Treatment consistent with idiopathic multicentric Castleman disease guidelines is associated with improved outcomes.

Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder with an unknown etiology. Clinical presentation is heterogeneous, ranging from mild constitutional symptoms with lymphadenopathy to life-threatening multiorgan dysfunction. International, consensus treatment guidelines developed in 2018 relied upon a limited number of clinical trials and small case series; however, to our knowledge, real-world performance of these recommendations has not been subsequently studied. Siltuximab, a monoclonal antibody against interleukin 6 (IL6), is approved for the treatment of iMCD and recommended first-line, and tocilizumab, a monoclonal antibody directed against the IL6 receptor, is recommended when siltuximab is unavailable. Chemotherapy, rituximab, and immunomodulators are recommended as second- and third-line treatments based on limited evidence. Corticosteroid monotherapy is used by clinicians, although not recommended. Here, we draw upon the ACCELERATE Natural History Registry to inventory regimens and evaluate regimen response for 102 expert-confirmed iMCD cases. Siltuximab with/without (w/wo) corticosteroids was associated with a 52% response, whereas corticosteroid monotherapy was associated with a 3% response. Anti-IL6-directed therapy with siltuximab or tocilizumab demonstrated better response and more durability than was observed with rituximab w/wo corticosteroids. Cytotoxic chemotherapy was associated with a 52% response and was predominantly administered in patients characterized by thrombocytopenia, anasarca, fever, renal failure/reticulin fibrosis, and organomegaly. Our results provide evidence in support of current recommendations to administer anti-IL6 as first-line treatment, to administer cytotoxic chemotherapy in patients with severe refractory disease, and to limit corticosteroid monotherapy. Evidence remains limited for effective agents for patients who are refractory to anti-IL6-directed therapy. This trial was registered at www.clinicaltrials.gov as #NCT02817997.

International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease.

Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)-associated MCD, POEMS-associated MCD, and HHV-8-/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti-interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients.

International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease.

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8-negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease.

Human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research.

Prevalence and correlates of human herpesvirus 8 infection among Peruvian men who have sex with men.

BACKGROUND: Infection with human herpesvirus 8 (HHV-8) is common among men who have sex with men (MSM) in North America and Europe and is also found to be endemic in some regions of South America. Little is known about HHV-8 prevalence and its correlates among MSM in the Andean region. METHODS: We assessed HHV-8 seroprevalence among 497 MSM recruited for the 2002 Peruvian HIV sentinel surveillance program using a combined HHV-8 enzyme immunoassay and immunofluorescence assay algorithm. Logistic regression analysis was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) to determine the association between selected covariates and HHV-8 seropositivity. RESULTS: One hundred thirty-one (66.5%, 95% CI 63.1% to 69.9%) of 197 HIV-infected and 80 (26.7%, 95% CI 24.4% to 29.0%) of 300 HIV-uninfected MSM had serologic evidence of HHV-8 infection. Factors independently associated with HHV-8 infection were education<12 years (OR 1.7, 95% CI 1.1 to 2.7), anal receptive sex with the last partner (OR 2.0, 95% CI 1.2 to 3.3), self-reported sexually transmitted infection symptoms during the last year (OR 1.9, 95% CI 1.2 to 3.0), coinfection with HIV (OR 4.2, 95% CI 2.8 to 6.4) and chronic hepatitis B (OR 4.9, 95% CI 1.5 to 15.8). MSM with long-standing HIV infection were more likely to have serologic evidence of HHV-8 infection when compared with men with recently acquired HIV (OR 3.8, 95% CI 1.7 to 9.1). CONCLUSIONS: HHV-8 infection is common among both HIV-infected and HIV-negative MSM in Lima, Peru. HHV-8 seropositivity is correlated with anal receptive sex, self-reported sexually transmitted infection symptoms, and HIV infection among these MSM and thus seems to be sexually transmitted. HHV-8 infection seems to be acquired after HIV infection, suggesting that future studies should evaluate the mode of HHV-8 transmission and prevention strategies among HIV-uninfected MSM.