Distinct Human and Viral Interleukin-6 Profiles and Other Viral and Immunologic Abnormalities In KSHV-Associated Multicentric Castleman Disease: Relationship with Disease Activity and Individual Disease Manifestations

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1573-1573
Author(s):  
Mark N Polizzotto ◽  
Thomas S Uldrick ◽  
Victoria Wang ◽  
Karen Aleman ◽  
Kathleen M Wyvill ◽  
...  
Keyword(s):  
Disease Activity ◽  
Respiratory Symptoms ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Human Herpesvirus ◽  
Castleman Disease ◽  
Multicentric Castleman Disease ◽  
Tnf Α ◽  
Gi Symptoms ◽  
Individual Disease

Abstract Abstract 1573 Background: Multicentric Castleman disease (MCD) is a polyclonal B-cell lymphoproliferative disorder characterized by flares of severe inflammatory symptoms, including fever and cachexia, with cytopenias and biochemical abnormalities. In the idiopathic form, its pathogenesis is linked to overproduction of interleukin (IL)-6. A distinct form of MCD is caused by Kaposi sarcoma-associated herpesvirus (KSHV, also called human herpesvirus [HHV]-8). KSHV encodes a viral homolog of IL-6, vIL-6, and this has been hypothesized to be central to KSHV-MCD pathogenesis. However, viral and human cytokines have not been examined together in KSHV-MCD, and their contribution to disease activity and symptoms is not known. Methods: Patients with pathologically-proven KSHV-MCD were enrolled on a prospective natural history study incorporating pilot evaluation of novel therapies (NCT00099073). Factors potentially important in pathogenesis were assayed at flare and complete clinical and laboratory remission: KSHV viral load (VL) in peripheral blood mononuclear cells, vIL-6, IL-1β, IL-5, human IL-6 (hIL-6), IL-8, IL-10, IL-12p70, IFN-γ and TNF-α. Paired analyses were performed for each patient comparing initial flare and remission. Associations between cytokines and individual disease manifestations were explored across all flares. Results: 21 patients had at least one flare for analysis (19 [90%] male; med age 44 [range 29–52]). 34 flares were observed (range 1–3 per patient) and followed to remission (20 patients) or death (1). All were HIV infected: CD4 med 252cells/μL (range 24–1319), HIV VL med <48 copies/mL (<48–64,100), 94% receiving antiretrovirals. Clinical symptoms included fever (present in 62%, med 38°C [range 36.1–40.5]); fatigue (91%, med CTC grade 2 [0–3]), gastrointestinal (GI) symptoms (68%, med grade 1 [0–3]) and respiratory symptoms (61%, med grade 1 [0–2]). Laboratory findings included anemia (97%, 9.9g/L [6.8–14.4]), thrombocytopenia (68%, 100×103cells/μL [6–567]), hypoalbuminemia (97%, 2.7g/L [1.2–3.9]) hyponatremia (68%, 133mEg/L [127–143]) and C-reactive protein (CRP) elevation (100%, 87.3g/L [6.3–339.5]). Factors elevated during initial flares were: KSHV VL (med 14,700/106 PBMCs [range 0–3,913,000] P <0.0001 compared with remission); vIL-6 (detected in 48%, <1560pg/mL [<1560-20,500] P= 0.0039); hIL-6 (15.9pg/mL [1.4-171.5] P= 0.0006); IL-10 (449pg/mL [2.8-85,900] P= 0.0007); TNF-α (29.0 pg/ml [7.9–90.8] P= 0.0083) and IL-1β (1.2 pg/ml [0.1–5.7] P= 0.0027). IL-5 was decreased compared with remission (0.6 [0.1–15.4] P= 0.016). Differences were most marked for vIL-6 (undetectable in all remissions), hIL-6 (med increase from remission 520%) and IL-10 (med increase from remission 5000%). KSHV VL was correlated with hIL-6 (R = 0.68, P= 0.001) and IL-10 (R=0.82, P= 0.001) across all flares and remissions; other correlations were weaker. There was also a strong association between KSHV VL and vIL-6 (P= 0.001 by Jonckheere-Terpstra). For hIL-6 and vIL-6 only, we observed distinct profiles across flares: vIL-6 elevation only (2 flares, 6%), hIL-6 only (17 flares, 50%), and hIL-6 with vIL-6 (13 flares, 38%). In 2 flares (6%), neither vIL-6 nor hIL-6 were detected at onset, but in both hIL-6 alone soon became elevated. In contrast, KSHV VL, IL-10, TNF-α and IL-1β were consistently elevated during flares. Compared with hIL-6-only flares, hIL-6 with vIL-6 flares exhibited significantly higher CRP (P =0.0009); worse hyponatremia (P =0.02); higher KSHV VL (P =0.016) and IL-10 (P= 0.012); and lower IL-5 (P= 0.009). In linear/logistic regression models of disease manifestations with cytokines, best predictors were: GI symptoms, respiratory symptoms, temperature, platelet count: hIL-6 alone; hemoglobin: hIL-6 and vIL-6; sodium: hIL-6, vIL-6 and IL-10; albumin: IL-1β and vIL-6. Conclusions: This prospective analysis shows for the first time that vIL-6 and hIL-6 can independently or together lead to flares of KSHV-MCD. It shows novel associations of KSHV-MCD flares with IL-1β and TNF-α elevation and IL-5 depression while confirming associations with KSHV VL and IL-10. It further suggests that vIL-6 and hIL-6 may jointly contribute to the severity of some symptoms during flares. As vIL-6 can signal independently of the ligand-binding IL-6 receptor-a, these findings have implications for the development of novel KSHV-MCD therapies targeting IL-6 and its downstream signaling. Disclosures: No relevant conflicts of interest to declare.

