Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease.
Sheila K PiersonSushila ShenoyAna B OromendiaAlexander M GorzewskiRuth-Anne Langan PaiChristopher Shield NabelJason R RuthSophia A T ParenteDaniel J ArenasMary GuilfoyleManjula ReddyMichael WeinblattNancy A ShadickMark BowerAlessia Dalla PriaYasufumi MasakiLaura KatzJason MezeyPhilip BeinekeDavid LeeCraig TendlerTaku KambayashiAlexander FossåFrits van RheeDavid C FajgenbaumPublished in: Blood advances (2021)
Idiopathic multicentric Castleman disease (iMCD) is a poorly understood hematologic disorder involving cytokine-induced polyclonal lymphoproliferation, systemic inflammation, and potentially fatal multiorgan failure. Although 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 US Food and Drug Administration-approved treatment. Few options exist for siltuximab nonresponders, 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, discovery of siltuximab response biomarkers, and identification of therapeutic targets for siltuximab nonresponders. Proteomic quantification of 1178 analytes was performed on serum of 88 iMCD patients, 60 patients with clinico-pathologically overlapping diseases (human herpesvirus-8-associated MCD, N = 20; Hodgkin lymphoma, N = 20; rheumatoid arthritis, N = 20), and 42 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 Janus kinase (JAK)/signal transducer and activator of transcription 3 signaling as a candidate therapeutic target that could potentially be targeted with JAK inhibitors in siltuximab nonresponders. Our discoveries demonstrate the potential for accelerating discoveries for rare diseases through multistakeholder collaboration.
Keyphrases
- end stage renal disease
- ejection fraction
- newly diagnosed
- rheumatoid arthritis
- chronic kidney disease
- prognostic factors
- peritoneal dialysis
- randomized controlled trial
- stem cells
- hodgkin lymphoma
- deep learning
- systemic lupus erythematosus
- clinical trial
- oxidative stress
- study protocol
- toll like receptor
- open label
- human health
- bone marrow
- inflammatory response
- interstitial lung disease
- idiopathic pulmonary fibrosis