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.

scRNA-seq reveals the landscape of immune repertoire of PBMNCs in iMCD.

The etiology of idiopathic multicentric Castleman disease (iMCD) is poorly understood, and the identification of targetable disease mediators remains an unmet clinical need. Thus, we firstly employed single-cell RNA sequencing (scRNA-seq) to elucidate the landscape of the immune repertoire of peripheral blood mononuclear cells (PBMNCs) in iMCD and to identify additional driver cytokines/cells/pathways to address IL-6 blockade-refractory cases. We revealed that the inflammatory cytokine storm observed in iMCD was a significant phenomenon pervasive across all immune cells. B-plasma cell subsets was the main source of IL-6. The IL-6 signaling pathway was significantly activated across a spectrum of immune cells. Systemic upregulation of CXCL13 is mainly driven by peripheral helper T (Tph) and regulatory T (Treg) cells. Notably, a significant positive interaction was observed between CXCL13-expressing T cells and IL-6 signaling-activated B cells. This study provides an immune perspective on PBMNCs in iMCD at the single-cell level, unveiling pathways or targets characterized by atypical inflammatory expression that could potentially serve as promising candidates for therapeutic intervention in iMCD.

Immunology and targeted therapy in Castleman disease.

INTRODUCTION: Castleman disease (CD) is a benign lymphoproliferative disease causing severe systemic inflammation. Interleukin-6 (IL-6) is a major pathogenesis of multicentric CD (MCD), but only 30-60% of patients respond to IL-6 inhibitors. Novel agents for IL-6 inhibitor-refractory cases are needed. Clinical data and samples are being collected on a large scale and the clinical, pathological, and pathogenetic aspects are being elucidated. AREAS COVERED: The pathological and clinical classification of CD is outlined. Focusing on idiopathic MCD (iMCD), this review identifies therapeutic targets and summarizes currently recommended drugs and promising therapeutic candidates. EXPERT OPINION: The pathogenesis of MCD has been implicated in the activation of the Janus kinase (JAK)-transcriptional signaling activator (STAT) 3 pathway and the phosphatidylinositol 3-kinase (PI3K)/Akt/mechanical target of rapamycin (mTOR) signaling pathway. iMCD-TAFRO (thrombocytopenia, anasarca, fever/elevated CRP, reticulin myelofibrosis/renal dysfunction, organ enlargement) is resistant to IL-6 inhibitors, and cyclosporine and mTOR inhibitors are sometimes effective. JAK inhibitors and mTOR inhibitors may be therapeutic agents for iMCD. Recently, we have shown that peripheral helper T (Tph) cell abnormalities are at the core of iMCD pathogenesis. Therapies targeting chemokine (C-X-C motif) ligand 13 (CXCL13) produced by Tph cells and blocking the Tph-CXCL13-B cell pathway may satisfy unmet need in refractory cases.

[Paraneoplastic pemphigus with underlying Castleman's disease in a 16-year-old girl]. / Morbus Castleman-assoziierter paraneoplastischer Pemphigus bei einer 16-jährigen Patientin.

Paraneoplastic pemphigus is a rare, life-threatening autoimmune disease that is clinically characterized by mostly extensive and refractory mucosal erosions and polymorphous skin lesions. We report here on a 16-year-old girl with isolated oral erosions, in whom mucosal pemphigoid was initially suspected and after treatment with prednisolone and dapsone marked improvement was achieved. However, a few months later the patient developed massive respiratory insufficiency as a result of bronchiolitis obliterans, so that a lung transplant was planned. As part of the preparatory diagnostic workup, unicentric, abdominally localized Castleman's disease was diagnosed, which ultimately led to the diagnosis of paraneoplastic pemphigus as evidenced by envoplakin autoantibodies. Tumor resection and subsequent lung transplantation achieved good results with sustained mucocutaneous remission.

Host-Level Susceptibility and IRF1 Expression Influence the Ability of IFN-γ to Inhibit KSHV Infection in B Lymphocytes.

Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with vascular endothelial cell tumor, Kaposi's sarcoma (KS) and lymphoproliferative disorder, multicentric Castleman's disease (MCD), primary effusion lymphoma (PEL) and KSHV inflammatory cytokine syndrome (KICS). Dysregulation of proinflammatory cytokines is found in most KSHV associated diseases. However, little is known about the role of host microenvironment in the regulation of KSHV establishment in B cells. In the present study, we demonstrated that IFN-γ has a strong inhibitory effect on KSHV infection but only in a subset of tonsil-derived lymphocyte samples that are intrinsically more susceptible to infection, contain higher proportions of naïve B cells, and display increased levels of IRF1 and STAT1-pY701. The effect of IFN-γ in responsive samples was associated with increased frequencies of germinal center B cells (GCB) and decreased infection of plasma cells, suggesting that IFN-γ-mediated modulation of viral dynamics in GC can inhibit the establishment of KSHV infection.

Successful rituximab treatment of an elderly Japanese patient with HHV8-positive, HIV-negative multicentric Castleman disease.

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.

Immunoglobulin G4-related disease and idiopathic multicentric Castleman's disease: confusable immune-mediated disorders.

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.

Mediterranean fever gene variants modify clinical phenotypes of idiopathic multi-centric Castleman disease.

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.

Weathering the COVID-19 storm: Lessons from hematologic cytokine syndromes.

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.

Positive disease-specific autoantibodies have limited clinical significance in diagnosing IgG4-related disease in daily clinical practice.

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.

Case Report: Extensive Phosphorylation of Interleukin-1 Receptor-Associated Kinase 4 in a Patient With Schnitzler Syndrome.

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.

Analysis of Clinical Characteristics, Pathological Changes and Changes of Interleukin-6 (IL-6) and C-Reactive Protein (CRP) in Children with Castleman's Disease.

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.

Type I IFN response associated with mTOR activation in the TAFRO subtype of idiopathic multicentric Castleman disease.

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.

Case report on mesangial proliferative glomerulonephritis with multicentric Castleman's disease: Approach to the onset mechanism of immunoglobulin A nephropathy.

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.

Association of vascular endothelial growth factor and renal thrombotic microangiopathy-like lesions in patients with Castleman's disease.

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.

Discovery of IL-6 and Development of Anti-IL-6R Antibody.

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.