Human Herpesvirus Type 8-positive Multicentric Castleman Disease

2016 ◽  
Vol 16 ◽  
pp. S159-S165 ◽  
Author(s):  
Anait L. Melikyan ◽  
Elena K. Egorova ◽  
Hunan L. Julhakyan ◽  
Alla L. Kovrigina ◽  
Valeriy G. Savchenko
Keyword(s):  
Human Herpesvirus ◽  
Castleman Disease ◽  
Herpesvirus Type ◽  
Multicentric Castleman Disease ◽  
Human Herpesvirus Type

scholarly journals Serum Proteomics Reveals Distinct Subtypes Associated with Treatment Response in Idiopathic Multicentric Castleman Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3716-3716
Author(s):  
Dustin Shilling ◽  
Jason R Ruth ◽  
Christopher Sheild Nabel ◽  
Sheila K Pierson ◽  
Mary Guilfoyle ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Treatment Options ◽  
Castleman Disease ◽  
Employment Equity ◽  
Multicentric Castleman Disease ◽  
Serum Proteomics ◽  
Equity Ownership

Abstract Human herpesvirus-8(HHV-8)-negative/idiopathic multicentric Castleman disease (iMCD) is a rare and poorly understood disorder diagnosed in ~1,000 individuals in the USA each year. It involves polyclonal lymphoproliferation, constitutional symptoms, systemic inflammation and an uncontrollable cytokine storm resulting in life-threatening multi-organ failure. Diagnosis and treatment can be difficult due to limited etiological understanding and heterogeneous presentation - clinical, laboratory, and histopathological abnormalities overlap with infectious, autoimmune and oncological diseases. iMCD symptoms and disease progression are largely believed to be driven by interleukin-6 (IL-6). However, approximately 66% of iMCD patients did not respond to anti-IL-6 therapy, siltuximab, the only FDA-approved iMCD therapy, in its phase II study (NCT01024036). Few treatment options exist for anti-IL-6 refractory patients because alternative driver cytokines and signaling pathways are not known. Herein we report the largest study to-date of iMCD serum proteomes with correlative anti-IL6 response data from 92 iMCD patients in disease flare (n=75 of which were collected as part of NCT01024036), in order to: (1) molecularly define iMCD, (2) identify predictors of response to anti-IL6 therapy, and (3) gain insights into the pathogenesis of iMCD. Proteomes of HHV8-positive MCD (n=20), Hodgkin lymphoma (n=20), rheumatoid arthritis (n=20) and healthy individuals (n=44) were also analyzed. Of the ~1,300 analytes measured using SomaLogic SOMAscan, 1,178 passed QC and were included in analyses. Each analyte was log2 transformed and capped at the 2.5th and 97.5th percentiles. Clinical and laboratory data collected at the time of sample draw were used to calculate disease activity following a modified CHAP scale: C-reactive protein, hemoglobin and albumin; missing performance status. Response to siltuximab was determined in NCT01024036. Data analysis was performed using the Medidata Rave Omics machine learning platform and R v3.4.4. Clustering of baseline proteomic data for iMCD patients identified six clusters that ranged in size from seven to 27 subjects. No associations with race, site, sex, age, or batch were found. Analytes identified among the strongest differentiators include cytokines, chemokines and inflammatory molecules. Interestingly, the largest cluster was associated with response to siltuximab (p<0.05; 65% (11/17) vs 19% (5/27) in all others), higher disease activity (p<0.01), and higher IL-6 levels (p<0.01). Analysis of data for the entire study population separated HHV-8-positive MCD, Hodgkin lymphoma, and rheumatoid