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Concept: Castleman's disease

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Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a polyclonal B-cell lymphoproliferative disorder. Human IL-6 and a KSHV-encoded homolog, viral IL-6, have been hypothesized to contribute to its pathogenesis but their relative contributions to disease activity is not well understood. We prospectively characterized KSHV viral load (VL), viral (v) and human (h) IL-6, and other cytokines during KSHV-MCD flare and remission in 21 patients with 34 flares and 20 remissions. KSHV-VL, vIL-6, hIL-6 , IL-10, and to a lesser extent TNF-α, and IL-1β were each elevated during initial flares compared with remission. Flares fell into three distinct IL-6 profiles: those associated with elevations of vIL-6 only (2 flares, 6%), hIL-6 elevations only (17 flares, 50%), and elevations in both hIL-6 and vIL-6 (13 flares, 38%). Compared with hIL-6-only flares, flares with elevated hIL-6 plus vIL-6 exhibited higher CRP (P=0.0009); worse hyponatremia (P=0.02); higher KSHV VL (P=0.016) and higher IL-10 (P=0.012). This analysis shows vIL-6 and hIL-6 can independently or together lead KSHV-MCD flares, and suggests that vIL-6 and hIL-6 may jointly contribute to disease severity. These findings have implications for the development of novel KSHV-MCD therapies targeting IL-6 and its downstream signaling. This study was registered at clinicaltrials.gov as NCT099073.

Concepts: Lymphocyte, Cancer, Kaposi's sarcoma, Sarcoma, Lymphoproliferative disorders, Post-transplant lymphoproliferative disorder, Kaposi's sarcoma-associated herpesvirus, Castleman's disease

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For clinical trials of therapeutic monoclonal antibodies (mAbs) to be successful, their efficacy needs to be adequately evaluated in preclinical experiments. However, in many cases it is difficult to evaluate the candidate mAbs using animal disease models because of lower cross-reactivity to the orthologous target molecules. In this study we have established a novel humanized Castleman’s disease mouse model, in which the endogenous interleukin-6 receptor gene is successfully replaced by human IL6R, and human IL6 is overexpressed. We have also demonstrated the therapeutic effects of an antibody that neutralizes human IL6R, tocilizumab, on the symptoms in this mouse model. Plasma levels of human soluble IL6R and human IL6 were elevated after 4-week treatment of tocilizumab in this mouse model similarly to the result previously reported in patients treated with tocilizumab. Our mouse model provides us with a novel means of evaluating the in vivo efficacy of human IL6R-specific therapeutic agents.

Concepts: Immune system, Monoclonal antibodies, Monoclonal antibody therapy, Interleukin 6, Tocilizumab, Interleukin-6 receptor, Castleman's disease, Nomenclature of monoclonal antibodies

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Human Herpesvirus-8 (HHV-8)-negative/idiopathic multicentric Castleman disease (iMCD) is a poorly understood disease involving polyclonal lymphoproliferation with dysmorphic germinal centers, constitutional symptoms, and multi-organ failure. Patients can experience thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly, and normal immunoglobulin levels, - iMCD-TAFRO. Others experience thrombocytosis, milder effusions, and hypergammaglobulinemia, -iMCD-Not Otherwise Specified (iMCD-NOS). Though the etiology is unknown in both subtypes, iMCD symptoms and disease progression are believed to be driven by a cytokine storm, often including interleukin-6 (IL-6). However, approximately two-thirds of patients do not respond to anti-IL-6 therapy; alternative drivers and signaling pathways are not known for anti-IL-6 non-responders. To identify potential mediators of iMCD pathogenesis, we quantified 1,129 proteins in 13 plasma samples from six iMCD patients during flare and remission. The acute phase reactant NPS-PLA2 was the only significantly increased protein (P=0.017); chemokines and complement were significantly enriched pathways. Chemokines represented the greatest proportion of up-regulated cytokines, suggesting that iMCD involves a chemokine storm. The chemokine CXCL13, which is essential in homing B cells to germinal centers, was the most up-regulated cytokine across all patients (log2 fold-change=3.22). Expression of CXCL13 was also significantly increased in iMCD lymph node germinal centers compared to controls in a stromal meshwork pattern. We observed distinct proteomic profiles between the two iMCD-TAFRO patients, who both failed anti-IL-6-therapy, and the four iMCD-NOS patients, in whom all three treated with anti-IL-6-therapy responded, suggesting that differing mechanisms may exist. This study reveals proteomic differences between flare and remission and the potential to molecularly define iMCD subgroups. This article is protected by copyright. All rights reserved.

