Multicentric Castleman's Disease Research Articles

Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease.

Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder with heterogeneous presentations ranging from moderate constitutional symptoms to life-threatening multiorgan system involvement. There are vastly different clinical subtypes, with some patients demonstrating thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin fibrosis/renal failure, and organomegaly (TAFRO) and others having milder/more moderate symptoms with potential for severe disease (not otherwise specified, NOS). Due to its rarity and heterogeneity, the natural history and long-term burden of iMCD are poorly understood. We investigated real-world medical data from ACCELERATE, a large natural history registry of patients with Castleman disease, to better characterize the long-term disease burden experienced by these patients. We found that iMCD-TAFRO patients face a significant hospitalization burden, requiring more time in the hospital than iMCDNOS patients during the year surrounding diagnosis (median [interquartile range]: 36 [18-61] days vs. 0 [0-4] days; P<0.001). In addition, we found life-sustaining interventions, such as mechanical ventilation (17%) and dialysis (27%), were required among iMCD patients, predominantly those with iMCD-TAFRO. iMCD-NOS patients, however, spent a significantly greater proportion of time following disease onset in a state of disease flare (median 52.3% vs. 18.9%; P=0.004). Lastly, we observed severe iMCD-related morbidities, such as acute renal failure, sepsis and pneumonia, among others, arising after iMCD diagnosis, impairing the patients' quality of life. These data demonstrate a substantial disease burden experienced by iMCD patients and emphasize the importance of ongoing research into iMCD to aid disease control.

Single-cell landscape of idiopathic multicentric Castleman disease in identical twins

AbstractIdiopathic multicentric Castleman disease (iMCD) is a rare cytokine-driven disorder characterized by systemic inflammation, generalized lymphadenopathy, and organ dysfunction. Here, we present an unusual occurrence of iMCD in identical twins and examined the immune milieu within the affected lymphoid organs and the host circulation using multiomic high-dimensional profiling. Using spatial enhanced resolution omics sequencing (Stereo-seq) transcriptomic profiling, we performed unsupervised spatially constrained clustering to identify different anatomic structures, mapping the follicles and interfollicular regions. After a cell segmentation approach, interleukin 6 (IL-6) pathway genes significantly colocalized with endothelial cells and fibroblastic reticular cells, confirming observations using a single-cell sequencing approach (10× Chromium). Furthermore, single-cell sequencing of peripheral blood mononuclear cells revealed an “inflammatory” peripheral monocytosis enriched for the expression of S100A family genes in both twins. In summary, we provided evidence of the putative cell-of-origin of IL-6 signals in iMCD and described a distinct monocytic host immune response phenotype through a unique identical twin model.

Kaposi's sarcoma herpesvirus exploits the DNA damage response to circularize its genome.

To establish lifelong, latent infection, herpesviruses circularize their linear, double-stranded, DNA genomes through an unknown mechanism. Kaposi's sarcoma (KS) herpesvirus (KSHV), a gamma herpesvirus, is tightly linked with KS, primary effusion lymphoma, and multicentric Castleman's disease. KSHV persists in latently infected cells as a multi-copy, extrachromosomal episome. Here, we show the KSHV genome rapidly circularizes following infection, and viral protein expression is unnecessary for this process. The DNA damage response (DDR) kinases, ATM and DNA-PKcs, each exert roles, and absence of both severely compromises circularization and latency. These deficiencies were rescued by expression of ATM and DNA-PKcs, but not catalytically inactive mutants. In contrast, γH2AX did not function in KSHV circularization. The linear viral genomic ends resemble a DNA double strand break, and non-homologous DNA end joining (NHEJ) and homologous recombination (HR) reporters indicate both NHEJ and HR contribute to KSHV circularization. Last, we show, similar to KSHV, ATM and DNA-PKcs have roles in circularization of the alpha herpesvirus, herpes simplex virus-1 (HSV-1), while γH2AX does not. Therefore, the DDR mediates KSHV and HSV-1 circularization. This strategy may serve as a general herpesvirus mechanism to initiate latency, and its disruption may provide new opportunities for prevention of herpesvirus disease.

Chronic urticaria as a manifestation of multicentric Castleman disease treated with rituximab

AbstractWe present the case of a 26‐year‐old female with chronic urticaria (CU) with systemic symptoms in whom comprehensive laboratory and imaging studies led to the diagnosis of idiopathic multicentric Castleman disease. Treatment with rituximab induced resolution of CU. The association between these two entities is rare, and common autoimmune and autoinflammatory pathways may be involved in their production. Our case also emphasized the association of CU with an underlying systemic disease.

