About

David C. Fajgenbaum, MD, MBA, MSc, is an Associate Professor of Medicine (on leave) in Translational Medicine & Human Genetics at the University of Pennsylvania. He is the Founding Director of the Center for Cytokine Storm Treatment & Laboratory (CSTL), Co-Founder and President of Every Cure, and Co-Founder and President of the Castleman Disease Collaborative Network (CDCN). Dr. Fajgenbaum is a patient battling idiopathic multicentric Castleman disease (iMCD) and is recognized for transforming the treatment and survival of patients with Castleman disease and other rare diseases. He discovered a repurposed treatment that saved his own life and others, which he chronicled in his national bestselling memoir ‘Chasing My Cure,’ now being adapted into a film. His research focuses on elucidating the etiology, dysregulated cell types, signaling pathways, and effector cytokines involved in iMCD and related cytokine storm disorders. He employs a variety of techniques, including whole genome sequencing, proteomics, flow cytometry, and cellular signaling assays, to understand disease mechanisms and identify effective treatments. Dr. Fajgenbaum has advanced 14 repurposed treatments for cancers and rare diseases, leveraging innovative approaches such as computational pharmacophenomics utilizing AI to predict drug repurposing opportunities. His work aims to accelerate drug development and improve patient outcomes, supported by his leadership roles, numerous scientific publications, and recognition through prestigious awards and media profiles.

Research topics

• Medicine
• Internal medicine

Selected publications

• Comparative proteomic analysis of saliva, urine, and serum in mucopolysaccharidosis type I patients

  Molecular Genetics and Metabolism · 2026-02-01

  article
  PublisherDOI

• Quantify unmet medical need across the disease landscape – A large language model-based methodology

  PLoS Medicine · 2026-03-12 · 1 citations

  articleOpen accessSenior author

  BACKGROUND: Despite the ultimate goal of medical researchers and funders being to maximize patient benefit, there is no systematic process for quantifying unmet medical need across diseases. While a relative unmet medical need scoring system would be valuable for prioritization of medical research, systematically performing this effort across all 22,701 human diseases is technically challenging, time-consuming, and expensive. Using a large language model-based (LLM) architecture, we built a scalable method demonstrating feasibility to quantify "unmet medical need" criteria across all diseases, combine those criteria into a single weighted score, and extend the method into new criteria or diseases in the future. We aimed to quantitatively determine which diseases have the greatest unmet medical need and, therefore, which diseases are priority targets for new repurposed treatments. METHOD AND FINDINGS: We defined 11 scoring criteria across three categories of unmet medical need. For each criterion, we tested LLM models and refined prompts to generate a score per criteria for each disease and then defined a weighting for each criterion to contribute to a final score. A 30-disease development set was used to iterate on the prompting, and a 10-disease evaluation set was held out and used to evaluate the performance of the final prompt. All 22,701 human diseases in the MONDO disease ontology were quantitatively scored for their unmet medical need across all 11 weighted criteria. The resulting scores allowed for relative comparison between diseases of unmet medical needs. Inter-expert agreement was strong, indicating reliability of the scoring framework with 95% of ratings within a 1-point difference. Across multiple LLMs, gpt-4o is most closely aligned with expert rankings, achieving low mean and standard deviation differences relative to human scores. Furthermore, LLM-generated scores demonstrated strong Spearman's rho correlations with expert assessments across key clinical criteria, such as mortality (ρ = 0.845) and quality-adjusted life years lost (ρ = 0.822), supporting their suitability for prioritizing unmet medical need. All data were generated in ~1 hour with no missing data, at a total cost of $120 USD of compute and the results of the Unmet Medical Need Index are publicly available. The main limitation of this study is the combined size of the development and evaluation set being 40 diseases. CONCLUSIONS: This accessible, scalable methodology enables funders and researchers, across governments, universities, healthcare organizations, and disease groups to tailor prioritization efforts according to unmet medical need in the context of their organizational objectives, by selecting appropriate criteria and weighting of those criteria. This method creates a pragmatic and transparent tool to streamline research prioritization. Future research should consider expanding the disease set size used to create scores.

