Idiopathic Multicentric Castleman Disease Research Articles

Treatment-resistant idiopathic multicentric Castleman disease with thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly managed with Janus kinase inhibitors: A case report

Thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome are nonmalignant but life-threatening systemic inflammatory disorders. However, many patients are refractory to treatment, resulting in significant morbidity and mortality. Additionally, established treatment options are unavailable. Therefore, we present 2 cases of adults with the iMCD-TAFRO syndrome refractory to initial treatment but responded to Janus kinase (JAK) inhibitors with ruxolitinib. The report reveals that these rare adult cases of the refractory and treatment-resistant iMCD-TAFRO syndrome can be treated using JAK inhibitors. Case 1 is a 36-year-old previously healthy male patient who presented with fever and general fatigue for 2 weeks. Case 2 is a 42-year-old previously healthy female patient who presented with fever and general fatigue. The diagnosis met the 2015 criteria for TAFRO syndrome, as determined by All Japan TAFRO Syndrome Research Group in the Research Program for Intractable Disease by the Ministry of Health, Labor and Welfare (MHLW) Japan. Treatment with tocilizumab and several immunosuppressants were ineffective. So, we performed ruxolitinib. Each patient received ruxolitinib, the general condition improved, and CRP levels decreased. These cases showed that ruxolitinib was effective for treatment-resistant/ refractory TAFRO syndrome. Further prospective studies are needed on using ruxolitinib with a small number of cases.

Maladies de Castleman : épidémiologie, classification et critères diagnostiques

Castleman disease is a group of rare disorders characterized by lymph node enlargement, specific microscopic changes to the lymph nodes, and a broad range of symptoms and laboratory findings. The two main subtypes are unicentric Castleman disease (UCD) and multicentric Castleman disease (MCD). The multicentric subtype can be further classified into two categories: HHV-8 positive multicentric Castleman disease and idiopathic multicentric Castleman disease (iMCD). In the United States (US), the annual incidence of Castleman disease (CD) has been estimated to range from 6500 to 7700 in a 2014 study. Approximately 75 percent were estimated to be unicentric CD and the remaining 25 percent were estimated to be split between HHV-8-associated MCD or HHV-8-negative/idiopathic MCD. Diagnostic criteria for iMCD have been established by an international working group of pediatric and adult pathology and clinical experts. The proposed consensus criteria require characteristic histopathologic findings on lymph node biopsy, enlargement of multiple lymph node regions, the presence of multiple clinical and laboratory abnormalities, and the exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. © 2022 Published by Elsevier Masson SAS on behalf of Société nationale française de médecine interne (SNFMI).

Approche thérapeutique des maladies de Castleman : l’émergence des thérapies ciblées

The spectrum of Castleman disease encompasses several different disorders. Nowadays three different forms of the disease are individualized: unicentric Castleman disease, multicentric HHV-8 associated Castleman disease and idiopathic multicentric Castleman disease. In the latter a severe form called TAFRO syndrome (thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly) tend to be individualized. Improvement in the classification and understanding of the physiopathology of CD have allowed improvement in treatment strategies. Treatment of rare but often severe manifestations, such as paraneoplastic pemphigus and bronchiolitis obliterans in unicentric CD and hemophagocytic syndrome and/or Kaposi' sarcoma in HHV8 associated CD, are better adapted. Most of current treatment strategies are based on retrospective and very few prospective studies. Both anti-IL6/6R and anti-CD20 biotherapies have greatly improved the management of certain forms of the disease. We report in this review the most relevant studies and national or international expert consensus statements for the treatment in the different types of CD. © 2022 Published by Elsevier Masson SAS on behalf of Société nationale française de médecine interne (SNFMI).

CXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease

Idiopathic multicentric Castleman disease (iMCD) is a rare and poorly-understood cytokine storm-driven inflammatory disorder. Interleukin-6 (IL-6) is a known disease driver in some patients, but anti-IL-6 therapy with siltuximab is not effective in all patients, and biomarkers indicating success at an early time point following treatment initiation are lacking. Here we show, by comparison of levels of 1,178 proteins in sera of healthy participants (N = 42), patients with iMCD (N = 88), and with related diseases (N = 60), a comprehensive landscape of candidate disease mediators and predictors of siltuximab response. C-X-C Motif Chemokine Ligand-13 (CXCL13) is identified and validated as the protein most prominently up-regulated in iMCD. Early and significant decrease in CXCL13 levels clearly distinguishes siltuximab responders from non-responders; a 17% reduction by day 8 following siltuximab therapy initiation is predictive of response at later time points. Our study thus suggests that CXCL13 is a predictive biomarker of response to siltuximab in iMCD.