Immune-mediated thrombocytopenia and IL-6-mediated thrombocytosis observed in idiopathic multicentric Castleman disease.

Idiopathic multicentric Castleman disease (iMCD) is a rare haematological disorder characterized by generalized lymphadenopathy with atypical histopathological features and systemic inflammation caused by a cytokine storm involving interleukin-6 (IL-6). Three clinical subtypes are recognized: thrombocytopenia, anasarca, fever, renal dysfunction, organomegaly (iMCD-TAFRO); idiopathic plasmacytic lymphadenopathy (iMCD-IPL), involving thrombocytosis and hypergammaglobulinaemia; and iMCD-not otherwise specified (iMCD-NOS), which includes patients who do not meet criteria for the other subtypes. Disease pathogenesis is poorly understood, with potential involvement of infectious, clonal and/or autoimmune mechanisms. To better characterize iMCD clinicopathology and gain mechanistic insights into iMCD, we analysed complete blood counts, other clinical laboratory values and blood smear morphology among 63 iMCD patients grouped by clinical subtype. Patients with iMCD-TAFRO had large platelets, clinical severity associated with lower platelet counts and transfusion-resistant thrombocytopenia, similar to what is observed with immune-mediated destruction of platelets in immune thrombocytopenic purpura. Conversely, elevated platelet counts in iMCD-IPL were associated with elevated IL-6 and declined following anti-IL-6 therapy. Our data suggest that autoimmune mechanisms contribute to the thrombocytopenia in at least a portion of iMCD-TAFRO patients whereas IL-6 drives thrombocytosis in iMCD-IPL, and these mechanisms likely contribute to disease pathogenesis.

The Cytokine Storm of Multicentric Castleman Disease.

As described throughout this book, different triggers can elicit a variety of different cytokine storm disorders that share overlapping clinical features (Fig. 31.1). Even within a particular cytokine storm disorder, multiple different triggers can elicit the syndrome. Like HLH, multicentric Castleman disease (MCD) serves as a great example of this as it can be caused by a viral infection, neoplastic cell population, or an unknown cause. Furthermore, the idiopathic subtype of MCD (iMCD) provides one of the first examples of a cytokine storm disorder that could be abrogated with targeted neutralization of a single cytokine when inhibition with the anti-interleukin-6 (IL-6) receptor monoclonal antibody tocilizumab was shown to effectively treat iMCD in the 1990s. Of course, this "iMCD treatment," tocilizumab, has been used in a variety of cytokine storm settings over the last 30+ years.

An Unusual Case of HHV-8 Negative, Idiopathic, Multicentric Castleman Disease Following Chronic Lymphocytic Leukaemia.

Castleman disease is a rare condition characterised by polytypic lymphocytes proliferation and lymphadenopathy generally with a benign course. Whereas high grade lymphoma (Richter syndrome) is a classical complication seen in chronic lymphocytic leukaemia with a poor outcome, benign conditions mimicking this entity are infrequent. We describe the case of an 81-year-old Caucasian male who developed a human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) following a treated Binet C chronic lymphocytic leukaemia (CLL). The clinical and radiological pattern raised initially the suspicion of a classical Richter transformation. Blood analysis showed auto-immune haemolytic anaemia and thrombocytopenia. He had normal immunoglobulin levels. The anatomopathological analysis of a cervical adenomegaly showed hypervascularisation and a polytypic plasmocytic proliferation compatible with a plasmocytic iMCD type. Interestingly, bone marrow examination showed reticuline fibrosis but, in the absence of anasarca or generalised oedema, we were not allowed to conclude to the diagnosis of a TAFRO syndrome. We excluded all other mimicking conditions, comprising haematological malignancies, infections, and auto-immune diseases He was first treated with corticosteroids with poor results but dramatically responded to tocilizumab (anti-Il6). To our knowledge, this the first case described of a Castleman disease following CLL and surprisingly mimicking Richter syndrome. Clinicians should be aware of this rare misleading condition. Castleman disease can mimic a Richter transformation in a CLL patient.

Transcriptome analysis of the cytokine storm-related genes among the subtypes of idiopathic multicentric Castleman disease.