  PublisherDOI

• Correction: Quantify unmet medical need across the disease landscape – A large language model-based methodology

  PLoS Medicine · 2026-04-10

  articleOpen accessSenior author

  [This corrects the article DOI: 10.1371/journal.pmed.1004798.].

  PublisherOA PDFDOI

• Lenalidomide‐Dexamethasone as an Effective and Well‐Tolerated Treatment Option for Refractory Rosai‐Dorfman‐Destombes Disease: A Clinical and Pharmacophenomic Study

  American Journal of Hematology · 2026-04-02 · 1 citations

  article

  A combined clinical and computational pharmacophenomic study from the Coastal Rare Inflammatory Diseases Program and Every Cure. Rosai-Dorfman-Destombes (RDD) disease is a rare histiocytic neoplasm that commonly presents with skin and subcutaneous masses, lymphadenopathy, and bone lesions [1]. Management is guided by disease extent, symptom burden, presence of targetable mutations, and treatment response [1, 2]. Although recent studies have highlighted the role of the mitogen-activated protein kinases-extracellular signal-regulated kinases (MAPK–ERK) pathway mutations in histiocytic disorders [3, 4], approximately 60% of patients with RDD lack targetable mutations on next generation sequencing (NGS), underscoring the need for alternative therapeutic strategies. Immunomodulatory drugs (IMiDs), including thalidomide and lenalidomide, exert anti-inflammatory and antineoplastic effects through modulation of cytokine signaling and cereblon-mediated pathways [5, 6]. Given that RDD pathophysiology involves cytokine-driven inflammation—including tumor necrosis factor and interleukin-6—lenalidomide represents a biologically rational therapeutic candidate. The National Cancer Care Network (NCCN) guidelines list lenalidomide as an “other recommended regimen,” and expert consensus supports its use in refractory disease [1, 7]. Clinical activity of IMiDs in RDD has been described in numerous case reports [8-10], and a recent phase II study demonstrated an overall response rate of 87% in 23 patients treated with lenalidomide and dexamethasone (len/dex) [11]. Computational pharmacophenomics is an emerging approach for systemic drug repurposing that evaluates the therapeutic potential of approved agents across diseases and disease subtypes [12]. Given the vast amount of data available: with approximately 4000 FDA-approved drugs and 18 500 recognized human diseases, manual identification alone of the 75 000 000 possible combinations is impossible. Biomedical knowledge graphs enable this approach by integrating diverse biomedical data sources, including drug–disease associations and mechanisms of action, to identify therapies with shared biological or pathophysiologic features [13]. This approach is particularly valuable in rare diseases such as RDD, where conventional large-scale trials are often infeasible. In this study, we conducted a combined clinical and pharmacophenomic analysis of len/dex in RDD. First, we conducted a retrospective review of patients enrolled in the Coastal Rare Inflammatory Diseases (CoRID) program, a Canadian rare disease program directed by one of the senior authors (LC). Ethics approval was obtained from the University of British Columbia Clinical Research Ethics Board. Eleven patients with histopathologically confirmed RDD treated with len/dex were included. Demographic, clinical, radiographic, and outcome data were abstracted from medical records, with a data cutoff of October 31, 2025. Treatment response was assessed by clinical evaluation and/or imaging (PET-CT, CT, or MRI) and categorized as complete response, partial response, stable disease, or progressive disease based on adapted consensus response criteria for histiocytoses [14]. Second, a computational pharmacophenomics approach (manuscript in preparation) was used to evaluate drug repurposing opportunities for RDD. An ensemble machine learning model trained on known drug–disease relationships was applied to a biomedical network integrating the RTX-KG2 and ROBOKOP knowledge graphs [15, 16]. Network nodes were embedded using Node2Vec, and drug and disease embeddings were used to generate prediction scores for drug–disease pairs. Model outputs were normalized to produce a ‘treat score’ (0–1), reflecting the predicted biological plausibility of a drug for RDD, with 0.00 being the lowest and 0.99 being the highest. Results were then re-ranked according to various strategic criteria, including consideration of unmet medical need, existing evidence (both preclinical