arthritis into distinct clusters. Of note, iMCD patients did not form a single or unique cluster, reinforcing the heterogeneity of the disease, and a subset of iMCD patients demonstrated similar, but not overlapping, proteomic profiles to those of Hodgkin lymphoma. These results indicate that previously undiscovered proteomically-distinct iMCD subtypes or disease states exist, which can be used to inform treatment options. Given that iMCD may have a sudden and severe onset, predictive markers of anti-IL6 therapy response are critical for timely administration of the correct treatment. Additionally, overlapping proteomic profiles of a subset of iMCD patients with Hodgkin lymphoma provide etiological insights. More broadly, this study represents the first use of high-quality serum proteomics data to study a rare non-malignant lymphoproliferative disorder and to assist with molecularly defining a heterogeneous disease, developing candidate diagnostic biomarkers, predicting response or failure to therapy, and identifying novel candidate therapeutic targets. Disclosures Guilfoyle: Janssen Pharmaceuticals, Inc.: Employment. Tendler:Janssen Pharmaceuticals, Inc.: Employment, Equity Ownership. Reddy:Janssen Pharmaceuticals, Inc.: Employment, Equity Ownership. Weinblatt:Amgen: Consultancy, Research Funding; Sanofi/Regeneron: Consultancy, Research Funding; Crescendo Bioscience: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; UCB Pharmaceuticals: Consultancy, Research Funding. Bower:Merck: Honoraria; ViiV: Honoraria; Gilead: Honoraria; Janssen Pharmaceuticals: Honoraria. Masaki:Ono: Research Funding; Phizer: Research Funding; Astellas: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding. Beineke:Medidata Solutions: Employment, Equity Ownership. Miljovska:Medidata Solutions: Employment. Katz:Medidata Solutions: Employment. Shenoy:Medidata Solutions: Consultancy. Oromendia:Medidata Solutions: Employment, Equity Ownership. Mezey:Medidata Solutions: Consultancy. Wiser:Medidata Solutions: Employment, Equity Ownership. Benbanaste:Medidata Solutions: Employment, Equity Ownership. Lee:Medidata Solutions: Employment. Fosså:Janssen Pharmaceuticals, Inc.: Honoraria. Fajgenbaum:Janssen Pharmaceuticals, Inc.: Research Funding.

scholarly journals Kaposi sarcoma–associated herpesvirus/human herpesvirus 8–associated lymphoproliferative disorders

Blood ◽  
2019 ◽  
Vol 133 (11) ◽  
pp. 1186-1190 ◽  
Author(s):  
Eric Oksenhendler ◽  
David Boutboul ◽  
Lionel Galicier
Keyword(s):  
B Cells ◽  
Primary Effusion Lymphoma ◽  
Human Herpesvirus ◽  
Kaposi Sarcoma ◽  
Castleman Disease ◽  
Lymphoproliferative Disorders ◽  
Human Herpesvirus 8 ◽  
Herpesvirus 8 ◽  
Multicentric Castleman Disease ◽  
Infected Cells

Abstract Kaposi sarcoma–associated herpesvirus/human herpesvirus 8 is associated with multicentric Castleman disease (MCD) and primary effusion lymphoma (PEL). In MCD, infected B cells, although polyclonal, express a monotypic immunoglobulin Mλ phenotype, probably through editing toward λ light chain in mature B cells. They are considered to originate from pre–germinal center (GC) naive B cells. Both viral and human interleukin-6 contribute to the plasmacytic differentiation of these cells, and viral replication can be observed in some infected cells. PEL cells are clonal B cells considered as GC/post-GC B cells. One can also hypothesize that they originate from the same infected naive B cells and that additional factors could be responsible for their peculiar phenotype.