Idiopathic multicentric Castleman disease (iMCD) is a type of Castleman disease unrelated to the Kaposi sarcoma-associated herpesvirus/human herpesvirus type 8 (KSHV/HHV8) infection. Presently, iMCD is classified into iMCD-IPL (idiopathic plasmacytic lymphadenopathy), iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly), and iMCD-NOS (not otherwise specified). The most common treatment for iMCD is using IL-6 inhibitors; however, some patients resist IL-6 inhibitors, especially for iMCD-TAFRO/NOS. Nevertheless, since serum IL-6 levels are not significantly different between the iMCD-IPL and iMCD-TAFRO/NOS cases, cytokines other than IL-6 may be responsible for the differences in pathogenesis. Herein, we performed a transcriptome analysis of cytokine storm-related genes and examined the differences between iMCD-IPL and iMCD-TAFRO/NOS. The results demonstrated that counts per million of STAT2, IL1R1, IL1RAP, IL33, TAFAIP1, and VEGFA (P < 0.001); STAT3, JAK2, MAPK8, IL17RA, IL18, TAFAIP2, TAFAIP3, PDGFA, VEGFC, CXCL10, CCL4, and CXCL13 (P < 0.01); and STAT1, STAT6, JAK1, MAPK1, MAPK3, MAPK6, MAPK7, MAPK9, MAPK10, MAPK11, MAPK12, MAPK14, NFKB1, NFKBIA, NFKBIB, NFKBIZ, MTOR, IL10RB, IL12RB2, IL18BP, TAFAIP6, TNFAIP8L1, TNFAIP8L3, CSF2RBP1, PDGFB, PDGFC, and CXCL9 (P < 0.05) were significantly increased in iMCD-TAFRO/NOS. Particularly, upregulated IL33 expression was demonstrated for the first time in iMCD-TAFRO/NOS. Thus, inflammatory signaling, such as JAK-STAT and MAPK, may be enhanced in iMCD-TAFRO/NOS and may be a cytokine storm.

When idiopathic multicentric Castleman disease meets COVID-19: a multicenter retrospective study from China.

Idiopathic multicentric Castleman disease (iMCD) is a rare and cytokine storm-driven inflammatory disorder. The exact cause of iMCD is still unknown, although several hypotheses have been proposed. However, regardless of the underlying cause, the ultimate result is the activation of the inflammatory pathway, which can lead to damage in multiple organs. Currently, there have been several reports highlighting the intricate link between coronavirus disease 2019 (COVID-19) and iMCD. To better understand the impact of COVID-19-induced immune storm on iMCD, we conducted a multicenter retrospective study in three hospitals in China. A total of 28 patients with iMCD were included, among whom 25 had confirmed COVID-19 infection, and we presented 4 cases that showed different disease progression after the infection of COVID-19, including 2 who did not receive any treatment for Castleman disease before. Our findings underscore the necessity of carefully monitoring iMCD patients with COVID-19 and promptly intervening to address any changes in their condition. Besides, this study also summarized the shared cytokines between COVID-19 and iMCD. Recent studies have shown promising results in treating severe COVID-19 and iMCD using tocilizumab, an interleukin-6 receptor antagonist. Therefore, it suggests that other potential cytokine storm therapy targets that have been effective in COVID-19 may also be explored for the treatment of iMCD.

Outcomes in Kaposi's sarcoma-associated herpesvirus -associated primary effusion lymphoma and multicentric Castleman's disease in patients with human immunodeficiency virus (HIV) in a safety-net hospital system.

To describe cases of Kaposi's sarcoma-associated herpesvirus (KSHV)-associated multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL) in patients with HIV from a large, safety-net hospital system in Dallas, Texas, USA. We conducted a retrospective review of patients with HIV-associated PEL and/or MCD. Twelve patients with PEL and 10 patients with MCD were identified. All patients were male and 17 of 20 were men who have sex with men; 66.7% of PEL patients and 50% of MCD patients had concurrent KS at the time of diagnosis; 42% of patients with PEL and 20% of patients with MCD died during the follow-up period. We noted improved survival in our cohort compared to previous studies, particularly in our PEL patients with a median survival of 11.4 months compared to 3-6-month median survival historically. Median follow-up time for MCD patients was 17.5 months. This improved survival is despite suboptimal antiretroviral therapy (ART) adherence at diagnosis, with only 50% of patients on ART at the time of MCD/PEL diagnosis. These data highlight the importance of early recognition of PEL and MCD, and the larger-scale efforts needed to better understand the pathogenetic drivers of clinical outcomes in patients affected by KSHV-related diseases.