and clinical), and relevant drug safety information. Eleven patients were included (six males, five females), with a median age at diagnosis of 55 years (range 17–80 years), six of whom were included in previous publications [2, 17-19]. Extranodal disease was present in ten patients (Table I). Tissue NGS was performed in seven cases, identifying one KRAS p.K117N mutation three MAP2K1 mutations across two patients. Five patients received corticosteroids as first-line therapy. Additional systemic agents—including rituximab, sirolimus, cladribine, and methotrexate—and local interventions such as surgery or radiation did not provide clinical response. One patient with a KRAS mutation achieved a partial response to trametinib but discontinued therapy after 6 months due to cutaneous toxicity. All eleven patients received len/dex across lines of therapy ranging from first to fifth (Table 1). Lenalidomide was administered at doses ranging from 10 to 25 mg daily for 21 of every 28 days, in combination with dexamethasone at doses of 8 to 40 mg weekly based on standard doses at our cancer center [https://www.bccancer.bc.ca/chemotherapy-protocols-site/Documents/Lymphoma-Myeloma/MYLDREL_Protocol.pdf], along with low dose aspirin or anticoagulation. The median time on treatment was 18.1 months (range 4.0–59.2 months). Ten patients demonstrated clinical and/or radiographic benefit, and only one experienced progressive disease while on treatment (Figure 1). The median follow-up time from the date of diagnosis to the date of data cut-off was 33.1 months (range 11.0–78.7 months). KRAS p.K117N FUBP1 p.I443V ERBB4 p.V949I Computational pharmacophenomics analysis evaluated 2975 FDA-approved drugs for predicted activity in RDD. Among the highest-ranked candidates were cytotoxic agents and corticosteroids currently used in clinical practice (Figure 2A,C). Dexamethasone ranked 4th overall (treat score 0.9986), and lenalidomide ranked 23rd (0.9967). Dexamethasone, which often accompanies lenalidomide in clinical practice in this disease space, is the highest-rated corticosteroid. When excluding corticosteroids and traditional chemotherapies, lenalidomide emerged as the third-highest ranked agent, exceeding several NCCN “preferred” cytotoxic therapies, including cladribine and cytarabine (Figure 2B). In this series of patients with relapsed or refractory RDD, lenalidomide combined with dexamethasone was associated with consistent and clinically meaningful benefit across molecular subtypes and treatment lines. These findings address a key therapeutic gap in RDD, particularly for patients without actionable MAPK–ERK pathway mutations or those who have exhausted conventional systemic options. While targeted inhibitors have transformed management in mutation-positive disease, their utility is limited by mutation prevalence, access to molecular testing, drug availability, and toxicity. In contrast, lenalidomide and corticosteroids are broadly accessible even in lower-income countries, and do not require genomic stratification. Some cases are illustrative of the responses that can be seen with this regimen. An 80 year old man (case 3) presented with large peri-orbital masses affecting his vision and had no actionable mutations on NGS. He had minimal clinical or radiological response to rituximab, sirolimus, cladribine, and local radiation. Lenalidomide and dexamethasone given in fifth-line resulted in substantial clinical and radiographic improvement (Figure S1C,D). Case 8 had an 8.6 cm right thigh soft tissue lesion causing significant discomfort from femoroacetabular impingement. Although she had a MAP2K1 mutation, medication coverage issues precluded the use of targeted therapy in first line. After 7 months of lenalidomide and dexamethasone, the mass was no longer palpable and symptoms resolved (Figure S1A,B). Lenalidomide and dexamethasone were also generally well tolerated, with only low-grade adverse events observed and toxicities were consistent with the known safety profile of IMiDs [7]. Most adverse events were limited to grade 1 toxicities, which were manageable without routine dose modification. One patient (case 11) had composite marginal zone lymphoma/RDD, frailty, and multiple comorbidities. He had initial response to len/dex but then developed fatal transformation to aggressive B-cell lymphoma. Lenalidomide is associated with increased risk of secondary malignancies in myeloma cohorts [20]; no other secondary malignancies were observed in this study and no