Idiopathic Multicentric Castleman Disease Research Articles

Tacrolimus Treatment for TAFRO Syndrome

TAFRO syndrome is an acute systemic inflammatory disorder characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. While its lymph node pathology is similar to that of idiopathic multicentric Castleman disease (iMCD), the clinical features of TAFRO syndrome differ from those of typical iMCD, as they include a more aggressive clinical course and high mortality. However, an optimal treatment strategy for TAFRO syndrome has not yet been established, owing to a poor understanding of its pathogenesis. The limited cases we encountered suggest that tacrolimus treatment in combination with glucocorticoids may potentially be effective and well tolerated as an initial treatment, and hold promise as a glucocorticoid-sparing agent. Herein, we report an additional case and review the sparse literature available regarding TAFRO syndrome treated via tacrolimus.

Sirolimus is effective for refractory/relapsed idiopathic multicentric Castleman disease: A single-center, retrospective study.

Refractory/relapsed idiopathic multicentric Castleman disease (R/R iMCD) has limited treatment options. With studies showing increased mTOR activation in iMCD patients, sirolimus becomes an attractive and promising therapy for R/R iMCD. Here we report the results of a retrospective study involving 26 R/R iMCD patients treated with sirolimus-containing regimen. The median age at sirolimus initiation was 40.5 years (23-60), with a median prior treatment line of 2 (1-5). 18 patients (69.2%) achieved symptomatic and biochemical response, with a median time to at least overall partial remission of 1.9 months (0.5-14.6). The median follow-up time from sirolimus initiation was 11.7 months (1.6-50.7) and the median time to next treatment (TTNT) was 46.2 months. No patients died at the end of follow-up. Most of the patients in the cohort are in ongoing responses and continue sirolimus therapy. Sirolimus is well tolerated with minor adverse effects. In conclusion, sirolimus is effective for R/R iMCD patients with good tolerance.

Can We Differentiate Between Primary Sjögren Syndrome and Idiopathic Multicentric Castleman Disease Based on the Characteristics of Pulmonary Cysts?

To identify radiological characteristics that could help differentiate cystic lung diseases between primary Sjögren syndrome (pSS) and idiopathic multicentric Castleman disease (iMCD). Patients with pSS or iMCD who had cysts were enrolled. Cyst characteristics (number, size, morphology, and distribution) and other accompanying manifestations (nodules, ground-glass opacities, calcification, and thickening of the bronchovascular bundles and interlobular septa) were compared between them. Eleven patients with pSS and 25 patients with iMCD were eligible for our study. Eleven patients with pSS (100.0%) and 23 patients with iMCD (92.0%) had round or oval cysts. None of the patients with pSS had irregular cysts, but 21 (84.0%) patients with iMCD had irregular cysts (P = 0.005). Smooth-walled cysts were present in 11 patients with pSS (100.0%) and 18 patients with iMCD (72.0%). Only 1 patient with pSS (9.1%) exhibited non-smooth-walled cysts, whereas 23 patients with iMCD (92.0%) had non-smooth-walled cysts (P = 0.003). The presence of nodules was common in both groups (P = 1.000). However, the nodules were more likely to be larger and more numerous in patients with iMCD (P < 0.001). Cysts with mural nodules (52.2%) and central nodules (47.8%) were only observed in iMCD (P = 0.007). Although regular and smooth-walled cysts were common in the 2 diseases, irregular and non-smooth-walled cysts were more often associated with iMCD than pSS. Nodules in iMCD tended to be larger and more numerous, and a close positional relationship between nodules and cysts was only observed in iMCD.

VEXAS syndrome: A new mimicker of idiopathic multicentric Castleman disease

Introduction: Idiopathic multicentric castleman disease (iMCD) is a complex and poorly understood pathophysiological entity, which encompasses a variety of conditions and can mimic or be associated with autoimmune/autoinflammatory diseases, making it challenging to diagnose and treat. Vacuoles, Enzyme E1, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is an adult-onset autoinflammatory disorder associated with hematological abnormalities and caused by acquired somatic mutations in the ubiquitin-like modifier activating enzyme 1 gene (UBA1) which shares several common clinical and biological signs with iMCD. In this article, we report a patient with VEXAS syndrome initially presenting as iMCD, questioning the link between these two entities.Case description: We report here a patient initially presenting as iMCD, proved on lymph node histology, which turns out to have a mutation at the splice acceptor site of exon 3 of UBA1 exhibiting VEXAS syndrome with Castleman-like lymph node.Conclusion: This is only the second case of VEXAS syndrome presenting as iMCD. VEXAS syndrome should therefore be considered in the presence of iMCD suspicion, including in cases of compatible histology.

