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1.
Int J Hematol ; 115(1): 129-134, 2022 Jan.
Article in English | MEDLINE | ID: mdl-34591291

ABSTRACT

Human herpesvirus-8 (HHV8)-positive, human immunodeficiency virus (HIV)-negative multicentric Castleman disease (MCD) is a rare and age-related lymphoproliferative disorder caused by cytokine storm. Rituximab treatment is currently recommended because B-cell depletion eliminates the primary reservoir for HHV8. We report the first case of effective rituximab treatment of a Japanese patient (an 87-year-old woman) with this disorder. Her inflammatory symptoms and lymphadenopathy improved after medium-dose steroid therapy, but these symptoms recurred during steroid tapering. After one course of rituximab therapy, she achieved sustained remission. HHV8-associated MCD should be considered as a possible diagnosis in HIV-negative patients with inflammatory symptoms and lymphadenopathy.


Subject(s)
Castleman Disease/drug therapy , Rituximab/administration & dosage , Rituximab/therapeutic use , Administration, Oral , Adult , Age Factors , Aged , Aged, 80 and over , B-Lymphocyte Subsets/immunology , Castleman Disease/diagnosis , Castleman Disease/immunology , Castleman Disease/virology , Female , HIV , Humans , Male , Middle Aged , Prednisolone/administration & dosage , Recurrence , Remission Induction
2.
Rheumatology (Oxford) ; 61(2): 490-501, 2022 02 02.
Article in English | MEDLINE | ID: mdl-34363463

ABSTRACT

IgG4-related disease (IgG4-RD) and idiopathic multicentric Castleman's disease (iMCD) are both rare systemic immune-mediated disorders. However, the pathogenesis differs markedly between the two diseases and differing therapeutic strategies are adopted: IgG4-RD is treated using a moderate dose of glucocorticoids or rituximab, while iMCD therapy involves an IL-6-targeted approach. Nonetheless, some clinical features of IgG4-RD and iMCD overlap, so differential diagnosis is sometimes difficult, even though the classification and diagnostic criteria of the diseases require careful exclusion of the other. The key findings in IgG4-RD are high IgG4:IgG ratio, allergic features and germinal centre expansion involving T follicular helper cells, while iMCD involves polyclonal antibody production (high IgA and IgM levels), sheet-like mature plasma cell proliferation and inflammatory features driven by IL-6. The distribution of organ involvement also provides important clues in both diseases. Particular attention should be given to differential diagnosis using combined clinical and/or pathological findings, because single features cannot distinguish IgG4-RD from iMCD. In the present review, we discuss the similarities and differences between IgG4-RD and iMCD, as well as how to distinguish the two diseases.


Subject(s)
Castleman Disease/diagnosis , Immunoglobulin G4-Related Disease/diagnosis , Biomarkers/metabolism , Castleman Disease/immunology , Castleman Disease/pathology , Diagnosis, Differential , Humans , Immunoglobulin G4-Related Disease/immunology , Immunoglobulin G4-Related Disease/pathology
4.
Clin Exp Immunol ; 206(1): 91-98, 2021 10.
Article in English | MEDLINE | ID: mdl-34096620

ABSTRACT

Four cases of idiopathic multi-centric Castleman disease (iMCD) reportedly have variants in hereditary autoinflammatory disease-related genes; however, the frequency and role of these variants in iMCD is still unknown. We therefore investigated such gene variants among patients with iMCD and aimed to reveal the relationship between iMCD and autoinflammatory disease-related genes. We reviewed 14 Japanese iMCD patients who were recruited between January 2015 and September 2019. All patients met both the Japanese tentative diagnostic criteria for Castleman disease and the international consensus diagnostic criteria for iMCD. We performed genetic analyses for 31 autoinflammatory disease-related genes by targeted next-generation sequencing. The MEFV gene variants were observed in 10 of 14 patients with iMCD. Although iMCD had a high percentage of exons 2 or 3 variants of MEFV, comparison of data from healthy Japanese subjects indicated that there was no significant difference in the percentage between healthy Japanese subjects and patients with iMCD. Variants of uncertain significance (VUS) in the TNFRSF1A and CECR1 genes were observed in two of the patients, respectively. We divided patients into two groups-those with MEFV variants (excluding E148Q variants) and those without MEFV variants-and compared the clinical characteristics between these two groups. Patients with MEFV variants, excluding E148Q variants, exhibited a significantly higher likelihood of fever and significantly lower levels of hemoglobin than those lacking MEFV variants. Our results indicated that patients with iMCD tended to have a high frequency of MEFV gene variants and the presence of such variants can affect iMCD clinical phenotypes.