Utility of renal biopsy in differentiating idiopathic multicentric Castleman disease from IgG4-related disease.

Idiopathic multicentric Castleman disease (iMCD) is a subtype of human herpesvirus type 8 (HHV-8)-related Castleman disease that causes multi-organ damage, including kidney damage due to polyclonal lymphoproliferation and interleukin (IL)-6-induced cytokine storm. However, its renal pathological findings are unclear. We report the case of a woman in her 80s who was diagnosed with iMCD based on renal pathological findings. Five years ago, hypergammaglobulinemia was detected, and her renal function declined. Renal biopsy revealed plasma cells infiltrating the stroma. Immunostaining revealed numerous IgG4-positive plasma cells. The serum IgG4 level was high, and she was initially diagnosed with IgG4-related disease (IgG4-RD) and treated with steroids. However, the therapeutic effect was poor. On re-examination, computed tomography revealed lymphadenopathy around the aorta and spleen. Renal histopathology showed numerous IL-6-positive plasma cells. Anemia and C-reactive protein (CRP) positivity persisted despite steroid administration. HHV-8 was negative, and polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes syndrome was not suspected. Thus, iMCD was diagnosed. Based on previous reports, there is no significant difference in IgG4 levels between iMCD and IgG4-RD, and IgG4-positive plasma cell infiltrates were observed in iMCD-affected organs. Therefore, it may be difficult to distinguish iMCD from IgG4-RD. In this case, high-serum IL-6 and CRP were observed, which are usually not seen in IgG4-RD but are common findings in iMCD, leading to the diagnosis. Patients with deep lymphadenopathy may be diagnosed with iMCD based on renal pathological findings. Renal biopsy is recommended for patients with suspected iMCD and decreased renal function.

A Prospective Study of Bortezomib, Cyclophosphamide and Dexamethasone in Newly-Diagnosed Idiopathic Multicentric Castleman's Disease

【Introduction】There is no standard treatment for idiopathic multicentric Castleman disease (IMCD) in countries or regions where siltuximab is inaccessible. This study aims to explore the efficacy and safety of bortezomib combined with cyclophosphamide and dexamethasone (BCD) in the treatment of newly-diagnosed IMCD. 【Methods】 A total of 30 newly-diagnosed IMCD patients in our hospital from December 2018 to March 2021 were enrolled in the study. BCD regimen (bortezomib 1.3 mg/㎡ weekly subcutaneously, oral cyclophosphamide 300 mg/㎡ weekly, oral dexamethasone 40 mg weekly for a 28-d cycle) was administered for 9 cycles; After 9 cycles of BCD treatment, BD regimen (bortezomib 1.3 mg/㎡ every two weeks subcutaneously, dexamethasone 20 mg every two weeks was used as maintenance for one year. The primary endpoint of the study was the overall response at 24 weeks. Treatment responses were evaluated according to the CDCN criteria. 【Results】The median age of 30 patients was 48 (22-77) years old, and the male to female ratio was 1.5:1, including 12 cases of non-severe IMCD NOS (40%), 11 cases of severe IMCD NOS (36.7%) and 7 cases of TAFRO syndrome (23.3%). The overall response rate (CR or PR) at 24 weeks of treatment was 70.0%, with an overall complete remission rate (CR) of 10.0% and an overall partial remission rate (PR) of 60.0%. The symptomatic, biochemical and lymph node remission rate at 24 weeks was 90.0%, 76.7% and 70.0%, respectively. The overall remission rate at 24 weeks was 66.7% in severe patients and 75.0% in non-severe patients. The median follow-up time was 26.5 months (range，2-46 months). The median time to next-line treatment (TTNT) was 37 months (range, 1-46 months). The median TTNT in severe patients was not reached, and the median TTNT in non-severe patients was 37 months (10-40 months) (HR 1.26, 95% CI 0.37-4.27). In terms of safety, no grade 3 or above adverse reactions or treatment-related deaths occurred. 【Conclusions】BCD regimen may be an effective and safe treatment for patients with newly-diagnosed IMCD, especially for patients in severe group. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Longitudinal, Real-World Data Reveal Treatment Effectiveness in Idiopathic Multicentric Castleman Disease and Support Current Treatment Guidelines