other hematological adverse events were observed. One patient discontinued therapy due to grade 1 transaminitis after achieving complete remission. The tolerability of len/dex and potential for time-limited therapy contrast with targeted MAPK pathway inhibitors, which often require indefinite treatment duration and have significant tolerability issues. In one study evaluating MEK and KRAS inhibitors in RDD, 56% of patients developed treatment-related adverse events leading to dose reduction or discontinuation [4]. A number of practical considerations limit the use of MEK and KRAS inhibitors in lower income jurisdictions: NGS testing is not universally available, 60% of RDD patients are wild-type, and targeted therapies are costly. In contrast, lenalidomide and dexamethasone are widely accessible, have a well-established safety profile, and can be effective irrespective of mutational status. In our cohort, responses were observed across both mutation-positive and wild-type cases, and durable disease control was achieved in several patients, including after treatment discontinuation. Our computational pharmacophenomics analysis further supports these clinical observations. Within this framework, the lenalidomide/dexamethasone combination received a higher probability score than other commonly used systemic therapies, irrespective of MAPK mutation status. Notably, even the MEK inhibitors cobimetinib and trametinib—the recommended first- and second-line therapies for MAPK-mutant RDD—received lower scores (0.84 and 0.80, respectively). This likely reflects the narrower therapeutic context of MEK inhibitors, which are effective primarily in mutation-positive disease, whereas the model assigns probability scores on an all-comers, mutation-agnostic basis. Importantly, the model appropriately identifies MEK as well as upstream signaling genes such as V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) and KRAS as relevant entities in its prediction process in making these determinations. Rituximab received the highest probability score, likely owing to the well-characterized mechanism of action and extensive literature coverage leading to stronger network connectivity within knowledge graphs. Taken together, our findings demonstrate that lenalidomide and dexamethasone can produce meaningful and durable responses in relapsed/refractory RDD, including in patients who lack targetable mutations or have exhausted multiple therapies. The low-grade, manageable toxicities further support the practicality of this regimen. Importantly, these clinical outcomes are consistent with favorable computational pharmacophenomic predictions, collectively suggesting lenalidomide-based therapy as a promising, accessible treatment option for refractory/relapsed or wild-type RDD. Luke Y.C. Chen's research is supported by a philanthropic gift from the Hsu & Taylor Family through the UBC & VGH Foundation. David C. Fajgenbaum's research is supported by the National Heart, Lung, and Blood Institute (R01HL141408) and US Food & Drug Administration (R01FD007632). Every Cure receives funding from The Advanced Research Projects Agency for Health (ARPA-H), Chan Zuckerberg Initiative, Lyda Hill Philanthropies, and the Audacious Project. Supported by funding from Every Cure and the Advanced Research Projects Agency for Health (ARPA-H, agreement number 140D042490001). The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the United States Government. Luke Y.C. Chen: Honoraria – Glaxo-Smith-Kline, Recordati Rare Diseases. Rebecca A. Harrison: Honoraria – Servier Canada, Novocure Canada. Julia Varghese: Honoraria – Janssen, Pfizer, GSK, FORUS, Recordati Rare Diseases, Sanofi. David C. Fajgenbaum: Research Funding and Consulting – Recordati Rare Diseases. This study was approved by the University of British Columbia Clinical Research Ethics Board; individual consent to participate and consent was waived for this minimal risk retrospective study. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Figure S1: Clinical and radiographic responses before and after treatment with lenalidomide and dexamethasone. A. Case 8, right thigh mass pre-treatment. B. Case 8, near resolution of right thigh mass post-treatment. C. Case 3, a 3.0 × 2.9 × 1.6 cm right orbital mass (red arrow) is shown causing severe right eye ptosis pre-treatment. D. Case 3, near resolution of orbital mass (red arrow) post-treatment with resolution of right eye ptosis. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