Idiopathic multicentric Castleman disease - TAFRO results in high levels of mTOR activator SVEP1, tissue factor, and endotheliopathy

AbstractIdiopathic multicentric Castleman disease (iMCD) is an inflammatory disease associated with a cytokine storm, activation of the PI3K/AKT/mTOR pathway, coagulopathy, and increased risk of thrombosis. The mechanisms underlying these pathologic processes remain elusive. We studied novel markers of mTOR activation and thrombosis in 1 patient with typical features of iMCD with TAFRO (thrombocytopenia, anasarca, fevers, reticulin myelofibrosis, and organomegaly) syndrome (iMCD-TAFRO). Plasma levels of SVEP1 (Sushi, von Willebrand factor type A, epidermal growth factor, and pentraxin domain–containing 1 protein), a newly identified mTOR activator associated with cardiovascular diseases and dementia, in addition to cytokines, chemokines and components of the coagulation cascade and complement system were evaluated by enzyme-linked immunosorbent assay (ELISA) and arrays. Compared with healthy controls, a 15-fold increase in SVEP1 was observed. High levels of factor VIIa/antithrombin and microparticles expressing functional tissue factor (TF) were detected. The anticoagulants thrombomodulin and soluble endothelial protein C receptor were elevated, indicating shedding from endothelial cells. Plasminogen activator inhibitor 1 was increased, consistent with hypofibrinolysis, whereas high levels of C3b and C5a are in keeping with complement activation. Furthermore, markers of endothelial cell activation (e.g. von Willebrand factor, angiopoietin-2), cell adhesion molecules, and angiogenesis mediators were upregulated. SVEP1 emerges as a potential mechanism of mTOR activation in iMCD-TAFRO, while multiple pathways influence coagulopathy. Immunothrombosis emerges as a potential therapeutic target for iMCD.

Hodgkin Lymphoma-related Inflammatory Modification-displayed Castleman Disease-like Histological Features and Positron Emission Tomography/Computed Tomography Usefulness for the Differential Diagnosis.

Hodgkin lymphoma (HL) and idiopathic multicentric Castleman disease (iMCD) are markedly different conditions. However, in some cases, histological similarities caused by elevated cytokines, including interleukin-6, can lead to a misdiagnosis of HL as Castleman disease (CD). We herein report a patient with HL who had been diagnosed with CD by an expert panel and for whom an additional biopsy was useful for determining the correct diagnosis. Furthermore, we analyzed the positron emission tomography/computed tomography findings at the diagnosis and found that the maximum standardized uptake value was useful for distinguishing HL from iMCD.

A prospective study of zanubrutinib, a Bruton tyrosine kinase inhibitor, in relapsed/refractory idiopathic multicentric Castleman disease.

Relapsed and refractory (R/R) idiopathic multicentric Castleman disease (iMCD) is a clinical challenge with no standard treatment. In this preliminary clinical trial, we investigated the efficacy and safety profiles of a Bruton tyrosine kinase inhibitor (BTKi), zanubrutinib, in patients with R/R iMCD. The primary endpoint was theoverall response rate at Week 12according to theCastleman Disease Collaborative Network (CDCN) response criteria. The trial was terminated early due to a lack of treatment response in the first enrolled 5 patients. Although 3 patients achieved symptomatic response, none of the 5 patients had an overall response by Week 12. One patient had progressive disease and the other 4 had stable disease. The study drug was well tolerated without grade 2 or higher adverse events. Our findings suggest that BTKi therapy is not effective for iMCD, and further attempts at single-agent therapy with zanubrutinib or other BTKis for iMCD should be consideredwith caution and probably avoided. This trial was registered at www.clinialtrials.gov as #NCT04743687.

Acquired Hemophilia: A Rare Complication of Pediatric Idiopathic Multicentric Castleman Disease.