Demographic characteristics and prognosis of HHV8-positive diffuse large B-cell lymphoma, not otherwise specified: Insights from a population-based study with a 10-year follow-up.

HHV8-positive diffuse large B-cell lymphoma, not otherwise specified (HDN) is a subtype of lymphoma that usually arises in association with HHV8-positive multicentric Castleman disease. However, the epidemiology, treatment patterns, and survival outcomes of HDN are poorly understood. A retrospective analysis was performed for 67 patients with HDN diagnosed from 2011 to 2020 using the SEER database. The demographic characteristics, treatment modalities, and survival outcomes of HDN patients were evaluated. Kaplan-Meier analysis and Cox regression analysis were employed to identify prognostic factors for overall survival (OS) and disease-specific survival (DSS). The age-adjusted incidence rate of HDN was 0.010 per 100,000 person-years. The median age at diagnosis was 51.8 years with male predominance. The primary site distribution was mainly nodal (79.1%), while the extranodal sites were rarely involved (20.9%). The majority of patients were white (65.7%). Only 3.0% of patients received radiotherapy, while 55.2% received chemotherapy. The 1-year, 3-year, and 5-year OS was 67.4%, 65.6%, 58.4%, and 56.3%, respectively, and the corresponding DSS was 73.1%, 73.1%, and 67.8%, respectively. The diagnosis year group of 2016-2020 had a significantly worse OS than the diagnosis year group of 2011-2015 (P = .040), but not for DSS (P = .074). No significant survival improvement was observed in patients underwent chemotherapy. Age and marital status were independent prognostic factors for OS, and age was an independent prognostic factor for DSS. In conclusion, HDN is a rare and aggressive disease, our study provides a comprehensive overview of the epidemiology, treatment patterns and survival outcomes of HDN patients for the first time. We revealed that older age and marital status of single were associated with worse survival of HDN, while chemotherapy was not associated with improved survival outcomes in HDN patients.

Circulating plasmablastic cells in a patient with HHV-8-associated multicentric Castleman disease and Kaposi sarcoma

Circulating plasmablastic cells in a patient with HHV-8-associated multicentric Castleman disease and Kaposi sarcoma

Եզակի օջախային Կաստլեմանի հիվանդության ախտորոշման և բուժման ժամանակակից մոտեցումները

Castleman disease is a rare lymphoproliferative disorder associated with HHV-8 and HIV viruses. Currently, there are two types of Castleman disease based on the prevalence of affected lymph nodes: Unicentric Castleman disease and Multicentric Castleman disease. Unicentric Castleman disease involves a lesion of one lymph node or lymph nodes in the same group. The diagnosis is made by histological and immunohistochemical examination of the removed lymph node. Furthermore, it is essential to distinguish Unicentric Castleman disease from Multicentric Castleman disease, for which PET/CT screening is an excellent method. The treatment approach of Unicentric Castleman disease is the surgical excision of all affected lymph nodes, and in non-resectable and asymptomatic cases, control is prescribed. In symptomatic cases, immunosuppressive therapy (rituximab, steroids, anti-IL6 antibodies) should be considered, followed by surgery or radiotherapy.

Evaluation of human herpesvirus-8 viremia and antibody positivity in patients with HIV infection with human herpesvirus-8-related diseases.