Subject(s)
Adenosine Deaminase , Castleman Disease , Hereditary Autoinflammatory Diseases , Intercellular Signaling Peptides and Proteins , Mutation, Missense , Pyrin , Receptors, Tumor Necrosis Factor, Type I , Adenosine Deaminase/genetics , Adenosine Deaminase/immunology , Adult , Aged , Amino Acid Substitution , Castleman Disease/genetics , Castleman Disease/immunology , Exons , Female , Hereditary Autoinflammatory Diseases/genetics , Hereditary Autoinflammatory Diseases/immunology , Humans , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/immunology , Male , Middle Aged , Pyrin/genetics , Pyrin/immunology , Receptors, Tumor Necrosis Factor, Type I/genetics , Receptors, Tumor Necrosis Factor, Type I/immunology
5.
Rheumatology (Oxford) ; 60(7): 3317-3325, 2021 07 01.
Article in English | MEDLINE | ID: mdl-33313857

ABSTRACT

OBJECTIVES: The 2019 ACR/EULAR classification criteria for IgG4-related disease (IgG4-RD) have exclusion criteria including positive disease-specific autoantibodies, and these have been documented to have a high specificity. This study aimed to further validate these criteria as well as identify characteristics of patients showing false-negative results. METHODS: We retrospectively analysed 162 IgG4-RD patients and 130 mimickers. The sensitivity, specificity and fulfilment rates for each criterion were calculated, and intergroup comparisons were performed to characterize the false-negative cases. RESULTS: Both the IgG4-RD patients and mimickers were aged ≥65 years with male predominance. The final diagnoses of mimickers were mainly malignancy, vasculitis, sarcoidosis and aneurysm. The classification criteria had a sensitivity of 72.8% and specificity of 100%. Of the 44 false-negative cases, one did not fulfil the entry criteria, 20 fulfilled one exclusion criterion and 27 did not achieve sufficient inclusion criteria scores. The false-negative cases had fewer affected organs, lower serum IgG4 levels, and were less likely to have received biopsies than the true-positive cases. Notably, positive disease-specific autoantibodies were the most common exclusion criterion fulfilled in 18 patients, only two of whom were diagnosed with a specific autoimmune disease complicated by IgG4-RD. In addition, compared with the true-positive cases, the 18 had comparable serum IgG4 levels, number of affected organs, and histopathology and immunostaining scores despite higher serum IgG and CRP levels. CONCLUSIONS: The ACR/EULAR classification criteria for IgG4-RD have an excellent diagnostic specificity in daily clinical practice. Positive disease-specific autoantibodies may have limited clinical significance for the diagnosis of IgG4-RD.


Subject(s)
Autoantibodies/immunology , Immunoglobulin G4-Related Disease/diagnosis , Aged , Anti-Citrullinated Protein Antibodies/immunology , Antibodies, Antineutrophil Cytoplasmic/immunology , Antibodies, Antinuclear/immunology , Aortic Aneurysm/diagnosis , Aortic Aneurysm/immunology , Aortic Diseases/diagnosis , Aortic Diseases/immunology , Aortitis/diagnosis , Aortitis/immunology , Castleman Disease/diagnosis , Castleman Disease/immunology , Dacryocystitis/diagnosis , Dacryocystitis/immunology , Diagnosis, Differential , False Negative Reactions , Female , Humans , Immunoglobulin G4-Related Disease/immunology , Kidney Diseases/diagnosis , Kidney Diseases/immunology , Lymphoma/diagnosis , Lymphoma/immunology , Male , Middle Aged , Neoplasms/diagnosis , Neoplasms/immunology , Pancreatic Diseases/diagnosis , Pancreatic Diseases/immunology , Pancreatitis/diagnosis , Pancreatitis/immunology , Retrospective Studies , Salivary Gland Diseases/diagnosis , Salivary Gland Diseases/immunology , Sarcoidosis/diagnosis , Sarcoidosis/immunology , Sialadenitis/diagnosis , Sialadenitis/immunology
6.
Front Immunol ; 11: 576200, 2020.
Article in English | MEDLINE | ID: mdl-33123160

