Humanized anti–interleukin-6 receptor antibody treatment of multicentric Castleman disease

Nishimoto, Norihiro; Kanakura, Yuzuru; Aozasa, Katsuyuki; Johkoh, Takeshi; Nakamura, Minoru; Nakano, Shuji; Nakano, Norihiko; Ikeda, Yasuo; Sasaki, Takeshi; Nishioka, Kiyoshi; Hara, Masamichi; Taguchi, Hirokuni; Kimura, Yukihiko; Kato, Yoshiro; Asaoku, Hideki; Kumagai, Shunichi; Kodama, Fumio; Nakahara, H.; Hagihara, Keisuke; Yoshizaki, Kazuyuki; Kishimoto, Tadamitsu

doi:10.1182/blood-2004-12-4602

Cited by 668 publications

(526 citation statements)

References 21 publications

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“…The clinical findings of systemic lymphadenopathy and hypergammaglobulinemia, which are characteristic of systemic IgG4-related lymphadenopathy, are also highly reminiscent of multicentric Castleman's disease. [15][16][17][18] However, none of our patients had anemia, hypoalbuminemia, or hypocholesterolemia, and elevated interleukin-6 and C-reactive protein were the exceptions. These findings are quite different from those of multicentric Castleman's disease.…”

Section: Discussionmentioning

confidence: 55%

“…The clinical findings are summarized in Tables 1 and 2 16 our patients with systemic IgG4-related lymphadenopathy showed more advanced age distribution, no significant elevation of C-reactive protein or interleukin-6 levels, no anemia, no hypoalbuminemia, and no hypocholesterolemia. These differences between the groups were statistically significant (Table 3).…”

Section: Clinical Findingsmentioning

confidence: 77%

“…These findings are quite different from those of multicentric Castleman's disease. [15][16][17][18] Interleukin-6 is a multifunction cytokine that has various biological activities in target cells and regulates immune responses, acute phase reactions, hematopoiesis, and bone metabolism. 25 Dysregulated overproduction of interleukin-6 is found in autoimmune diseases, such as rheumatoid arthritis, multicentric Castleman's disease, and Crohn's disease.…”

Section: Discussionmentioning

confidence: 99%

“…Abnormal laboratory findings include anemia, hypoalbuminemia, hypocholesterolemia, hypergammaglobulinemia, increased C-reactive protein, and interleukin-6. [13][14][15][16] These symptoms are closely related to high interleukin-6 levels, suggesting a cytokine disease. Idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia is considered identical to multicentric Castleman's disease in Western countries.…”

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confidence: 99%

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Systemic IgG4-related lymphadenopathy: a clinical and pathologic comparison to multicentric Castleman's disease

Kojima²,

et al. 2009

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Section: Discussionmentioning

confidence: 55%

Section: Clinical Findingsmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Systemic IgG4-related lymphadenopathy: a clinical and pathologic comparison to multicentric Castleman's disease

Kojima²,

et al. 2009

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“…An increased level of IL-6 in different autoimmune diseases indicates that IL-6 and IL-6-mediated signaling cascades are potential targets for autoimmune therapy. IL-6 receptor inhibition using tocilizumab has been documented in various clinical trials to reduce signs and symptoms (3,17), as well as radiologic progression, in patients with RA (24) and other inflammatory diseases (25,26).…”

Section: Discussionmentioning

confidence: 99%

In vivo effects of the anti–interleukin‐6 receptor inhibitor tocilizumab on the B cell compartment