Background: Idiopathic multicentric Castleman disease (iMCD) is an immunologic disorder with unknown etiology that is diagnosed in approximately 1200 individuals in the US annually. Presentation is heterogeneous - ranging from mild/moderate constitutional symptoms to severe multi-organ dysfunction. Treatment guidelines were developed by an international expert panel in 2017 based on the review of a limited number of clinical trials and small case series. Siltuximab, a monoclonal antibody against interleukin-6 (IL6) approved for the treatment of iMCD, is recommended first-line based on evidence from its phase II trial. High-dose steroids and cytotoxic chemotherapy are recommended for patients with severe disease who progress on anti-IL6 therapy. For patients with mild/moderate disease not responding to IL6 blockade, rituximab +/- immunomodulators is recommended. While concurrent steroids are recommended in some cases, steroid monotherapy is discouraged. Limited data exist on the effectiveness of these agents beyond siltuximab. Herein, we evaluate treatment regimens administered to a cohort of 83 iMCD patients with longitudinal treatment and response data. Methods: A review of cases in the ACCELERATE natural history registry by a panel of experts led to the identification of 83 patients with confirmed iMCD. Longitudinal treatment and response data were abstracted from medical records. Durable treatment response was defined as the best response according to the change in the proportion of abnormal clinical/laboratory criteria sustained for at least 1 year. Severity at the time of treatment initiation was defined as ≥2 of renal failure, fluid accumulation, severe anemia, pulmonary involvement, or hospitalization. Survival analysis for time-to-next-treatment, a proxy for time to treatment failure, was performed on regimens categorized in the guidelines: siltuximab +/- best supportive care (BSC), tocilizumab +/- BSC, rituximab +/- BSC, chemotherapy +/- other agents, and steroid monotherapy. BSC includes steroids, transfusions, and other supportive modalities. Log rank test was used to determine differences across treatment regimens, and pairwise comparisons were Bonferroni corrected. Results: Approximately half (47%) of the patients were female, with a mean (SD) age at diagnosis of 35.9 (16.2). A total of 261 regimens were administered across the cohort. Of the 41 patients who received siltuximab +/-BSC, 44% (N=18) achieved a durable response. Durable response rates to other treatments included: tocilizumab +/-BSC: 41% (7/17); rituximab +/-BSC: 23% (6/26); chemotherapy +/-BSC: 38% (8/21); steroid monotherapy: 6% (2/32). Steroid monotherapy was significantly less likely to induce a durable response than siltuximab +/-BSC (p=0.02). Notably, response rates were significantly lower across modalities in severe compared to mild/moderate disease (p=0.004). We also found that the treatment regimen significantly predicts time-to-next-treatment (p<0.0001, Figure 1). Median time-to-next-treatment for siltuximab +/-BSC is 742 days (95% CI: 1.26, no upper limit), tocilizumab +/-BSC is 689 days (234, no upper limit), rituximab +/- BSC is 153 days (116, 399), chemotherapy +/- other agents is 463 days (107, 791), and steroid monotherapy is 64 days (36,129). Pairwise comparison demonstrated that siltuximab +/-BSC, tocilizumab +/-BSC, and chemotherapy each have a significantly longer time-to-next-treatment compared with steroids (p<0.05). Further, siltuximab +/- BSC also had a significantly longer time-to-next-treatment than rituximab +/-BSC (p=0.02). There were no other differences between regimens. Discussion: Though guidelines were developed in 2017, this is the first systematic assessment of iMCD treatment regimens included in these guidelines. We found differences in durable response rates and in time-to-next-treatment between regimen approaches. Patients on steroids alone require additional drug-intervention a median of 2 months after treatment start, while patients treated on siltuximab +/-BSC remained on treatment for a median of 2 years before additional interventions were added. Our results support current recommendations to administer siltuximab first-line and limit steroid monotherapy use. These results also demonstrate that additional agents are needed for refractory patients, who have few options and are at risk of death due to progression. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Exploratory Validation of a Bespoke International Patient Symptom Survey in Idiopathic Multicentric Castleman's Disease Using Psychometric Testing: Implications for Clinical Practice and Routine Data Collection