ABSTRACT

Schnitzler syndrome (SchS) is a rare autoinflammatory disease, characterized by urticarial rash, recurrent fever, osteo-articular pain/arthritis with bone condensation, and monoclonal gammopathy. Diagnosis may be difficult due to overlapping signs with other diseases. Here, we describe the case of a 62-year-old man with SchS, who was initially misdiagnosed with multicentric Castleman disease (MCD). As excessive release of IL-6 is characteristic of MCD, in contrast to IL-1 in SchS, we measured the phosphorylation of intracellular signaling proteins of the respective pathways by flow cytometry. We found a distinct increase of phosphorylated IRAK-4 in our patient's B cells and monocytes while phosphorylation of STAT-3 was low, suggesting predominant IL-1 signaling. In accordance with these results and the classification criteria, we established the diagnosis of SchS instead of MCD and commenced therapy with the IL-1 receptor antagonist anakinra. We observed a rapid remission of signs accompanied by a reduction of phosphorylated IRAK-4 to normal levels. In conclusion, we propose phosphorylated IRAK-4 in B cells and monocytes as a potential marker for diagnosis of SchS and for treatment response to IL-1 blockade.


Subject(s)
B-Lymphocytes/enzymology , Interleukin-1 Receptor-Associated Kinases/metabolism , Monocytes/enzymology , Schnitzler Syndrome/enzymology , Antirheumatic Agents/therapeutic use , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , Biomarkers/metabolism , Castleman Disease/diagnosis , Castleman Disease/immunology , Castleman Disease/metabolism , Diagnosis, Differential , Diagnostic Errors , Flow Cytometry , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Male , Middle Aged , Monocytes/drug effects , Monocytes/immunology , Phosphorylation , Predictive Value of Tests , STAT3 Transcription Factor/metabolism , Schnitzler Syndrome/diagnosis , Schnitzler Syndrome/drug therapy , Schnitzler Syndrome/immunology , Treatment Outcome
7.
Med Sci Monit ; 26: e924783, 2020 Aug 15.
Article in English | MEDLINE | ID: mdl-32873770

ABSTRACT

BACKGROUND The aim of this study was to analyze the pathological changes, clinical characteristics and changes in immunity, interleukin-6 (IL-6) and C-reactive protein (CRP) in children with Castleman's disease (CD). MATERIAL AND METHODS A total of 15 CD child patients were enrolled as observation group, while 20 normal children receiving healthy examination were enrolled as healthy control group. The pathological changes, clinical characteristics and changes in immunity and serum IL-6 and CRP expressions were retrospectively analyzed in observation group. RESULTS The clinical manifestation of unicentric CD (UCD) was mainly enlargement of cervical lymph nodes without liver-spleen enlargement and fever, and the major pathological type was the hyaline-vascular type. Multicentric CD (MCD) child patients all had anemia, fever and other systemic symptoms, and the major pathological type was the plasma-cell type. There were expressions of the immune indexes, including cluster of differentiation 3 (CD3), CD4, CD8, CD20, and CD79, in a certain degree, while CD138 and VS38C expressions displayed the polyclonal proliferation of plasma cells, rather than neoplastic proliferation. The Epstein-Barr virus and human herpes virus-8 detection results were negative, and CD21 in follicular dendritic cells in abnormal germinal center was positive. The expression levels of serum IL-6 and CRP in observation group were higher than those in control group (P.


Subject(s)
C-Reactive Protein/metabolism , Castleman Disease/pathology , Interleukin-6/blood , Adolescent , Case-Control Studies , Castleman Disease/blood , Castleman Disease/immunology , Child , Child, Preschool , Female , Humans , Immunophenotyping , Male , Retrospective Studies
9.
Blood Rev ; 45: 100707, 2021 01.
Article in English | MEDLINE | ID: mdl-32425294

ABSTRACT

A subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a "Cytokine Storm Syndrome" (CSS). In this review we compare the clinical features, diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicentric Castleman disease (iMCD), and CAR-T cell therapy associated Cytokine Release Syndrome (CRS). Novel therapeutics targeting cytokines or inhibiting cell signaling pathways have now become the mainstay of treatment in these CSS. We review the evidence for cytokine blockade and attenuation in these known CSS as well as the emerging literature and clinical trials pertaining to COVID-CSS. Established markers of inflammation as well as cytokine levels are compared and contrasted between these four entities in order to establish a foundation for future diagnostic criteria of COVID-CSS.