  PublisherDOI

• Breast-implant associated unicentric castleman disease: a case report

  Current Problems in Cancer Case Reports · 2026-01-03

  articleOpen accessSenior authorCorresponding

  ALK-negative anaplastic large cell lymphoma is a well-established hematologic complication of prosthetic breast implantation, but other rare conditions should also be considered. We report a case of a 36-year-old female with bilateral retropectoral breast implants since age 20 who presented with fatigue, lower extremity edema, fevers, and a slowly growing left breast mass. Ultrasound of the left breast revealed a 6 × 6 cm left upper quadrant mass. Surgical excision identified pathologic features consistent with hyaline-vascular unicentric Castleman disease (UCD). This is the first case of breast-implant associated UCD, expanding the differential diagnosis for masses associated with prosthetic breast implantation.

  PublisherDOI

• Identifying repurposing opportunities using computational pharmacophenomics in major depressive disorder: a meta-analysis and systematic review of glabellar injection of Botulinum Toxin A

  Psychiatry Research Communications · 2026-04-27

  articleOpen accessSenior author

  Major depressive disorder (MDD) is a Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V) recognized condition impacting hundreds of millions worldwide, with significant unmet need that may be addressed through drug repurposing. Botulinum Toxin A (BoNT/A) was identified as a potential treatment for MDD via a technique we are pioneering called computational pharmacophenomics, wherein machine learning models are used to identify novel or previously investigated drug repurposing opportunities. We conducted a meta-analysis and systematic literature review to investigate this potential drug repurposing opportunity further. Using PRISMA guidelines and Cochrane Handbook standards, we performed a systematic literature search, identifying 548 publications, of which six publications detailing seven randomized, placebo-controlled clinical trials met all predefined inclusion criteria. In a meta-analysis of these trials, BoNT/A demonstrates a moderate-to-large effect size ( d = -1.01, 95% CI [-1.81; -0.21]) in the ability to reduce clinical measures of depression, suggesting benefit in this patient population, though these data were subject to substantial heterogeneity and potential small studies biases (I 2 = 88.8%). The benefits of this intervention are also supported by other non-randomized interventional studies as well as mechanistic data in preclinical models. While this effect size may in part be influenced by small studies effects, displays heterogeneity, and substantial variability in placebo response, this treatment warrants further investigation and efforts to identify meaningful responder subpopulations. • Computational pharmacophenomics is a novel tool for rapidly identifying drug repurposing ideas • Botulinum toxin A (BoNT/A) was surfaced in this screen as a high-ranking treatment for depression • As many as 12 clinical studies were identified, with 7 randomized, placebo-controlled trials • A quantitative meta-analysis was performed, demonstrating a moderate-to-large effect size • BoNT/A for depression may warrant further study and use within psychiatric care pathways

  PublisherDOI

• Dysregulated lymphocyte localization in idiopathic multicentric Castleman disease

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-15 · 1 citations

  articleOpen accessSenior author

  Idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening hematologic disease involving episodic flares of uncontrollable systemic inflammation by unknown causes. Hallmark features of iMCD include multiple enlarged lymph nodes with characteristic histopathological phenotypes and a potentially fatal, cytokine release syndrome. The key pathophysiologic drivers of disease are poorly understood and few effective treatment options exist. Here, we discovered an association between elevated chemokines, namely CXCL13, and lymph node size in iMCD, providing one possible explanation for the lymphadenopathy observed clinically. Instead of a concurrent increase in circulating CXCL13 and CXCR5-expressing cells that has been described in other contexts, during active disease, chemokine-responsive lymphocytes downregulated CXCR5 levels in iMCD. Despite heightened chemokine production by lymph node stromal cells, T and B cells failed to appropriately respond to their cues locally within the tissue and were particularly scarce within CXCL13-expressing germinal centers (GC). Inflammatory signals in iMCD lymph nodes appeared to restrict the production and movement of T follicular helper cells, which play an important role in facilitating appropriate GC responses. Together, these data provide a link between dysregulated chemokine production and germinal center lymphocyte trafficking, highlighting a potential mechanism and therapeutic target in iMCD lymphadenopathy. One Sentence Summary: Lymphocyte chemotaxis to discrete areas of lymphoid tissue is disrupted in idiopathic multicentric Castleman disease.