Human herpesvirus-8 (HHV-8) viremia is associated with refractory conditions in patients infected with HIV-1. Therefore, we evaluated the factors related to plasma HHV-8-DNA. Participants included patients infected with HIV-1 who visited our hospital. Plasma HHV-8-DNA levels were measured using real-time polymerase chain reaction, and anti-HHV-8 antibodies were assessed through enzyme immunoassays using multiple antigens (K8.1, ORF59, ORF65, and LANA). Factors related to plasma HHV-8-DNA were examined using Fisher's exact test or Mann-Whitney U test. The study involved 36 patients infected with HIV-1, of whom 19 were histologically diagnosed with Kaposi's sarcoma (KS), two had multicentric Castleman's disease (MCD), and 15 did not exhibit HHV-8-related disease. Before the introduction of antiretroviral therapy (ART), plasma HHV-8-DNA was detected in 44% (7/16) of patients with KS and in 9% (1/11) of patients without HHV-8-related disease. Among patients with KS, elevated plasma HHV-8-DNA levels (≥0.05 copies/µL) correlated with the presence of CDC category C diseases other than KS (p = 0.0337), anti-HHV-8 antibody negativity (p = 0.0337), anemia (p = 0.0474), and thrombocytopenia (p = 0.0146). Following ART initiation, the percentage of patients positive for plasma HHV-8-DNA decreased from 44% (7/16) to 6% (1/17), and the percentage of patients positive for anti-HHV-8 antibodies increased from 44% (7/16) to 88% (15/17). Finally, plasma HHV-8-DNA positivity and anti-HHV-8 antibody negativity were observed in two patients with MCD. Our findings suggest that insufficient production of anti-HHV-8 antibodies was associated with HHV-8 viremia, and that anti-HHV-8 antibody production was recovered with ART; thus, indicating the possibility of involvement of humoral immunity in suppressing HHV-8 viremia.

Unicystic Castleman disease presenting in the neck: a case report and review of the literature

Background: Castleman’s disease (CD) is an uncommon hyperplastic disorder of lymphoid tissue, clinically categorized into unicentric CD (UCD) and multicentric CD (MCD), contingent upon the number of lymph node engagement. Unicentric Castleman disease (UCD) manifests as a solitary lump, predominantly found in the mediastinum, and infrequently in the head and neck region. Unlike multicentric Castleman disease (MCD), which displays peripheral lymph node enlargement and a multitude of systemic indications, UCD usually lacks generalized symptoms. Methods: We present a case of UCD presenting as a neck mass, in a 55-year-old woman as well as a detailed literature review for Castleman’s disease. The patient had undergone surgical excision of the mass. Results: The diagnostic findings following Immunohistochemistry were consistent with Hyaline vascular type Castleman’s disease. The patient remains stable with no signs or symptoms of recurrent disease after the mass removal. Conclusion: It is crucial to include Castleman’s’ disease in the differential diagnoses of lymphadenopathies due to the fact that it can be clinically mistaken for other common causes of lymphadenopathy such as lymphoma, tuberculosis, and nodal metastases.

POEMS-associated Multicentric Castleman Disease: A diagnostic and Therapeutic Conundrum

Abstract Introduction/Objective A rare multisystemic, paraneoplastic hematologic disorder, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) is associated with an overproduction of pro-inflammatory cytokines caused by a plasma cell proliferative disorder. Castleman disease is a rare clinical entity described as a polyclonal lymphoid proliferation, that leads to generalized lymphadenopathy. It is rarely presented in association with POEMS Syndrome. Methods/Case Report A 55-year-old hispanic male, when being evaluated for liver mass, revealed bile duct thickening and a pancreatic head mass. Endoscopic fine needle aspiration biopsies were negative; however, the cross sectional imaging identified enlarged left axillary lymph nodes. His excisional lymph node biopsy showed human herpese virus-8 (HHV-8) negative multicentric Castleman disease (MCD). Several features of POEMS syndrome were noted. The axillary lymph node biopsy demonstrated florid follicular hyperplasia, scattered regressed germinal centers and concentric rings of mantle zone lymphocytes. CD138, kappa-ISH, and lambda-ISH highlight scattered polytypic plasma cells. Our case fulfills the mandatory criteria of POEMS syndrome with the presence of neuropathy and a constellation of other major and minor criterion including, axillary Castleman, splenomegaly, hepatomegaly, skin changes, ascites and bilateral renal cortical lesions. Furthermore the patient also has a history of cerebrovascular accident and chronic cough favoring POEMS syndrome. Results (if a Case Study enter NA) NA Conclusion The complexity and multi-organ involvement, leads to frequent misdiagnosis of POEMS disease. In addition significant overlap of symptoms of POEMS syndrome makes it difficult to differentiate from other plasma cell disorders associated with MCD. Our study includes a brief review of the literature delineating the characteristics and overlap between POEMS syndrome and other diseases.