Subject(s)
COVID-19/immunology , Castleman Disease/immunology , Cytokine Release Syndrome/immunology , Immunologic Factors/therapeutic use , Lymphohistiocytosis, Hemophagocytic/immunology , SARS-CoV-2/pathogenicity , Adrenal Cortex Hormones/therapeutic use , Antibodies, Monoclonal/therapeutic use , Biomarkers/blood , C-Reactive Protein/immunology , C-Reactive Protein/metabolism , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Castleman Disease/drug therapy , Castleman Disease/pathology , Clinical Trials as Topic , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Ferritins/blood , Ferritins/immunology , Gene Expression Regulation , Humans , Immunotherapy, Adoptive/adverse effects , Interleukin-1/antagonists & inhibitors , Interleukin-1/blood , Interleukin-1/immunology , Interleukin-6/antagonists & inhibitors , Interleukin-6/blood , Interleukin-6/immunology , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/pathology , Signal Transduction
10.
JCI Insight ; 5(9)2020 05 07.
Article in English | MEDLINE | ID: mdl-32376796

ABSTRACT

The TAFRO clinical subtype of idiopathic multicentric Castleman disease (iMCD-TAFRO) is a rare hematologic illness involving episodic disease flares of thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly (TAFRO) and progressive multiple organ dysfunction. We previously showed that the mTOR signaling pathway is elevated in lymph nodes of iMCD-TAFRO patients and that an mTOR inhibitor is effective in a small cohort of patients. However, the upstream mechanisms, cell types, and mediators involved in disease pathogenesis remain unknown. Here, we developed a targeted approach to identify candidate cellular drivers and mechanisms in iMCD-TAFRO through cellular and transcriptomic studies. Using paired iMCD-TAFRO PBMC samples collected during flare and remission, we identified T cell activation and alterations in NK cell and monocyte subset frequencies during iMCD-TAFRO flare. These changes were associated with increased Type I IFN (IFN-I) response gene signatures across CD8+ T cells, NK cells, and monocytes. Finally, we found that IFN-ß stimulation of monocytes and T cells from iMCD-TAFRO patient remission samples induced increased mTOR activation compared with healthy donors, and this was abrogated with either mTORC1 or JAK1/2 inhibition. The data presented here support a potentially novel role for IFN-I signaling as a driver of increased mTOR signaling in iMCD-TAFRO.


Subject(s)
CD8-Positive T-Lymphocytes , Castleman Disease/immunology , Interferon Type I/immunology , Killer Cells, Natural , Monocytes , TOR Serine-Threonine Kinases/immunology , Adolescent , Adult , Aged , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Female , Humans , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Longitudinal Studies , Male , Middle Aged , Monocytes/cytology , Monocytes/immunology
12.
Clin Immunol ; 212: 108347, 2020 03.
Article in English | MEDLINE | ID: mdl-31978558

ABSTRACT

Galactose-deficient immunoglobulin A1 (Gd-IgA1) was recently identified as a critical effector molecule in the pathogenesis of IgA nephropathy (IgAN). Gd-IgA1 is produced by the mucosal immune system. IgAN is thought to develop because of the deposition of a circulating immune-complex containing Gd-IgA1 in the kidney. Multicentric Castleman's disease (MCD) is a rare non-neoplastic lymphoproliferative disorder. As an etiology model, hypercytokinemia, including increased levels of interleukin-6, is the primary pathogenesis of many MCD cases. Here, we present two cases of mesangial proliferative glomerulonephritis with MCD. According to renal biopsy findings, one was diagnosed with non-IgAN and the other with IgAN. Surprisingly, in both cases, Gd-IgA1 was produced by plasma cells in the lymph nodes, suggesting that Gd-IgA1 production alone does not cause IgAN; rather, it may be produced without induction by mucosal immunity. Our findings demonstrate the diversity of the development of IgAN and help to reconsider the onset mechanism of IgAN.