High levels of human herpesvirus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric Castleman disease in HIV-infected patients

Blood ◽  
2000 ◽  
Vol 96 (6) ◽  
pp. 2069-2073 ◽  
Author(s):  
Eric Oksenhendler ◽  
Guislaine Carcelain ◽  
Yoshiyasu Aoki ◽  
Emmanuelle Boulanger ◽  
Anne Maillard ◽  
...  
Keyword(s):  
Viral Load ◽  
Interleukin 6 ◽  
Lymphoproliferative Disorder ◽  
Human Herpesvirus ◽  
Castleman Disease ◽  
Human Herpesvirus 8 ◽  
C Reactive Protein ◽  
Herpesvirus 8 ◽  
Multicentric Castleman Disease ◽  
Reactive Protein

Abstract Multicentric Castleman disease (MCD) is a distinct type of lymphoproliferative disorder associated with inflammatory symptoms and interleukin-6 (IL-6) dysregulation. In the context of human immunodeficiency virus (HIV) infection, MCD is associated with human herpesvirus 8 (HHV8) infection. In a prospective study of 23 HIV-infected patients with MCD, clinical symptoms of MCD were present at 45 visits, whereas patients were in chemotherapy-induced clinical remission at 50 visits. Symptoms were associated with a high level of serum C reactive protein, high HHV8 viral load in peripheral blood mononuclear cells, and high plasma human IL-6 and IL-10 levels. Strong correlations between plasma IL-6 and plasma IL-10 with the HHV8 viral load suggest that both cytokines may be involved in the pathogenesis of this virus-associated lymphoproliferative disorder.

scholarly journals Human Herpesvirus 6 and 7 Reactivation and Disease Activity in Multiple Sclerosis

Medicina ◽  
2011 ◽  
Vol 47 (10) ◽  
pp. 75 ◽  
Author(s):  
Zaiga Nora-Krukle ◽  
Svetlana Chapenko ◽  
Inara Logina ◽  
Andrejs Millers ◽  
Ardis Platkajis ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Human Herpesvirus ◽  
Interleukin 12 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Serum Concentrations ◽  
Human Herpesvirus 6 ◽  
Chain Reaction ◽  
Tnf Α ◽  
Herpesvirus 6

Recent studies have focused on the associations between human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7), and multiple sclerosis (MS). The aim of this study was to investigate the associations between HHV-6 and HHV-7 reactivation and MS disease activity, and interleukin 12 (IL-12) and tumor necrosis factor α (TNF-α) production. Material and Methods. The frequency of plasma viremia by nested polymerase chain reaction and transcription of viral mRNA in peripheral blood mononuclear cells by reverse transcriptasepolymerase chain reaction (RT-PCR) of 14 relapsing/remitting (RR) and 14 secondary progressive (SP) MS patients were studied in comparison with clinical manifestation of the disease. Serum concentrations of cytokines IL-12 and TNF-α were analyzed by enzyme-linked immunosorbent assay. Results. Plasma samples from 25 of the 28 MS patients with estimated latent/persistent HHV-6 and/or HHV-7 infection were examined during relapse and remission/relative remission. HHV-6 reactivation was found in 4 of the 7 RRMS and 4 of the 7 SPMS patients, and HHV-7 reactivation was identified in 3 of the 7 RRMS and 1 of the 7 SPMS patients (all in relapse). In 2 of the 3 RRMS patients without viremia in relapse, HHV-6 mRNA transcription was detected. In RRMS and SPMS patients with active HHV-6 and HHV-7 infection in relapse, the serum concentrations of IL-12 and TNF-α were significantly higher than in those with latent virus infection. Conclusions. HHV-6 and HHV-7 reactivation could be implicated in the exacerbation of MS via activation of Th1 lymphocyte subsets.

Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease

2021 ◽  
Vol 5 (17) ◽  
pp. 3445-3456
Author(s):  
Sheila K. Pierson ◽  
Sushila Shenoy ◽  
Ana B. Oromendia ◽  
Alexander M. Gorzewski ◽  
Ruth-Anne Langan Pai ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Immunoglobulin E ◽  
Multiorgan Failure ◽  
Human Herpesvirus ◽  
Castleman Disease ◽  
Janus Kinase ◽  
Multicentric Castleman Disease ◽  
Hematologic Disorder ◽  
Established Disease ◽  
Response Biomarkers

Abstract 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.