Idiopathic multicentric Castleman's disease with TAFRO syndrome: a case report

Abstract Introduction/Objective Multicentric Castleman's disease(MCD) is a nonneoplastic lymphoproliferative disorder. Individuals affected by MCD exhibit systemic symptoms accompanied by the presence of multiple enlarged lymph nodes. MCD can be associated with human herpesvirus type-8, POEMS syndrome, or idiopathic (iMCD). TAFRO syndrome, a clinical subtype of MCD is a recently recognized disorder with an unclear cause, it comes with a combination of symptoms, namely thrombocytopenia, anasarca, fever, renal dysfunction, and organomegaly. This case report aims to shed light on the diagnostic challenges due to the rarity and nonspecific nature of TAFRO syndrome. Methods/Case Report We report a 30-year-old female who presented with night sweats, fever, fatigue, and cough. She had significant leucocytosis, lymphopenia, thrombocytopenia, anemia requiring transfusion, and elevated creatinine, CT showed ground glass opacities in the lungs and extensive lymphadenopathy. Axillary lymph node excisional biopsy revealed paracortical hyperplasia with increased vascularity, extensive polytypic plasmacytosis, and some follicular hyperplasia. On IHC staining it was positive for CD20, CD79a, PAX 5, and negative cyclin D1 for B lymphocytes. T lymphocytes were positive for CD3, CD5, CD2, CD7, CD4&amp;gt;CD8, Bcl2 and CD43. Plasma cells were composed mainly of IgG cells and some IgG4(IgG4/IgG &amp;lt;20%). HHV8 was negative. Flow cytometry showed 89% lymphocytes with a heterogenous population of T-cells and polytypic B cells. Serology revealed markedly elevated IL- 6, IL-2, VEGF CRP, and ESR while HIV and ANA were negative. Bone marrow biopsy was suggested. A final diagnosis of idiopathic multicentric castle man disease suggestive of TAFRO syndrome was made. The patient received steroids and is currently on siltuximab. Results (if a Case Study enter NA) NA Conclusion Our case fulfills at least four of the five major diagnostic criteria of TAFRO syndrome. It serves as a valuable addition to the scarce literature on TAFRO syndrome, providing insights into its diagnostic challenges

Symptom Burden in Idiopathic Multicentric Castleman Disease: Protocol for the Development of a Novel Standardized Patient Reported Outcome Measure

Background and Significance Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder with a high symptom burden. These symptoms impact many aspects of daily life for people living with iMCD, including work/education, social life, travel, mobility, personal relationships and sexual functioning. Despite this significant impact [Shupo F et al. Hemasphere 2022, Jun 23;6(Suppl):802-803], no validated disease-specific measure exists to assess symptom burden in iMCD. This is a major unmet need, considering the mainstay of iMCD treatment is symptom control and preventing serious complications. A novel symptom burden scale for iMCD is therefore timely and important and would be a beneficial clinical tool, both in routine clinical practice and clinical trials, for the comprehensive assessment of disease burden at diagnosis, during progression, and for treatment efficacy. Study Design and Methods A protocol for the development of a novel, standardized, patient reported outcome measure (PROM) for assessing symptom burden in iMCD has been developed and approved by a multi-stakeholder group (including patients, clinicians, industry representatives, and researchers). A four-stage development process has been proposed, alongside the generation of a novel patient advisory group and wider multi-stakeholder advisory group. In stage one, draft PROM content will be generated from existing literature and expert opinions. In stage two, the content validity of the draft PROM will be assessed in online qualitative interviews with people living with iMCD, with any revisions to the content decided in consultation with patient and expert advisors. In stage three, the revised PROM will be administered alongside existing measures of symptom burden and/or health-related quality of life to evaluate its psychometric performance and inform decisions on content for the final PROM, using classical test theory and/or Rasch psychometric analyses. The PROM will be finalized based on the qualitative and quantitative evidence generated in consultation with project advisors. Finally, in stage four, the PROM will be re-administered to observe change in symptom burden over time. This will be complemented with qualitative interviews in a mixed methods design to estimate a minimally clinically important difference (MCID) for the measure. The project will involve investigators and iMCD patients from the U.S., U.K., Canada, Australia, New Zealand and Brazil. Conclusion This is an international effort to develop and validate a novel iMCD symptom burden PROM through a collaboration of iMCD patients, clinical, health economics, public health, statistical, psychometrics, and industry experts. The development of the measure follows U.S. Food and Drug Administration (FDA) regulatory guidance, with modifications for rare diseases as required. Special Considerations This project has been submitted to clintrials.gov, documentation sent to ASH and Secretary, and awaiting approval of the submission.

