMCD into disease categories, discoveries of siltuximab response biomarkers, and identification of therapeutic targets for siltuximab non-responders. Proteomic quantification of 1,178 analytes was performed on serum of 88 iMCD patients, 60 patients with clinico-pathologically overlapping diseases (human herpesvirus-8(HHV8)-associated MCD, N=20; Hodgkin lymphoma, N=20; rheumatoid arthritis, N=20), and 44 healthy controls. Unsupervised clustering revealed iMCD patients have heterogeneous serum proteomes that did not cluster with clinico-pathologically overlapping diseases. Clustering of iMCD patients identified a novel subgroup with superior response to siltuximab, which was validated using a 7-analyte panel (apolipoprotein E, amphiregulin, serum amyloid P-component, inactivated complement C3b, immunoglobulin E, IL-6, erythropoietin) in an independent cohort. Enrichment analyses and immunohistochemistry identified JAK-STAT3 signaling as a candidate therapeutic target that could potentially be targeted with JAK inhibitors in siltuximab non-responders. Our discoveries demonstrate the potential for accelerating discoveries for rare diseases through multi-stakeholder collaboration.