HAART Does Not Improve the Outcome of HIV-Related Multicentric Castleman Disease: Results of a Multicentric Retrospective Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4918-4918 ◽  
Author(s):  
Chiara Cattaneo ◽  
Emanuela Vaccher ◽  
Alessandro Re ◽  
Salvatore Casari ◽  
Erika Borlenghi ◽  
...  
Keyword(s):  
Median Time ◽  
Conflicts Of Interest ◽  
Primary Effusion Lymphoma ◽  
Case Series ◽  
Central Nervous System Lymphoma ◽  
Castleman Disease ◽  
Time Interval ◽  
Female Ratio ◽  
Multicentric Castleman Disease

Abstract Abstract 4918 Background. Multicentric Castleman Disease (MCD) is a rare lymphoproliferative disorder, strictly related to Kaposi Sarcoma (KS) as both associated to HHV-8 infection. Like other HIV-related diseases, such as Non Hodgkin Lymphoma (NHL) and Primary Central Nervous System Lymphoma, MCD prevalence is known to be increased in HIV-pos subjects. However, limited case series among this subset of patients (pts) are reported and data regarding epidemiological variations in the pre and post HAART era are often non conclusive. In order to evaluate possible differences between pre- and post-HAART era, we retrospectively evaluated epidemiological and clinical characteristics of all pts affected by HIV-pos MCD afferent to two Italian Institutions. Patients and Methods. Data concerning biological, clinical and prognostic factors of HIV-pos MCD pts were collected and reported on a database. Pts were grouped according to the date of diagnosis in pre- (before 1997) and post-HAART (after 1997) era. Results. During a 21-year period (1990-2011), 35 HIV-pos MCD pts were observed at our Institutions, nine in the pre- and 26 in the post-HAART era. Male/Female ratio was 30/5; median age 37y (23-65). Histological subtype in 34 evaluable cases was hyaline-vascular in 6, plasmacytic in 20 and mixed cellularity in 8. Median time interval from HIV-pos detection to MCD diagnosis was 24 months (range 0–157) and CD4 count at MCD diagnosis 233/mcL (26-839). All these MCD baseline characteristics were not statistically different between pre- and post-HAART era. A concomitant diagnosis of KS was made in 18/35 (51.4%) cases, all but one in the post-HAART era. NHL was diagnosed concurrently with MCD in 2/35 (5.7%) pts (1 Primary Effusion Lymphoma, PEL, and 1 Plasmablastic Lymphoma, PBL); in 8/35 (22.8%) cases NHL developed after MCD diagnosis (2 PEL, 1 PBL, 2 Diffuse Large Cell, DLC, 1 unspecified, respectively). Median time from MCD to NHL was 19 mo (0-71). Evolution toward NHL was observed in 3 (33%) cases in the pre-HAART era and in 5 (19%) in the post-HAART era (p=0.39, Fisher's exact test). Six pts did not receive any type of treatment, 6 were treated with HAART only and 23 with different therapies, including antivirals, steroids, chemotherapy and rituximab (alone in 1 pt, in combination with chemotherapy in 5). Nineteen/23 pts received HAART together with other therapies. Two pts treated with rituximab developed NHL (1 PEL and 1 DLC). A complete or partial radiological response, together with clinical improvement was observed in 19/25 of evaluable pts (76%). Thirty pts were evaluable for relapse/progression, mainly in the post-HAART era. Overall, 19/30 pts showed MCD progression or transformation to NHL; median PFS was 15 months. Nineteen pts died and 5 were lost to follow-up. Overall survival (OS) of the entire series was 28 months, without significant differences between pre and post-HAART era (18 and 28 months, OR 0.643 [CI 0.2406–1.045], median follow-up 18 and 9 months, respectively). Causes of death were evaluable in 18 cases: NHL (7), MCD (6), opportunistic infections (1), liver cyrrhosis (1), acute myocardial infarction (1), KS (1) and therapy-related toxicity (1). NHL and MCD were the most frequent cause of death in the post-HAART era (4 and 5 of the 10 cases, respectively). Although no differences in OS between MCD pts without or with NHL were seen (19 vs 28 months, OR 0.6786 [CI 0.2763–1.081], median follow-up 13 and 23 months, respectively), eight/10 pts with NHL died, in comparison with 11/21 pts without NHL evaluable for outcome and median time from NHL diagnosis to death was 2 months (0-31). Conclusions. Our data confirm that the prognosis of HIV-related MCD remains poor even after the advent of HAART. Unlike other lymphoproliferative disorders, HAART did not impact on outcome of HIV-related MCD, suggesting that MCD can “escape” immune reconstitution. A concomitant diagnosis of NHL and uncontrolled MCD seem to be the main reason for an unfavourable outcome, particularly in the post-HAART era. New therapeutic approaches, including rituximab, should therefore aim at avoiding NHL transformation and controlling “MCD-related cytokine storm”. Disclosures: No relevant conflicts of interest to declare.

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