Description of Patients with HIV and Multicentric Castleman's Disease at the National Institute of Cancerology- Mexico: A 9-Year Experience

Castleman disease is a diverse group of lymphoproliferative disorders with four variants sharing common morphological features on lymph node biopsy but having different etiologies, presentations, treatments, and outcomes. It is classified into unicentric and multicentric variants (MCD), the latter being a systemic disease with multiple lymphadenopathy, where the most common pathological finding is changes in plasma cell type. Based on etiopathogenic characteristics, it can be divided into Kaposi sarcoma herpesvirus (HHV8)-associated, idiopathic, and those related to an overlap with POEMS syndrome. This disease can occur in both HIV-positive individuals and immunocompromised individuals due to other causes. Here, we report our experience with a cohort of HIV-associated MCD cases from 2014 to 2022. A total of 21 patients diagnosed with HIV and HHV8-associated MCD were observed at INCAN during the study period. The majority were men (95%), with a median age of 33y (range, 25 to 54y). The main histologic MCD type was plasma cells (52%), followed by the mixed variant (28%) and the hyaline vascular type (19%). Almost half of the patients were newly diagnosed with HIV (43%), and half of them had a CD4 cell count below 200 cells/mm3 at the time of MCD diagnosis (48%). Only 38% of known HIV patients were taking combination antiretroviral therapy (cART) at the moment of MCD diagnosis. The vast majority (95.2%) were HHV-8 positive by immunohistochemistry, and 66.7% were associated with Kaposi sarcoma. About 52.4% of cases had another active opportunistic infection documented. The most frequently associated infection was syphilis (33.3%), EBV coinfection (23.8%), hepatitis B (14.3%), hepatitis C (4.8%), and CMV viremia (4.8%). 90% of patients developed B symptoms, 71% had fever, 100% had palpable adenopathy, 71% developed hepatosplenomegaly, and 19% had pleural effusion at presentation. In blood analysis, elevated LDH was present in 42.9%, hypoalbuminemia in 71.4%, thrombocytopenia (&amp;lt;100,000) in 35%, anemia (Hb &amp;lt; 8g/dl) in 20%, and renal failure (GFR &amp;lt;30 ml/min/1.73m2) in 10% of cases. The treatment for Kaposi sarcoma at entry was a bleomycin and vincristine-based regimen in 52% of patients, with a median of 2 cycles (range 1-7). Five patients (23%) achieved a complete response without requiring additional treatment. Three patients (14%) with MCD attack criteria resolved systemic symptoms only with cART. Unfortunately, 14% of patients died before receiving treatment, and 38% were managed with “wait and watch” because they did not meet the criteria for MCD attack. The remaining 47% received treatment, with the most common regimens being R-Dox (20%), RCHOP (30%), CHOP (30%), Dox-liposomal (10%), and R-Etoposide (10%), with a median of 4 cycles (range 1-7). Eight patients (38%) received ganciclovir maintenance treatment until reaching negative HHV8 viral load. During the 9 years of follow-up, a total of 5 patients (23.8%) died, with 80% of them experiencing disease progression. The overall survival at 24 months was 77% (figure 1) , and the median survival was not reached at the time of evaluation. In conclusion, our patients with HIV-associated MCD demonstrated similarities to global epidemiological data, with a predominant male population and onset between the fourth and fifth decade of life. The most common histology was the plasmacytic cell subtype, and B symptoms were frequently observed. Hepatosplenomegaly was more prevalent than previously described, anemia and thrombocytopenia appeared to be more common hematological manifestations than reported. Due to a significant percentage of patients having uncontrolled HIV at diagnosis, and unknown KS at the same time of the diagnosis, further research is needed to establish a direct association with MCD and HIV pathophysiology in which clinical manifestations of the disease are diverse an lack specificity, and the prognosis varies greatly. Additionally, concomitant infections may play a role as activators of systemic inflammation and require active screening for MCD in patients with these characteristics. While Kaposi sarcoma treatment was effective in controlling both diseases in some cases, additional management may be necessary, with promising results seen with different treatments. Early intervention for cytokine release syndrome is essential to improve patient outcomes. 1.Blood 2020 Apr16;135(16):1353-64. 2.Nat Rev Dis 2021 Nov 25;7(1):84

Identification of Autoantibodies Associated with Connective Tissue Disorders in Idiopathic Multicentric Castleman Disease