Concepts: Immune system, Protein, Cytokine, Signal transduction, Lymph node, Cytokines, Chemokine, Castleman's disease

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Multicentric Castleman disease (MCD) describes a heterogeneous group of disorders involving proliferation of morphologically benign lymphocytes due to excessive proinflammatory hypercytokinemia, most notably of Interleukin-6 (IL-6). Patients demonstrate intense episodes of systemic inflammatory symptoms, polyclonal lymphocyte and plasma cell proliferation, autoimmune manifestations, and organ system impairment. Human Herpes Virus-8 (HHV-8) drives the hypercytokinemia in all HIV-positive patients and some HIV-negative patients. There is also a group of HIV- and HHV-8-negative patients with unknown etiology and pathophysiology, which we propose referring to as idiopathic MCD (iMCD). Here, we synthesize what is known about iMCD pathogenesis, present a new sub-classification system, and propose a model of iMCD pathogenesis. MCD should be subdivided into HHV-8-associated MCD and HHV-8-negative or iMCD. The lymphocyte proliferation, histopathology, and systemic features in iMCD are secondary to hypercytokinemia, which can occur with several other diseases. We propose one or more of the following three candidate processes may drive iMCD hypercytokinemia: systemic inflammatory disease mechanisms via autoantibodies or inflammatory gene mutations, paraneoplastic syndrome mechanisms via ectopic cytokine secretion, and/or a non-HHV-8 virus. Urgent priorities include elucidating the process driving iMCD hypercytokinemia, identifying the hypercytokine-secreting cell, developing consensus criteria for diagnosis, and building a patient registry to track cases.

Concepts: Immune system, Inflammation, Pathology, Infection, Systemic inflammatory response syndrome, Rheumatoid arthritis, Immune system disorders, Castleman's disease

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Human herpes virus 8 (HHV-8) is the underlying infectious cause of Kaposi sarcoma (KS) and other proliferative diseases; that is, primary effusion lymphoma and multicentric Castleman disease. In regions with high HHV-8 seroprevalence in the general population, KS accounts for a major burden of disease. Outside these endemic regions, HHV-8 prevalence is high in men who have sex with men (MSM) and in migrants from endemic regions. We aim to conduct a systematic literature review and meta-analysis in order 1) to define the global distribution of HHV-8 seroprevalence (primary objective) and 2) to identify risk factors for HHV-8 infection, with a focus on HIV status (secondary objective).Methods/design: We will include observational studies reporting data on seroprevalence of HHV-8 in children and/or adults from any region in the world. Case reports and case series as well as any studies with fewer than 50 participants will be excluded. We will search MEDLINE, EMBASE, and relevant conference proceedings without language restriction. Two reviewers will independently screen the identified studies and extract data on study characteristics and quality, study population, risk factors, and reported outcomes, using a standardized form. For the primary objective we will pool the data using a fully bayesian approach for meta-analysis, with random effects at the study level. For the secondary objective (association of HIV and HHV-8) we aim to pool odds ratios for the association of HIV and HHV-8 using a fully bayesian approach for meta-analysis, with random effects at the study level. Sub-group analyses and meta-regression analyses will be used to explore sources of heterogeneity, including factors such as geographical region, calendar years of recruitment, age, gender, ethnicity, socioeconomic status, different risk groups for sexually and parenterally transmitted infections (MSM, sex workers, hemophiliacs, intravenous drug users), comorbidities such as organ transplantation and malaria, test(s) used to measure HHV-8 infection, study design, and study quality.

Concepts: HIV, AIDS, Epidemiology, Infectious disease, Medical statistics, Kaposi's sarcoma, Kaposi's sarcoma-associated herpesvirus, Castleman's disease

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Multicentric Castleman disease (MCD) is a rare systemic lymphoproliferative disorder and is infrequently associated with renal complications that include amyloid A (AA) amyloidosis. Although it has been reported that patients with MCD and amyloidosis usually have a poor prognosis, recently, tocilizumab, a humanized anti-interleukin-6 receptor antibody, has emerged as an effective and specific treatment for AA amyloidosis secondary to chronic inflammatory disorders. Here we report a case of an MCD patient with secondary AA renal amyloidosis who was successfully treated with tocilizumab. The patient was initially referred to nephrology specialists because of a decline in renal function and proteinuria. Percutaneous renal biopsy revealed the presence of Congo red-positive amorphous depositions and AA protein-positive areas in glomeruli, vessel walls, and interstitium, confirming a diagnosis of renal AA amyloidosis secondary to MCD. At 1 year after starting tocilizumab treatment, a second renal biopsy showed the clearance of amyloid deposits in the interstitium. These observations suggest that tocilizumab may be an effective therapy for AA amyloidosis secondary to MCD.
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Concepts: Inflammation, Nephrology, Diseases and disorders, Medical terms, Patient, Amyloidosis, Immune system disorders, Castleman's disease