Subject(s)
Castleman Disease/immunology , Glomerulonephritis, IGA/immunology , Glomerulonephritis, Membranoproliferative/immunology , Immunoglobulin A/immunology , Plasma Cells/immunology , C-Reactive Protein/immunology , Castleman Disease/complications , Castleman Disease/pathology , Glomerulonephritis, IGA/complications , Glomerulonephritis, IGA/pathology , Glomerulonephritis, Membranoproliferative/complications , Glomerulonephritis, Membranoproliferative/pathology , Humans , Hypergammaglobulinemia/immunology , Immunity, Mucosal/immunology , Interleukin-6/immunology , Lymphadenopathy/immunology , Male , Middle Aged
13.
Keio J Med ; 68(4): 96, 2019.
Article in English | MEDLINE | ID: mdl-31875623

ABSTRACT

A series of our studies on IL-6 have revealed that it has a pleiotropic activity in various tissues and cells and its deregulated expression is responsible for several chronic inflammations and hemopoietic malignancies.Humanized antibody against 80kd IL-6R (Tocilizumab) has shown significant therapeutic effect in RA, JIA, Castleman's diseases and several other autoimmune inflammatory diseases, such as, giant cell arteritis, reactive arthritis, polymyalgia rheumatica and adult still's disease. Cytokine storm induced by CAR-T cell therapy has been shown to be controlled by Tocilizumab.Therapeutic effect of Tocilizumab confirmed that over and constitutive-production of IL-6 is responsible for the pathogenesis of autoimmune diseases.Then, the question to be asked is how is IL-6 production regulated. We identified a novel molecule called Arid5a which binds with the 3'-UTR of IL-6 mRNA and protects its degradation by competing with Regnase-1. Interestingly, this molecule is present in nuclei and inflammatory stimulation induced translocation of Arid5a from nuclei into cytoplasm and it competes with Regnase-1 for the protection of mRNA of IL-6.Our study indicates that Arid5a is one of the key molecules for inflammation as well as the development of septic shock.The results also suggest the therapeutic potential of anti-agonistic agents for Arid5a in the prevention of various inflammatory diseases and septic shock.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Arthritis, Rheumatoid/drug therapy , DNA-Binding Proteins/genetics , Immunologic Factors/therapeutic use , Interleukin-6/genetics , Receptors, Interleukin-6/genetics , 3' Untranslated Regions , Antibodies, Monoclonal, Humanized/biosynthesis , Arthritis, Reactive/drug therapy , Arthritis, Reactive/genetics , Arthritis, Reactive/immunology , Arthritis, Reactive/pathology , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/pathology , Castleman Disease/drug therapy , Castleman Disease/genetics , Castleman Disease/immunology , Castleman Disease/pathology , DNA-Binding Proteins/immunology , Gene Expression Regulation , Giant Cell Arteritis/drug therapy , Giant Cell Arteritis/genetics , Giant Cell Arteritis/immunology , Giant Cell Arteritis/pathology , Humans , Immunologic Factors/biosynthesis , Interleukin-6/immunology , Polymyalgia Rheumatica/drug therapy , Polymyalgia Rheumatica/genetics , Polymyalgia Rheumatica/immunology , Polymyalgia Rheumatica/pathology , Protein Binding , Proteolysis , Receptors, Interleukin-6/antagonists & inhibitors , Receptors, Interleukin-6/immunology , Ribonucleases/genetics , Ribonucleases/immunology , Signal Transduction
15.
Amyloid ; 26(4): 197-202, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31364863

ABSTRACT

Introduction: HHV8-negative Castleman disease (CD) is classified as hyaline vascular (HV) type, or mixed or plasma cell (PC) types. It may present as multicentric CD (MCD) or unicentric CD (UCD). CD is a rare cause of AA amyloidosis (AAA). We aimed to report the main features of CD with secondary AAA through a description of new cases and a systematic literature review. Patients and methods: New cases were identified from the French National Reference Center for AAA. A systematic literature review was performed to identify HHV8-negative CD cases associated with AAA. Results: Thirty-seven patients were analysed, consisting of two new cases and 35 from literature. Twenty-three had UCD and 14 had MCD. PC was the main histologic subtype (n = 25; 68%) in both UCD and MCD patients. Surgical excision of UCD was performed in 21 patients (91%) with a favourable outcome, except for four patients (19%). Clinical and biologic remission was achieved in six patients with MCD (43%), all of whom were treated with anti-interleukin-6 (IL-6) therapy. Conclusions: AAA is a rare complication of CD, namely idiopathic MCD and UCD presenting with the PC histologic subtype. Surgical excision of UCD should be the first-line treatment whenever possible, while anti-IL-6 therapies seem effective for MCD.