Objective Idiopathic multicentric Castleman's disease (iMCD) is a rare lymphoproliferative disorder driven by proinflammatory hypercytokinemia. Patient perspective of the burden and associated symptoms of iMCD on their daily life have not been previously studied. We developed a bespoke international online survey to investigate, characterize, and map the symptoms and associated burden on daily life experienced by patients with various subtypes of iMCD. Statistical analysis was conducted to explore the psychometric properties of the survey. Methods A survey to elicit the burden of disease-related symptoms and their effects on daily life from a patient perspective was developed using information from clinical practice and published literature. Eligible patients were >18 years old having physician-confirmed diagnosis of iMCD. The survey was distributed within iMCD communities in Australia, Canada, the UK, and the US through the Castleman Disease Collaborative Network (CDCN). Hypotheses were generated based on expert opinion (one clinician, one patient, and one caregiver) in one-to-one interviews to understand whether specific questions and response options within the patient questionnaire could be: 1. grouped together as the same; 2. related to one another; or 3. if items were related, the expected strength of the relationship and the potential direction of relationship. Spearman's rank absolute correlation strength and Cohen's-d standardized effect size methods, alongside estimating relevant p-values, were used to explore these relationships. The overall study programme is depicted in Figure 1, with details of the study design captured in Figure 2. Results Overall, 57 patients with iMCD completed the survey between April-November 2021. Patients experienced a mean number of 7 symptoms a week (range: 0 to 22 symptoms), highlighting the burden iMCD on patient. To explore the robustness of these results, three a priori hypothesis sets were generated as a result of the expert interviews: 1. how specific symptoms relate to each other; 2. number of symptoms and their relationship with aspects of daily life; and 3. receiving treatment or not, and the overall relationship with aspects of daily life. 9 symptom pairs were identified for exploration, however as the number of symptoms experienced by patients with iMCD was so high and heterogeneous, in reality only 2 of the pairs were identified to be statistically significant due to small response numbers for other pairings. There was a moderate positive relationship between tiredness and physical weakness, and a weak positive relationship between tiredness and dizziness. There was a strong correlation between having a higher number of symptoms and greater adverse association with daily life, as depicted in Table 1. On reflection, it was realised that cross-sectional data as is the case in this survey was not appropriate for exploring links between treatment or not, and associated aspects of daily life as we have no indication of the baseline for the patients. The collecting of longitudinal data in such future research would support such analysis and increase the likelihood of making meaningful observations. A longitudinal approach would further add value to these results be gathering information on how iMCD progresses from a patient perspective. Conclusion To our knowledge this is the first study to characterise symptom burden of iMCD and its impact on daily living. The exploratory psychometric testing provides a level of confidence in the construct validity of the survey such that the results can hopefully be used to ultimately develop symptom burden score that can help assessment of disease severity, treatment decisions and evaluating responses in daily practice and clinical research. The exploratory testing also highlighted the challenges of working with naturally small samples sizes and the importance of recognising the limitations of what can be done with a data set given the data collection design. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Increased Comorbidities and Hospitalizations Associated with Idiopathic Multicentric Castleman Disease

Background: Castleman disease (CD) describes a group of disorders that share characteristic lymph node histopathology with heterogeneous symptoms. Unicentric Castleman disease (UCD) involves a single region of enlarged lymph nodes, localized symptoms, and is typically curable with excision. In contrast, multicentric Castleman disease (MCD) involves multiple regions of enlarged lymph nodes, systemic inflammation, cytopenias, and life-threatening multiorgan dysfunction. MCD can be associated with human herpesvirus-8 infection or is idiopathic (iMCD). Presentation is heterogeneous, and multiple clinical phenotypes exist, including iMCD patients who meet criteria for the most severe form of the disease, the TAFRO subtype (thrombocytopenia, anasarca, fevers, reticulin fibrosis, organomegaly). Furthermore, iMCD is difficult to diagnose. Though there is an FDA-approved therapy (siltuximab) for iMCD, major unmet need exists as many patients do not receive this treatment and a subset of patients do not respond to siltuximab. To elucidate the burden of iMCD, we interrogated hospitalization and comorbidity data from patients with iMCD and UCD, as well as from a comparator group of patients who demonstrated iMCD-like features determined to result from a reactive process ('Other'). Methods: The ACCELERATE Natural History registry was leveraged to identify a cohort of 193 patients with a pathology report suggestive of CD. All patients were reviewed by a panel of expert CD physicians to confirm or reject a CD diagnosis. Following review, 85 patients were categorized as having iMCD - including 49 (58%) iMCD-TAFRO, 65 were UCD, and 43 patients were consistent with an inflammatory or reactive processes not reflective of iMCD (Other). Results: The mean (SD) age of patients was 39 (16) with a range of 1-75. Prior to diagnosis, the top 10 comorbidities found among both iMCD and UCD patients included common chronic diseases observed in the general US population, such as diabetes, hypertension, GERD, obesity, asthma, anxiety, and depression. Among UCD patients, the top common comorbidities remained unchanged after diagnosis. Among iMCD patients, however, a number of other comorbidities emerged as top-most common, such as acute renal failure (20%), pneumonia (11%), sepsis (8%), chronic kidney disease (8%), thrombotic microangiopathy (7%), acute cholecystitis (7%), and diverticulitis (6%). We also found that the iMCD patients spent a significantly longer time hospitalized in the 1st year following diagnosis (mean 34.3 days) compared to UCD (mean 14 days) (p<0.05), but there was no significant difference from patients with an Other diagnosis (22 days). We saw a similar trend in days hospitalized per year since diagnosis, with iMCD patients hospitalized for a significantly greater time than UCD (24.2 vs. 10.5 average days hospitalized per year of diagnosis, p<0.001). There was no difference with the Other group (16.2 days). iMCD patients also spent an average of 12.1 days hospitalized before the first iMCD-treating drug and 44.7 days after the administration of the first iMCD-treating drug. Further, a large proportion of iMCD patients required supportive interventions, such as dialysis (23.6%, n=20) and mechanical ventilation (16.5%, n=14). This compares to 7% (n=3) of Other patients and no UCD patients who required dialysis and 9.3% (n=4) of Other patients and 4.6% (n=3) UCD patients who required mechanical ventilation. Discussion: Overall, these data demonstrate that iMCD patients face a significant disease burden, even years after a diagnosis is rendered and treatment is initiated. While siltuximab can effectively control symptoms in a subset of iMCD patients, not all patients receive siltuximab and not all patients treated respond to siltuximab. We found that patients require hospitalization and costly intervention such as dialysis and mechanical ventilation for extended periods of time. These findings have real implications for patient healthcare costs and hospital systems. iMCD patients demonstrate relatively common comorbidities prior to diagnosis and subsequently develop life-threatening conditions such as acute kidney failure and sepsis following diagnosis. These data highlight the importance of continuing research into iMCD etiology, subgroups, treatments, and outcomes, to control the burden of disease and improve outcomes and prognosis for this severely ill group of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