Acquired hemophilia is caused by acquired autoantibodies to 1 of the factors of the coagulation cascade, usually factor VIII or IX, and is an exceedingly rare phenomenon in children. The finding of an acquired factor VIII inhibitor in a pediatric patient with idiopathic multicentric Castleman disease has never been reported. Patients with acquired hemophilia can have life-threatening bleeds that are refractory to blood product support, requiring bypassing agents to manage bleeding symptoms. We present the novel finding of acquired hemophilia resulting from an autoantibody to factor VIII in a pediatric patient with idiopathic multicentric Castleman disease and discuss the optimal management of bleeding in a patient with acquired hemophilia.

TAFRO Syndrome: A Syndrome or a Subtype of Multicentric Castleman Disease?

TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis of bone marrow/renal dysfunction, organomegaly) syndrome is a systemic inflammatory disorder of unknown etiology. It has been recognized as a subtype of idiopathic multicentric Castleman disease (iMCD), and the international diagnostic criteria for iMCD-TAFRO require a lymph node histopathology consistent with iMCD. Furthermore, TAFRO syndrome is defined as a heterogeneous clinical entity caused by underlying diseases such as malignancy, autoimmune diseases, or infections. However, the cases that led to the proposal of TAFRO syndrome lacked recognizable lymphadenopathy and were inconsistent with any other diseases, despite vigorous efforts in differential diagnosis. Irrespective of the presence or absence of Castleman disease (CD)-like histology, TAFRO syndrome exhibits homogeneous clinical, laboratory, and prognostic features, setting it apart from iMCD without TAFRO syndrome. Defining iMCD-TAFRO apart from TAFRO syndrome is deemed meaningless and confusing. MCD is a heterogeneous lymphoproliferative disorder consisting of several subtypes with different pathogenesis, clinical manifestations, and histological features. Typical MCD in Japan, characterized by the histology of plasma cell type and marked polyclonal hypergammaglobulinemia, is identical to idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia (IPL). Although IPL is classified into iMCD-NOS (not otherwise specified), it should be recognized as a distinct clinicopathological entity. Furthermore, we propose to separate TAFRO syndrome from the MCD category as a defined disorder.

Diagnostic challenges of the idiopathic plasmacytic lymphadenopathy (IPL) subtype of idiopathic multicentric Castleman disease (iMCD): Factors to differentiate from IgG4-related disease

Aims and methodsIdiopathic multicentric Castleman disease (iMCD) is currently considered to be classified into three clinical subtypes, including idiopathic plasmacytic lymphadenopathy (IPL), thrombocytopaenia, anasarca, fever, reticulin fibrosis/renal dysfunction, organomegaly (TAFRO)...

Idiopathic multicentric Castleman disease (iMCD)-idiopathic plasmacytic lymphadenopathy: A distinct subtype of iMCD-not otherwise specified with different clinical features and better survival.

Idiopathic multicentric Castleman disease (iMCD) is subclassified into iMCD-thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly (TAFRO) and iMCD-not otherwise specified (NOS) according to the Castleman Disease Collaborative Network (CDCN) consensus criteria. With a deeper understanding of iMCD, a group of patients with iMCD-NOS characterised by polyclonal hypergammaglobulinaemia, plasmacytic/mixed-type lymph node histopathology and thrombocytosis has attracted attention. This group of patients has been previously described as having idiopathic plasmacytic lymphadenopathy (IPL). Whether these patients should be excluded from the current classification system lacks sufficient evidence. This retrospective analysis of 228 patients with iMCD-NOS identified 103 (45.2%) patients with iMCD-IPL. The clinical features and outcomes of patients with iMCD-IPL and iMCD-NOS without IPL were compared. Patients with iMCD-IPL showed a significantly higher inflammatory state but longer overall survival. No significant difference in overall survival was observed between severe and non-severe patients in the iMCD-IPL group according to the CDCN severity classification. Compared with lymphoma-like treatments, multiple myeloma-like and IL-6-blocking treatment approaches in the iMCD-IPL group resulted in significantly higher response rates and longer time to the next treatment. These findings highlight the particularities of iMCD-IPL and suggest that it should be considered a new subtype of iMCD-NOS.