Subject(s)
Amyloidosis/epidemiology , Castleman Disease/epidemiology , Adult , Amyloidosis/etiology , Amyloidosis/therapy , Castleman Disease/complications , Castleman Disease/immunology , Castleman Disease/therapy , Databases, Factual , Female , France/epidemiology , Humans , Immunotherapy , Interleukin-6/antagonists & inhibitors , Male , Middle Aged
16.
Acta Derm Venereol ; 99(11): 984-989, 2019 Oct 01.
Article in English | MEDLINE | ID: mdl-31282978

ABSTRACT

Castleman's disease is a rare disease of the lymph nodes and related tissues, presenting as angiofollicular or giant lymph node hyperplasia. Although various skin manifestations have been reported to occur in Castleman's disease, a comprehensive study of cutaneous disorders in Castleman's disease is lacking. Therefore, the aim of this study was to investigate Castleman's disease-associated cutaneous disorders. The medical records of 57 patients with Castleman's disease who visited our hospitals from January 2007 to May 2018 were analysed retrospectively. Patients were classified according to the presence of skin involvement. Plasma variant-type Castleman's disease and multicentric Castleman's disease were more commonly found in patients with Castleman's disease with a cutaneous disorder than in those without a cutaneous disorder. In addition, the skin disorders were classified according to pathomechanisms: immune complex-related (paraneoplastic pemphigus, xanthogranulomas), cytokine-related (vasculitis-like lesion, cherry angioma, hyperpigmentation), and non-specific (pruritus). This study builds on previous case reports of cutaneous disorders in Castleman's disease and proposes a new classification system.


Subject(s)
Antigen-Antibody Complex/immunology , Castleman Disease/complications , Cytokines/immunology , Skin Diseases/etiology , Skin/immunology , Adolescent , Adult , Castleman Disease/immunology , Castleman Disease/pathology , Child , Child, Preschool , Female , Humans , Male , Middle Aged , Retrospective Studies , Risk Factors , Seoul , Skin/pathology , Skin Diseases/immunology , Skin Diseases/pathology , Skin Pigmentation , Young Adult
17.
Nephrology (Carlton) ; 25(2): 125-134, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31264312

ABSTRACT

AIM: Renal thrombotic microangiopathy (TMA) is a common pathological manifestation of Castleman's disease (CD)-associated renal lesions. Increased level of plasma vascular endothelial growth factor (VEGF) has been shown in single-case reports. We aimed to investigate the dysregulation of VEGF in the pathogenesis of CD-associated TMA-like lesions (CD-TMA) in a larger cohort. METHODS: Nineteen patients with clinico-pathologically diagnosed CD with renal involvement were enrolled. Ten patients with pregnancy TMA or TMA of unknown reasons were enrolled as TMA control group. The plasma levels of VEGF, soluble Flt-1 and interleukin-6 (IL-6) were detected using enzyme-linked immunosorbent assay kits. The expression of VEGF in the kidney biopsied tissue sections and the lymph node specimens were detected by immunostaining. RESULTS: The plasma levels of VEGF and IL-6 levels were the highest in CD-TMA group compared to TMA control group and healthy controls. The levels of plasma VEGF was positively correlated with that of IL-6, and increased expression of VEGF and IL-6 was also observed in the lymph nodes from CD-TMA patients. However, the expression of VEGF in the glomerular podocytes was significantly decreased in CD-TMA group as well as in the TMA control. CONCLUSION: Our findings suggest that renal VEGF expression might be important in the pathogenetic mechanism of CD-associated TMA-like lesions.