LRG1, a Novel Serum Biomarker for Idiopathic Multicentric Castleman Disease Activity

Objective: To investigate the relationship between serum Leucine-Rich α-2-Glycoprotein-1 (LRG1) and idiopathic multicentric Castleman disease (iMCD) activity, and to verify the effectiveness of LRG1 in monitoring treatment response. Methods: Clinical data and serum samples were collected from iMCD patients in flare and remission state diagnosed between August 2015 and April 2022 in Peking Union Medical College Hospital. Enzyme-linked Immunosorbent Assay was performed to quantify LRG1 concentration, which was further analyzed with patients' clinical data. Results: 81 patients were included, with 10 cases of iMCD-TAFRO and 40 cases of severe-disease, and 110 serum samples were acquired. The average LRG1 concentration was 113.5±14.27μg/mL in 76 samples of disease flare, 47.48±14.23μg/mL in 16 biochemical PR, and 14.4±1.18μg/mL in 18 biochemical CR samples. The difference is significant among different disease states (Flare vs PR, p = 0.0019; Flare vs CR, p < 0.0001; PR vs CR, p = 0.0349). Paired sample of 20 cases showed significant decrease of serum LRG1 from Flare to PR/CR (-35.36±5.94μg/mL, p < 0.0001) after treatment (figure 1A). Serum LRG1 level was also elevated in those iMCD-TAFRO cases with normal serum CRP level during disease flare. Baseline LRG1 level was significantly higher in patients with severe disease (142.6±23.2μg/mL vs 81.2±14.0μg/mL, p = 0.0271), which could be identified efficiently by baseline LRG1 over 57.75μg/mL (AUC = 0.655, p = 0.0203, sensitivity 70%, specificity 63.89%). Among 38 patients using thalidomide-cyclophosphamide-prednisone (TCP) regimen as first-line treatment, the median time to next treatment in patients with baseline LRG1 over 57.75μg/mL was significantly shorter than those under 57.75μg/mL (10 vs 30 months, HR: 2.254, 95% CI: 1.052-4.828, p = 0.0277) (figure 1B). Conclusion: Serum LRG1 level could mirror disease activity, and could be utilized to monitor the treatment response, especially in iMCD-TAFRO subtype. Serum LRG1 level over 57.75μg/mL could efficiently identify patients with severe iMCD, and had the potential to predict the efficacy of TCP regimen. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Idiopathic Multicentric Castleman Disease Interactive Disease Awareness and Educational Tool for Pathologists