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Multicentric Castleman disease (MCD) is a systemic inflammatory disease potentially caused by an increase in the serum interleukin-6 (IL-6) level. Idiopathic MCD (iMCD) is histopathologically classified into three types: plasmacytic (PC), mixed, and hypervascular (hyperV) types. Recently, a unique clinical phenotype with a poor prognosis overlap with iMCD, thrombocytopenia, anasarca, fever, renal failure or reticulin fibrosis, and organomegaly (TAFRO syndrome), has been reported from Japan, but its detailed clinicopathological features remain unclear. In this study, we performed a clinicopathological analysis of 70 nodal cases of iMCD with and without TAFRO syndrome (n=37 vs. n=33). Compared with iMCD without TAFRO, iMCD with TAFRO showed more atrophic lymphoid follicles (LF), greater distances between follicles, increased glomeruloid vascular proliferation within the germinal center, and increased follicular dendritic cells. In addition, the hyperV-type in particular demonstrated severe atrophic LF and interfollicular vascular proliferation. Among the mixed type cases, the serum IL-6 levels in iMCD with TAFRO were significantly higher than those in iMCD without TAFRO. Furthermore, compared to iMCD without TAFRO, the numbers of immunoglobulin G4 (IgG4)-positive and CD38-positive plasma cells were significantly decreased in iMCD with TAFRO.

Concepts: Immune system, Inflammation, Lymph node, Systemic inflammatory response syndrome, Lymphatic system, Dendritic cell, Castleman's disease, Germinal center

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Classic Hodgkin lymphoma (CHL) has four subtypes. Different morphologic variations can be seen in lymph nodes involved by CHL. Primary interfollicular (IF) involvement is not considered a separate subtype but an unusual diagnostically challenging morphologic variant. Our aim was to study the prevalence of IF growth pattern and coexistence of other morphologic variants in lymph nodes involved by CHL, to investigate the diagnostic challenges and clinical importance of this growth pattern, and to find helpful histologic clues in cases with subtle morphologic features to help avoid misinterpretation and missed diagnosis. We performed a retrospective review study over 10years. We searched for diagnosed cases of nodal CHL. We retrieved and reviewed cases of CHL with IF involvement. The clinical and pathologic features of each case were collected and compared. We found 103 cases of CHLs. Eight cases (7.8%) demonstrated IF growth patterns. The age range was between 3 and 48years with an average age of 26years. The male to female ratio was 7:1. Six cases were mixed cellularity HLs. Three cases had associated epithelioid granulomas, one had follicular involvement and one had an associated. HHV-8 negative plasma cell rich Castleman disease. One case was initially missed as benign follicular hyperplasia, one case was referred as CD and three cases were initially suspected as HL. IF growth pattern in nodal CHLs can be missed because it can be mild and focal with subtle morphologic features. The presence of epithelioid histiocytes, eosinophils and other coexistent morphologic variants are helpful histologic clues. In doubtful cases, immunohistochemistry study is essential. The majority were early stage cervical node MCHLs in young adults and children. Pathologists should be aware of this possibility when examining reactive lymph nodes. The clinical significance is limited and needs further validation by larger studies.

Concepts: Cancer, Diagnosis, Pathology, Lymph node, Lymphoma, Hodgkin's lymphoma, Case, Castleman's disease

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Kaposi Sarcoma-Associated Herpesvirus (KSHV) is the etiologic agent of Kaposi’s sarcoma (KS) but also in multicentric variant of Castleman disease (MCD) and primary effusion lymphoma (PEL), diseases occurring primarily in HIV-infected patients (1).….

Concepts: HIV, AIDS, Cancer, Kaposi's sarcoma, Sarcoma, Kaposi's sarcoma-associated herpesvirus, Castleman's disease

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IgG4-related disease is a heterogeneous immune-mediated fibroinflammatory condition that can affect every single organ. This disease is more prevalent in the elderly (the mean age of patients is above 60 years) and the prevalence rate is estimated to be over 4.6 per 100,000 population. Before making a diagnosis, the exclusion of malignancies, lymphoma, anti-neutrophil cytoplasmic antibody-associated vasculitis, multicentric Castleman disease, and other mimickers is crucial for appropriate treatment. Broad management guidelines have been published emphasizing the need for prompt treatment and the use of glucocorticoids as first-line drug therapy for induction of remission. However, the toxic effects of glucocorticoids are problematic because IgG4-related disease is more prevalent in patients above 60 years of age, a population with frequent comorbid conditions and polypharmacy. Immunosuppressants (cyclophosphamide, methotrexate, leflunomide, and tacrolimus) and targeted immunomodulators (rituximab, XmAb5871, and abatacept) are appealing to overcome potential toxic effects of glucocorticoids and as emerging glucocorticoid-sparing and/or maintenance treatments. In this review, we provide an overview of our understanding of the pathophysiology of the disease (T follicular helper cells, CD4+cytotoxic T cells, plasmablasts, and alternatively activated M2 macrophages) and clinical characteristics, and highlight the potential targets for treatment intervention.

Concepts: Epidemiology, Disease, Medical statistics, Rheumatoid arthritis, T helper cell, Incidence, Prevalence, Castleman's disease