Subject(s)
Castleman Disease , Interleukin-6 , Kidney , Lymph Nodes , Podocytes/immunology , Thrombotic Microangiopathies , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factor Receptor-1 , Adult , Biopsy/methods , Castleman Disease/immunology , Castleman Disease/pathology , Female , Humans , Immunohistochemistry , Interleukin-6/analysis , Interleukin-6/blood , Kidney/immunology , Kidney/pathology , Lymph Nodes/immunology , Lymph Nodes/pathology , Male , Middle Aged , Reproducibility of Results , Thrombotic Microangiopathies/immunology , Thrombotic Microangiopathies/pathology , Vascular Endothelial Growth Factor A/analysis , Vascular Endothelial Growth Factor A/blood , Vascular Endothelial Growth Factor Receptor-1/analysis , Vascular Endothelial Growth Factor Receptor-1/blood
18.
Blood ; 132(22): 2323-2330, 2018 11 29.
Article in English | MEDLINE | ID: mdl-30487129

ABSTRACT

Castleman disease (CD) describes a heterogeneous group of hematologic disorders that share characteristic lymph node histopathology. Patients of all ages present with either a solitary enlarged lymph node (unicentric CD) or multicentric lymphadenopathy (MCD) with systemic inflammation, cytopenias, and life-threatening multiple organ dysfunction resulting from a cytokine storm often driven by interleukin 6 (IL-6). Uncontrolled human herpesvirus-8 (HHV-8) infection causes approximately 50% of MCD cases, whereas the etiology is unknown in the remaining HHV-8-negative/idiopathic MCD cases (iMCD). The limited understanding of etiology, cell types, and signaling pathways involved in iMCD has slowed development of treatments and contributed to historically poor patient outcomes. Here, recent progress for diagnosing iMCD, characterizing etio-pathogenesis, and advancing treatments are reviewed. Several clinicopathological analyses provided the evidence base for the first-ever diagnostic criteria and revealed distinct clinical subtypes: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, organomegaly (iMCD-TAFRO) or iMCD-not otherwise specified (iMCD-NOS), which are both observed all over the world. In 2014, the anti-IL-6 therapy siltuximab became the first iMCD treatment approved by the US Food and Drug Administration, on the basis of a 34% durable response rate; consensus guidelines recommend it as front-line therapy. Recent cytokine and proteomic profiling has revealed normal IL-6 levels in many patients with iMCD and potential alternative driver cytokines. Candidate novel genomic alterations, dysregulated cell types, and signaling pathways have also been identified as candidate therapeutic targets. RNA sequencing for viral transcripts did not reveal novel viruses, HHV-8, or other viruses pathologically associated with iMCD. Despite progress, iMCD remains poorly understood. Further efforts to elucidate etiology, pathogenesis, and treatment approaches, particularly for siltuximab-refractory patients, are needed.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Antibodies, Monoclonal/therapeutic use , Castleman Disease/diagnosis , Castleman Disease/drug therapy , Immunologic Factors/therapeutic use , Animals , Castleman Disease/etiology , Castleman Disease/immunology , Disease Management , Herpesviridae Infections/complications , Herpesvirus 8, Human/isolation & purification , Humans , Interleukin-6/antagonists & inhibitors , Interleukin-6/immunology , Rituximab/therapeutic use
19.
Int J Rheum Dis ; 22(1): 121-131, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30411519

ABSTRACT

AIM: Paraneoplastic pemphigus (PNP) is a mucocutaneous autoimmune disorder accompanied with a neoplasm. Castleman's disease (CD), although rare, is the most common cause of PNP in children. It can be life-threatening when pulmonary involvement occurs. Our study aimed to describe the features of PNP resulting from CD and to find clues for the early diagnosis in pediatric patients. METHOD: We report the case of a 13-year-old girl who initially presented with oral ulcers and lichen planus, with progression to respiratory failure. A literature review of PNP and CD in children between 1997 and 2016 was performed. The clinical manifestations, pathological findings, treatment, and outcome were analyzed. RESULTS: Thirty-two children were included in our study: 16 boys and 16 girls. Intractable mucocutaneous lesions developed early before CD was diagnosed. The clinical manifestations comprised oral ulcers (100%), polymorphous skin rash (86.7%) and genital (62.5%) erosion. Histopathological findings revealed lymphoplasmacytic cells infiltration (92%), vacuolar interface change (72%), acantholysis (68%), and keratinocytes necrosis (36%). Thirty patients underwent tumor resection. These patients mainly had unicentric CD, with the hyaline-vascular variant dominant. Twenty-six patients (81.2%) exhibited pulmonary involvement. The mortality rate was 70.0%. Among them, 90.5% exhibited pulmonary involvement, and 81.0% died of respiratory failure. CONCLUSION: Intractable mucocutaneous lesions with a concurrent tumor in children strongly indicate PNP resulting from CD. Because stomatitis or skin erosion may be the first presentation, mucocutaneous tissue biopsy and early detection of the underlying tumor are important. Earlier diagnosis is mandatory for the effective treatment of PNP and pulmonary involvement.