Background: Idiopathic multicentric Castleman disease (iMCD) is a rare systemic lymphoproliferative disease that is challenging to diagnose. Diagnostic criteria require the identification of characteristic histopathology in the context of supportive clinical, radiologic, and serologic findings. However, the histologic features of iMCD can be subtle and nonspecific, which delays an accurate diagnosis. Timely diagnosis and early intervention are essential to reduce patient mortality. Developing a disease awareness and educational tool for pathologists may support the identification of future iMCD cases. Methods: International pathologists were identified to support the development of an interactive pathology tool for iMCD. To validate the tool, a selection of pathologists attended a virtual workshop to provide insight and help shape the content and format of the tool. Prior to workshop, attendees were asked to complete a 14-question survey on the diagnosis of iMCD, including exclusion of other diseases, conditions with similar histopathological features, and features specific to iMCD. Results: The educational tool is currently in development and takes into consideration the varied diagnostic journeys in different centers/countries. Histopathologic criteria for iMCD require evaluation of the degree of plasmacytosis, regressed germinal centers, follicular dendritic cell proliferation, vascular proliferation, and hyperplastic germinal centers. While the differences between high grade (grade 3) and normal (grade 0) findings are straightforward, differentiating grade 1 from grade 2 (the diagnostic cut-off) is challenging and subjective. The tool will focus on these diagnostic grey-zones to include points of differentiation between Grades 1 and 2 iMCD, disease exclusion criteria, and the use of diagnostic images that can be explored. Thus far, development of the tool has shown there is a need for standardized disease terminology between pathologists, that the use of template reports and language guidance may support the diagnostic process, and that patient case studies and the use of real-world examples support disease recognition. The educational tool is anticipated to be ready for release in September 2022. Conclusions: Diagnosis of iMCD is complex, and, despite the existence of well-established diagnostic criteria, pathological differentiation remains a challenge. Increasing awareness of iMCD-specifically the key diagnostic criteria-will assist with both timely diagnoses and the treatment of this disease.

Idiopathic Multicentric Castleman's Disease with Concurrent Renal Involvement

Introduction Castleman Disease (CD) is a rare non-clonal benign lymphoproliferative disease.CD can be classified into various subtypes based on etiology, clinical and histological findings. Management of CD varies based on the diagnosis and patient's condition and it can range from surgical excision to more aggressive systemic therapies such as anti-IL-6, steroids, and chemotherapy. It can rarely present with renal involvement, which is poorly understood. Case Presentation A 31-year-old male patient with a history of hospital admission one month prior to the present illness for persistent abdominal pain, with an incidental finding of splenomegaly and generalized lymphadenopathy on imaging, was admitted to the hospital for a 2-week history of generalized swelling with associated 20-pound weight gain, poor oral intake, nausea, vomiting, and loose stools. Laboratory work-up (TABLE 1) revealed hyponatremia with sodium of 117 mmol/L and renal failure with a creatinine of 1.6 mg/dL. Urinalysis showed proteinuria of 2+ and 24-hour collection revealed 300 mg of total protein. Heart failure was not noted on echocardiogram and biochemical or imaging findings were not suggestive of liver cirrhosis. Fluid restriction and diuretics were initiated. The patient improved initially but his hospital course was complicated by worsening renal failure and normochromic, normocytic anemia. Nephrology, Gastroenterology, Pulmonology, and Surgery were consulted. Excisional lymph node biopsy was performed revealing multicentric Castleman's Disease, negative for HHV-8. A kidney biopsy was performed later, consistent with thrombotic microangiopathy (Figure 1). VEGF and IL-6 were elevated. Hemodialysis was entertained,steroids were started, and Siltuximab was ordered but could not be obtained at the institution. Tocilizumab was started instead. The patient had a dramatic improvement after the treatment initiation and a week later the patient was discharged home. The patient's renal function was back to baseline and he was asymptomatic during the one-month follow-up visit. Discussion CD is a rare lymphoproliferative disease and renal involvement in CD is even rarer. There is still no consensus on how to manage CD patients with renal involvement. Here, we present an iMCD-NOS patient with renal involvement. Given the different therapeutic approaches, a final diagnosis of CD subgroups is important. The diagnosis of TAFRO, a rare clinicopathologic variant of idiopathic multicentric Castleman disease characterized by thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly was under consideration but discarded due to the patient lacking thrombocytopenia and it was decided to classify the patient under the not otherwise specified category. Renal complications from CD are uncommon and can include a variety of histopathological findings on biopsy, including thrombotic microangiopathy and membranoproliferative glomerulonephritis, among others.Our patient had thrombotic microangiopathy based on the renal biopsy findings. The pathophysiology of CD is not well understood. It is well known that IL-6 plays a role as increased levels of this proinflammatory marker have been associated with disease activity. Interestingly, increased serum levels of IL-6 and other cytokines have been observed in patients with several diseases characterized by renal thrombotic microangiopathy. Therefore, we hypothesize that increased IL-6 levels in patients with CD create an unhealthy environment for the renal microarchitecture that may result in thrombotic microangiopathy. As demonstrated by our case, improvement of renal function can be achieved after treating this pro-inflammatory state with systemic therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Features and Outcome of Patients with Castleman Disease Subtypes: A Spanish Multicentric Study of 145 Patients from Geltamo