Background: Idiopathic multicentric Castleman disease (iMCD) is a rare, atypical lymphoproliferative disorder with significant morbidity and mortality and unknown etiology. While anti-interleukin-6 (IL-6) therapy with siltuximab is effective in 34-50% of iMCD patients, disease pathophysiology remains largely unknown. A fundamental question is whether iMCD is most appropriately considered an infectious disease caused by an as-yet-unknown pathogen, an autoimmune disease caused by autoantibodies, an autoinflammatory disease caused by germline mutations, or a neoplastic disease caused by somatic mutations in a clonal cell population. While limited evidence exists for each of these hypotheses, the pathogen hypothesis has been the most systematically evaluated to date. In this study, we quantified the levels of autoantibodies that may be involved in iMCD pathology. Methods: We constructed two custom bead-based protein arrays to screen serum samples for IgG autoantibodies from iMCD patients (n = 101) and healthy controls (HC, n = 30). The Connective Tissue Disease (CTD) array consisted of 52 antigens associated with traditional CTDs including in Scleroderma, Myositis/Overlap Syndromes, Systemic Lupus Erythematosus (SLE)/Sjögren's, GI/Endocrine, DNA-Associated, and Inflammation/Stress. The Anti-Cytokine Autoantibody (ACA) array included 38 cytokines, chemokines, and cell surface proteins. Serum samples came from the University of Pennsylvania (n = 38), University of Arkansas for Medical Sciences (n = 45), and Osaka University (Japan, n = 18). A “positive” autoantibody result in any sample was defined as greater than five standard deviations (SD) above the average mean fluorescent intensity (MFI) of the HC and at least 3,000 MFI. Fisher's exact tests were used to determine associations between autoantibody positivity and disease status. Results: To evaluate assay precision, we investigated anti-IL-6 antibodies given that a large portion (38%) of iMCD patients were on anti-IL-6 therapy. As expected, 40 iMCD samples were positive for anti-IL-6 antibodies, the most common autoantibody detected in iMCD subjects. IL-6 was then removed from further analyses. Next, we evaluated the proportion of CTD autoantibody positive iMCD patients. Overall, 46 (46%) iMCD subjects were positive for a CTD autoantibody compared to five (17%) in HCs (OR 4.1, P = 0.005) (Figure 1A). When investigating autoantibody prevalence in CTD subcategories, Myositis/Overlap Syndromes (OR 7.5, P = 0.026) and SLE/Sjögren's (OR 6.2, P = 0.073) autoantibodies trended higher in iMCD patients, but these associations did not survive multiple testing correction. The most common Myositis/Overlap Syndrome autoantibodies were anti-Mi2 (iMCD: 7/101 vs HC: 0/30), and anti-SRP54 (7/101 vs 0/30). The most common SLE/Sjögren's autoantibodies were anti-La/SSB (9/101 vs 0/30) and anti-Ro60 (5/101 vs 0/30). For the custom ACA array, there were significantly more ACA positive iMCD subjects (n = 40, 40%) than HC (n = 3, 10%; OR 5.8, P = 0.002) (Figure 1B). The most common ACAs in iMCD were anti-OSM (9/101 vs 0/30), anti-TNF (6/101 vs 0/30), anti-ITM2B (6/101 vs 0/30), and IFNe (5/101 vs 1/30). Conclusions: IgG autoantibodies associated with CTDs, such as anti-Mi2, anti-SRP54, anti-La, anti-Ro, and anti-Histone 3; and ACAs, such as anti-OSM, anti-TNF, and anti-ITM2B were common in iMCD patients. While autoantibodies suggest autoimmune involvement, the presence of autoantibodies does not directly implicate autoimmunity as a pathological mechanism. For example, Hodgkin's disease and other post-infectious etiologies can present with elevated autoantibodies. Although not surviving multiple hypothesis correction, myositis and SLE autoantibodies trended higher in iMCD patients. While most of these autoantibodies have not been reported, anti-Ro and and anti-La antibodies have been reported previously in iMCD case reports. The presence of anti-OSM is interesting, as OSM is a member of the IL-6 family. Two hypothesized mechanisms include that autoantibodies may be non-neutralizing leading to increased half-life and cytokine activity or autoantibodies are neutralizing and lack of negative feedback from OSM may lead to increased signaling via other IL-6-family cytokines. More research is needed to understand the role of these autoantibodies and, if pathogenic, whether iMCD should be considered an autoimmune disease.