TAFRO syndrome is associated with anti-SSA/Ro60 antibodies, in contrast to idiopathic castleman disease

TAFRO syndrome is an acute systemic inflammatory disease characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, and organomegaly. There have been increasing reports that TAFRO is a disease distinct from idiopathic multicentric Castleman disease and that TAFRO patients may be positive for anti-SSA antibodies. To assess anti-SSA antibody positivity and the clinical characteristics of the two diseases, we retrospectively compared 7 TAFRO and 10 iMCD patients in our hospital. The mean age of onset of TAFRO and iMCD was 48.0 (interquartile range [IQR], 41–53) and 45.0 (IQR, 35–53) years, respectively. The TAFRO and iMCD groups had 6 (86%) and 4 (40%) male patients, respectively, and the following pretreatment laboratory values: platelet count, 3.8 (IQR, 2.2–6.4) and 35.5 (IQR, 22.2–42.8) × 104/μL, respectively; C-reactive protein, 10.2 (IQR, 6.8–21.4) and 9.5 (IQR, 6.2–13.6) mg/dL, respectively; IgG, 1431 (IQR, 1112–1815) and 4725 (IQR, 3755–5121) mg/dL, respectively. RNA immunoprecipitation (5 cases for anti-SSA) or protein array (5 cases for anti-SSA/Ro60) detected anti-SSA antibodies in six (86%) TAFRO patients but not in iMCD patients; it did not detect anti-SSB antibodies in any of the patients. None of the patients were diagnosed with Sjögren syndrome. All iMCD patients treated with tocilizumab (TCZ) responded well. Meanwhile, two of six TAFRO patients treated with TCZ showed inadequate responses; thus, both patients were switched to rituximab, following which they achieved remission. TAFRO and iMCD have different clinical features. TAFRO may be categorized as a severe phenotype of the anti-SSA antibody syndrome.

TAFRO syndrome associated with C3 nephropathy (an analysis of clinical experience)

Aim. To present a clinical case of TAFRO syndrome – a recently described subtype of idiopathic multicentric Castleman disease of unknown etiology, characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis of the bone marrow and / or renal dysfunction, organomegaly associated with an increase in serum IL-6 secretion.Materials and methods. Herein, we report a young patient diagnosed with TAFRO combined with C3 nephropathy. The patient was treated with glucocorticoids (methylprednisolone), colchicine, sarilumab, rivaroxaban, and symptomatic treatment.Results. Key aspects of diagnosis, treatment and course of the syndrome were discussed. The possibility of the combined course of two rare pathologies – a subtype of idiopathic multicentric Castleman disease and C3 nephropathy is still unclear.Conclusion. The diagnosis of TAFRO syndrome can be considered after the exclusion of a number of infectious, paraneoplastic, systemic connective tissue diseases, POEMS syndrome, liver cirrhosis against the background of autoimmune hepatitis, autoimmune thrombocytopenic purpura, as well as hemolytic-uremic syndrome. Kidney damage in this category of patients, in most of the described clinical cases, is morphologically represented by thrombotic microangiopathy or mesangioproliferative glomerulonephritis. C3 nephropathy in that clinical case seems to be concomitant. Glucocorticoids in high and ultrahigh doses, cyclosporine, IL-6 type inhibitors, as well as anti-CD20 antibodies are used as therapy.

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

Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder with heterogeneous presentations ranging from moderate constitutional symptoms to life-threatening multiorgan system involvement. iMCD patients present with vastly different clinical subtypes, with some patients demonstrating thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin fibrosis/renal failure, and organomegaly (TAFRO) and others demonstrating more mild/moderate symptoms with potential for severe disease (not otherwise specified, NOS). Due to its rarity and heterogeneity, the natural history and long-term burden of iMCD are poorly understood. We investigated real-world medical data from ACCELERATE, a large natural history registry of Castleman disease patients, to better characterize the long-term disease burden experienced by these patients. We found that iMCD-TAFRO patients face significant hospitalization burden, requiring more time in the hospital than iMCD-NOS patients during the year surrounding diagnosis (median [IQR] 36 [18, 61] days vs. 0 [0, 4] days; p.

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

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

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

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

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

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

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

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

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

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

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

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