Background: Castleman disease (CD) is a heterogeneous rare disorder, characterized by lymph node enlargement with a common histopathological spectrum. This disease comprises the subtypes unicentric (UCD), HHV8-associated multicentric CD (HHV8 MCD), POEMS-associated MCD (POEMS MCD) and idiopathic multicentric CD (iMCD). Whereas UCD is a localized reversible disease, the other three subtypes are systemic diseases with multiple lymphadenopathies. The TAFRO (thrombocytopenia, anasarca, fever, reticulin myelofibrosis, organomegaly) syndrome is an aggressive form of iMCD. Each CD subtype has different clinical features, prognosis and treatment. Aims: To study a large series of patients diagnosed with CD to describe the clinical and biological characteristics, as well as the treatments and outcomes of the different CD subtypes. Methods: Multicentric retrospective study which includes patients diagnosed with different subtypes of CD in 20 Spanish hospitals from 2008 to 2022. Clinical and biological data were retrieved from the clinical records. The project was approved by the Ethical Committee of Germans Trias I Pujol Hospital (PI-20-103). Statistical analyses were performed using SPSS v24.0 (IBM, Somer, NY). Results: One hundred and forty-five patients with available data were included; 52 with UCD and 93 with any of the 3 subtypes of MCD. The median follow-up was 3.4 years. The main clinical and biological characteristics of the 4 CD subtypes are shown in table 1 and differences in OS in figure 1. Most patients with HHV-8 MCD were HIV-infected (74%), whom 78% had positive HIV load (median [range]: 85603.5 copies/mL [227, 10000000]); with median CD4 lymphocyte count 0.209x109/L (range: 0.016, 1.2) and 48% of them had concomitant or prior Kaposi's sarcoma. Three iMCD patients had TAFRO. All patients with UCD were treated with surgery. Patients with HHV-8 MCD were treated at front-line with rituximab +/- doxorubicin +/- antiviral (63%) or other treatments such as polychemotherapy +/- rituximab or steroids (37%). Patients with iMCD were treated with anti-IL-6 (27%), polychemotherapy plus rituximab (20%), rituximab alone (33%) and steroids (20%). Treatment of POEMS MCD was also diverse; 3 patients received lenalidomide plus dexamethasone, 2 polychemotherapy, 1 anti-IL-6 and 1 auto SCT (3 patients unrecorded). The results of the first-line treatments administered in each CD subtype are shown in Table 1. Eleven patients (7.6%) had concomitant or evolved lymphoma (2 UCD, 2 iMCD and 7 HHV-8 MCD). Thirty-four patients are dead (21 HHV8-MCD, 6 iMCD-TAFRO, 4 UCD, 3 POEMS), 7 of them from CD (5 HHV8-MCD, 1 iMCD-TAFRO, 1 UCD). Conclusions: Castleman Disease subtypes have different characteristics and outcomes. First-line treatment is heterogeneous in all MCD subtypes. Patients with CD have an increased risk of developing lymphoma being higher in HHV8-MCD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Clinical Pictures of Castleman Disease Subtypes - Do They Differ?

Background: Castleman disease (CD) encompasses a spectrum of rare disorders with characteristic histopathologic features. It is important to distinguish unicentric CD (UCD) from idiopathic multicentric CD (iMCD), and to identify MCD associated with human herpes virus 8 (HHV8-positive MCD). Diagnostic guidelines are available for both UCD and iMCD, but not for HHV8+MCD. The aim of this study was to compare the clinical presentations of these different CD subtypes. Methods: A systematic review was performed of all publications following the PRISMA guidelines to identify publications reporting on ≥5 patients with CD between 1995 and 2021. For each type of CD within each study, we extracted data on patients' demographics, clinical symptoms, and laboratory parameters, as stated in the 2017 international consensus diagnostic criteria for iMCD. As many of the included studies were published prior to these criteria and precise clinical and laboratory data were not reported, we extended the criteria to capture symptoms and laboratory parameters beyond the ranges defined in the consensus diagnostic criteria. We then estimated the mean percentage of patients meeting each diagnostic criterion for each CD subtype using meta-analyses conducted with random-effects logistic regression models to account for between-study heterogeneity. Results: A total of 47 studies were included in the analysis, including 32 studies (n=2055 patients) with aggregated cohort-level data and 15 studies (n=335 patients) with patient-level data. Not surprisingly, the aggregated cohort-level data showed that patients with UCD had lower rates of symptoms and laboratory abnormalities than those with iMCD and HHV8+MCD. Many symptoms and laboratory abnormalities occurred at similar rates in patients with iMCD and HHV8+MCD. However, renal dysfunction and potentially hypoalbuminemia were more common among patients with iMCD versus HHV8+MCD, while constitutional symptoms and hepatosplenomegaly were less frequent (Table 1). Analysis of patient-level data largely confirmed these findings. Conclusions: This systematic review revealed that some systemic symptoms may be present in patients with UCD. We found many similarities among the clinical presentations and laboratory findings in patients with iMCD and HHV8+MCD, but also some important differences. These differences probably reflect the heterogeneity of the underlying pathophysiology and/or the different comorbidity burdens of these MCD subtypes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