  PublisherOA PDFDOI

• Rare Disease Drug Repurposing

  JAMA Network Open · 2025-05-05 · 7 citations

  articleOpen accessSenior authorCorresponding

  Importance: Treatments are urgently needed for the more than 9500 rare diseases with no US Food and Drug Administration-approved therapies. Although repurposing can be less time- and cost-intensive compared with novel drug development, hurdles have impeded systematic repurposing. Rare disease nonprofit organizations (RDNPs) are well-positioned to overcome barriers and have spearheaded rare disease repurposing efforts for decades. However, no comprehensive data are available on the state of rare disease repurposing or features of successful efforts. Objective: To characterize the state of rare disease drug repurposing, identify factors associated with successful outcomes, and share thematic insights using the interactive Repurposing of All Drugs, Mapping All Paths (ROADMAP) Project web tool. Design, Setting, and Participants: The ROADMAP study was a qualitative study using a mixed-methods analysis of US-based RDNP leaders and their stakeholders, including a national survey and semistructured interviews of RDNP leaders, conducted from September 29, 2021, to January 6, 2022. Surveys and interviews revealed themes associated with RDNP strategies, timelines, and support mechanisms. Data were analyzed from January 22, 2024, to April 23, 2024. Main Outcomes and Measures: The primary survey outcome was the repurposing project stage (abandoned, early, clinical, late, or successful). Qualitative outcomes included themes characterizing repurposing experiences. Two random forest models of drug- and disease- specific as well as organization-specific variables were used to evaluate factor importance toward inferring the project stage. Orthogonal significance testing was conducted using Spearman rank correlation, and P values in each model were corrected for multiple hypothesis testing using a Benjamini-Hochberg procedure. Results: Representative organizations submitted survey responses, including 147 of 698 potential US-based RDNPs. The median RDNP age was 10 years (IQR, 5-20 years), and the median annual revenue was $355 390 (IQR, $90 028-$946 108). Among 34 leaders who were interviewed, representing 25 RDNPs, 23 were female (67.6%), and the RDNPs had a median age of 15 years (IQR, 6-19 years) and a median revenue of $670 719 (IQR, $193 587-$1 830 890). Among the surveyed RDNPs, 58 of 138 (42.0%) specifically identifying their involvement in repurposing supported repurposing projects, and 94 drugs were in various stages of repurposing, of which 23 met success criteria (5 with US Food and Drug Administration approval and 18 with off-label use with subjective benefit). Survey factors associated with successful outcomes included nonprofit-supported patient recruitment into trials (Gini importance, 3.90; ρ = 0.50; adjusted P < .001) and provision of nonfinancial research support (Gini importance, 0.69; ρ = 0.33; adjusted P = .02). Interview themes were synthesized into a 5-stage repurposing framework with roadblocks and recommendations that included (1) enabling drug repurposing, (2) identifying a drug therapy, (3) validating a drug therapy, (4) clinical use and testing, and (5) reaching an optimal end point for clinical practice. Conclusions and Relevance: The findings of this qualitative study of RDNP repurposing suggest that several opportunities were associated with successful outcomes and can be considered to optimize systematic repurposing among RDNPs, external collaborators, and policymakers with the use of an interactive tool showcasing insights to facilitate data-driven drug repurposing.

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• Common connective tissue disorder and anti-cytokine autoantibodies are enriched in idiopathic multicentric castleman disease patients