Subject(s)
Castleman Disease/complications , Paraneoplastic Syndromes/etiology , Pemphigus/etiology , Adolescent , Age Factors , Biopsy , Bronchiolitis Obliterans/etiology , Castleman Disease/diagnosis , Castleman Disease/immunology , Castleman Disease/surgery , Child , Early Diagnosis , Female , Fluorescent Antibody Technique , Humans , Lichen Planus/etiology , Male , Paraneoplastic Syndromes/diagnosis , Paraneoplastic Syndromes/immunology , Paraneoplastic Syndromes/therapy , Pemphigus/diagnosis , Pemphigus/immunology , Predictive Value of Tests , Risk Factors , Stomatitis, Aphthous/etiology , Tomography, X-Ray Computed , Treatment Outcome
20.
Clin Lab ; 64(10): 1671-1678, 2018 Oct 01.
Article in English | MEDLINE | ID: mdl-30336525

ABSTRACT

BACKGROUND: It can be difficult to distinguish between IgG4-related lymphadenopathy and multicentric Castleman's disease (MCD) because these conditions cannot be differentially diagnosed using immunohistochemical staining alone. In this study, we analyzed the clinical features of IgG4-related lymphadenopathy and MCD patients. METHODS: We retrospectively analyzed 27 patients with MCD, including 20 with plasma cell-type (PC-type) and 7 with hyaline vascular (HV) features (mixed-type). An additional 15 patients with IgG4-related lymphadenopathy were enrolled. Clinical data and immune pathological characteristics, including serum interleukin-6 (IL-6) levels, lymph node lesion biopsies, IgG4+/IgG+ expression, and 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) images, were collected. RESULTS: The serum levels of C-reactive protein (CRP), IgA, and IL-6 were significantly elevated in the PC/mixedtype group compared with the IgG4-related lymphadenopathy group (p < 0.05). By contrast, the mean age, eosinophilia, globulin, and serum levels of IgG and IgG4 were significantly higher in the IgG4-RD lymphadenopathy group (all p < 0.05). Thirty percent of patients with IgG4-RD lymphadenopathy had elevated IL-6 levels, and 50% with MCD had elevated serum IgG4 levels. Immunohistochemical studies demonstrated the presence of numerous IgG4+ plasma cells, which accounted for > 40% of IgG4/IgG+ cells in 7 of 27 cases in the PC/mixed-type group. We first found that the mean maximum standard uptake value (SUVmax) was strongly associated with albumin and IL-6 in the IgG4-RD lymphadenopathy group, but not in the MCD group. The number of involved organs, but not the standard uptake value (SUV), helped to distinguish between the two diseases. Most PC/mixed-type group patients responded poorly to glucocorticoids when administered alone or in combination with immunosuppressant drugs. CONCLUSIONS: MCD cannot be differentiated from IgG4-related lymphadenopathy using histology alone. Systematic comparative analysis; clinical and laboratory analyses, especially 18F-FDG-PET/CT; and responses to drug treatment are therefore important parameters for distinguishing between these two diseases.


Subject(s)
Castleman Disease/blood , Immunoglobulin G/blood , Interleukin-6/blood , Lymphadenopathy/blood , Adult , Aged , C-Reactive Protein/analysis , Castleman Disease/diagnostic imaging , Castleman Disease/immunology , Diagnosis, Differential , Humans , Immunoglobulin G/immunology , Immunologic Tests/methods , Lymphadenopathy/diagnostic imaging , Lymphadenopathy/immunology , Middle Aged , Positron Emission Tomography Computed Tomography/methods , Retrospective Studies , Sensitivity and Specificity , Tomography, X-Ray Computed/methods
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