HUMAN HERPESVIRUS 8 (HHV8)-NEGATIVE MULTICENTRIC CASTLEMAN DISEASE LEADING TO GROUP 1 PULMONARY ARTERY HYPERTENSION AND CLINICALLY SIGNIFICANT RIGHT VENTRICULAR SYSTOLIC DYSFUNCTION

HUMAN HERPESVIRUS 8 (HHV8)-NEGATIVE MULTICENTRIC CASTLEMAN DISEASE LEADING TO GROUP 1 PULMONARY ARTERY HYPERTENSION AND CLINICALLY SIGNIFICANT RIGHT VENTRICULAR SYSTOLIC DYSFUNCTION

IDIOPATHIC MULTICENTRIC CASTLEMAN DISEASE (IMCD) AS A MANIFESTATION OF POST-COVID-19 INFLAMMATORY SYNDROME

IDIOPATHIC MULTICENTRIC CASTLEMAN DISEASE (IMCD) AS A MANIFESTATION OF POST-COVID-19 INFLAMMATORY SYNDROME

La maladie de Castleman

The term "Castleman disease" covers a variety of entities that have very different clinical, biological, pathological and physiopathological features. In this issue, we review the characteristics of the unicentric Castleman disease, of the HHV8 associated multicentric Castleman disease and the idiopathic multicentric Castleman disease associated or not with TAFRO syndrome ("thrombocytopenia, anasarca, fever, reticulin myelofibrosis and/or renal insufficiency, organomegaly"). We detail the differential diagnostics of these entities.

Organ dysfunction, thrombotic events and malignancies in patients with idiopathic multicentric castleman disease: a population-level US health claims analysis

Organ dysfunction, thrombotic events and malignancies in patients with idiopathic multicentric castleman disease: a population-level US health claims analysis

Idiopathic Plasmacytic Lymphadenopathy Forms an Independent Subtype of Idiopathic Multicentric Castleman Disease.

Idiopathic multicentric Castleman disease (iMCD) is a type of Castleman disease that is not related to KSHV/HHV8 infection. Currently, iMCD is classified into iMCD-TAFRO (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) and iMCD-NOS (not otherwise specified). The former has been established as a relatively homogeneous disease unit that has been recently re-defined, while the latter is considered to be a heterogeneous disease that could be further divided into several subtypes. In 1980, Mori et al. proposed the concept of idiopathic plasmacytic lymphadenopathy (IPL), a disease presenting with polyclonal hypergammaglobulinemia and a sheet-like proliferation of mature plasma cells in the lymph nodes. Some researchers consider IPL to be a part of iMCD-NOS, although it has not been clearly defined to date. This is the first paper to analyze iMCD-NOS clinicopathologically, to examine whether IPL forms a uniform disease unit in iMCD. Histologically, the IPL group showed prominent plasmacytosis and the hyperplasia of germinal centers, while the non-IPL group showed prominent vascularity. Clinically, the IPL group showed significant thrombocytosis and elevated serum IgG levels compared to the non-IPL group (p = 0.007, p < 0.001, respectively). Pleural effusion and ascites were less common in the IPL group (p < 0.001). The IPL group was more likely to have an indolent clinical course and a good response to the anti-IL-6 receptor antibody, while the non-IPL counterpart frequently required more aggressive medical interventions. Thus, the IPL group is a clinicopathologically uniform entity that forms an independent subtype of iMCD.

Analysis of albumin as a prognostic factor in HHV-8/HIV-negative Castleman disease from a multicenter study

As a rare lymphoproliferative disorder, many patients with HHV-8/HIV-negative Castleman disease (CD) have hypoalbuminemia. However, data is limited on whether hypoalbuminemia is an independent predictor of CD. We retrospectively collected data from 230 patients diagnosed at 12 medical centers in China and the U.S. Different classifications included 147 patients with unicentric CD (UCD) and 83 with idiopathic multicentric CD (iMCD). Adjusted smooth curve fitting showed that the relationship between albumin and all-cause death of patients with CD and iMCD was linear. Cox proportional hazards regression modeling showed a negative association between the risk of death and albumin level (hazard ratio [HR]: 0.84; 95% CI, 0.76, 0.93). Using the Kaplan–Meier method, we determined that hypoproteinemia was a risk factor for poorer prognosis in patients with CD, UCD, and iMCD. Albumin was independently and negatively associated with the risk of death in CD patients, especially those with iMCD.