  Frontiers in Immunology · 2025-03-13 · 5 citations

  articleOpen accessCorresponding

  Introduction: Idiopathic Multicentric Castleman Disease (iMCD) is a polyclonal lymphoproliferative disorder involving cytokine storms that can lead to organ failure and death. The cause of iMCD is unknown, but some clinical evidence suggests an autoimmune etiology. For example, connective tissue disorders (CTDs) and iMCD share many clinical features, and autoantibodies have been anecdotally reported in individual iMCD patients. This study investigates whether common autoantibodies are shared across iMCD patients. Methods: We assembled custom bead-based protein arrays consisting of 52 autoantigens traditionally associated with CTDs and 38 full-length cytokines and screened serum samples from 101 iMCD patients for IgG autoantibodies. We also screened samples with a 1,103-plex array of recombinant human protein fragments to identify additional autoantibody targets. Finally, we performed receptor blocking assays on select samples with anti-cytokine autoantibodies (ACAs) identified by array. Results: We found that an increased proportion of iMCD patients (47%) tested positive for at least one CTD-associated autoantibody compared to healthy controls (HC) (17%). Commonly detected CTD-associated autoantibodies were associated with myositis and overlap syndromes as well as systemic lupus erythematosus (SLE) and Sjögren's Syndrome (SS). ACAs were also detected in a greater proportion of iMCD patients (38%) compared to HC (10%), while the protein fragment array identified a variety of other autoantibody targets. One iMCD sample tested positive for receptor blocking against interferon-ω (IFNω). Discussion: IgG autoantibodies binding autoantigens associated with common CTDs and cytokines are elevated in iMCD patients compared to HC, suggesting that autoimmunity may be involved in iMCD pathogenesis.

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• Distinct interleukin-6 production in IPL and TAFRO subtypes of idiopathic multicentric Castleman disease

  Haematologica · 2025-09-11 · 2 citations

  articleOpen access

  Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder characterized by systemic inflammation and lymphadenopathy. Two major clinical subtypes, idiopathic plasmacytic lymphadenopathy (iMCD-IPL) and iMCD with thrombocytopenia, anasarca, fever, renal dysfunction/reticulin fibrosis, and organomegaly (iMCD-TAFRO), have distinct pathophysiological mechanisms. While interleukin-6 (IL-6) is known to be elevated in iMCD, differences in the sources of IL-6 production between subtypes remain unclear. We examined the source of IL-6 production and its transcriptional regulation across iMCD subtypes using immunohistochemistry, in situ hybridization, and gene expression profiling. Immunohistochemistry and in situ hybridization revealed that plasma cells were the predominant IL-6-expressing cells in iMCD-IPL, whereas vascular endothelial cells expressed IL-6 in iMCD-TAFRO. Plasma cells exhibited stronger IL-6 protein expression in iMCD-IPL than in iMCD-TAFRO. Gene expression analysis revealed upregulation of XBP1, MZB1, DERL3, SSR4, FKBP11, FKBP2, PIM2, RABAC1, and SDF2L1 in iMCD-IPL, implicating endoplasmic reticulum stress and plasma cell differentiation in IL-6 dysregulation. Our findings suggest that XBP1-mediated IL-6 production may contribute to the pathogenesis of iMCD-IPL, potentially explaining its favorable responses to IL-6 blockade therapy. In contrast, IL-6 production in iMCD-TAFRO may be predominantly from vascular endothelial cells, suggesting that elevated serum IL-6 is a secondary phenomenon of the cytokine storm in this subtype. Future studies should clarify how proteomics and gene expression profiling could inform subtype-specific therapeutic strategies in iMCD.

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Recent grants

• JAK1/2 as a Central Regulator of iMCD Pathogenesis and Novel Therapeutic Target

  NIH · $756k · 2018–2023

• JAK1/2 as a Central Regulator of iMCD Pathogenesis and Novel Therapeutic Target

  NIH · $4.7M · 2018–2028

Frequent coauthors

• Frits van Rhee

  University of Arkansas for Medical Sciences

  58 shared

• Sheila K. Pierson

  University of Pennsylvania

  57 shared

• Megan S. Lim

  Memorial Sloan Kettering Cancer Center

  24 shared

• Jason R. Ruth

  University of Pennsylvania

  21 shared

• Gordan Srkalović

  Herman Miller (United States)

  18 shared

• Corey Casper

  Fred Hutch Cancer Center

  17 shared

• Mary Jo Lechowicz

  Winship Cancer Institute

  17 shared

• Amy Chadburn

  16 shared

Education

• MBA, Health Care Management

  University of Pennsylvania Wharton School

  2015

• MD, School of Medicine

  University of Pennsylvania

  2013

• MSc (By Research) Public Health, Public Health

  University of Oxford

  2008

• BS, Human Sciences

  Georgetown University

  2007

Awards & honors

• 2016 Atlas Award