Roll¹,

Muhammad²,

M³

et al. 2011

Arthritis & Rheumatism

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Objective. Interleukin-6 (IL-6) receptor inhibition by tocilizumab was recently licensed for the treatment of rheumatoid arthritis (RA). IL-6 induces in vitro differentiation of B cells into antibody-forming cells; however, the in vivo effects of IL-6 inhibition on the B cell compartment are currently not known. The purpose of this study was to examine this feature.Methods. Sixteen patients with active RA were treated in an open-label study with tocilizumab (8 mg/kg every 4 weeks). Immunophenotyping was performed at baseline, week 12, and week 24.Results. Memory B cell subsets declined significantly during tocilizumab therapy. Preswitch memory B cells decreased from a median of 19.6% to 12.3% at week 24 and postswitch memory B cells declined from a median of 18.6% to 15.0% at week 24 (P ‫؍‬ 0.04). In parallel, CD19؉IgA؉ and CD19؉IgG؉ B cells decreased significantly. The proportion of IgA-expressing B cells fell from a median of 9.2% at baseline to 4.3% at week 12 and to 3.6% at week 24 (P ‫؍‬ 0.01). IgG؉ B cells declined from a median of 6.7% at baseline to 4.9% at week 12 (P ‫؍‬ 0.007) and 2.8% at week 24 (P ‫؍‬ 0.01). In parallel, serum levels of IgA and IgG were significantly diminished at week 24 (P < 0.05). There was a good correlation between relative and absolute numbers of IgA؉ B cells with serum IgA at week 24.Conclusion. Tocilizumab induced a significant reduction in the frequency of peripheral preswitch and postswitch memory B cells. In addition, the number of IgG؉ and IgA؉ B cells declined and correlated well with reduced serum immunoglobulin levels. The data indicate that IL-6 blockade affects the B cell hyperreactivity in RA patients.

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Developmental Therapeutics Implications of Next-Generation Sequencing in Human Herpesvirus 8–Negative Castleman Disease

2017

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Castleman disease (CD) comprises a heterogeneous group of lymphoproliferative disorders that share similar histopathological lymph node changes. They are separated into unicentric CD (UCD), which is characterized by lymph node enlargement localized to 1 nodal region and few to no systemic symptoms, or multicentric CD (MCD), which is characterized by generalized lymphadenopathy and often systemic symptoms. Multicentric CD can be further subdivided into human herpesvirus 8 (HHV-8)-positive and HHV-8negative MCD (or idiopathic MCD). In this issue of JAMA Dermatology, Patel et al 1 documented a very elegant use of next-generation sequencing to explain the dramatic response to therapy in a very rare, cutaneous-only manifestation of CD and, by doing so, have provided important therapeutic and future study-design guidance for patients with CD.A perturbed interleukin 6 (IL-6) pathway is a key feature of all types of CD, though CD may present in quite diverse clinical contexts. Unicentric CD is not associated with HHV-8 or human immunodeficiency virus infection and is most often an isolated lymphoproliferative disorder of young adults. Patients are typically asymptomatic and diagnosed when an enlarged lymph node is identified on physical examination or imaging. The histopathological features of lymph nodes from these patients include germinal center hyperplasia, immunoblast and plasma cell accumulation, and increased vascularity. The pathogenesis is poorly understood, but the histopathological findings suggest a disorder characterized by chronic immune activation. Both UCD and MCD have been linked to human or viral interleukin IL-6 excess. Some studies have shown that lymph node excision resulted in relief of symptoms and a decrease in IL-6 levels. 2 Surgical extirpation is curative in 95% of UCD cases. 3 However, the cellular site of elevated IL-6 production has yet to be identified. Interleukin 6 receptor polymorphisms have been found in patients with human immunodeficiency virus-negative CD and are associated with elevated soluble IL-6 receptor levels. 4 Both HHV-8-positive and HHV-8-negative MCD (or idiopathic MCD) manifest as generalized lymphadenopathy with constitutional symptoms that may lead to sepsis, multiorgan failure, and death. The pathogenesis of HHV-8-positive MCD is now understood to be caused by excessive viral IL-6 release triggered by the HHV-8 virus, which also drives human IL-6, IL-10, and vascular endothelial growth factor (VEGF) secretion. In this condition, HHV-8 appears to preferentially infect immunoglobulin M-positive memory B cells, inducing their pro-

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Humanized anti–interleukin-6 receptor antibody treatment of multicentric Castleman disease

Abstract: Multicentric Castleman disease (MCD) is

Cited by 668 publications

References 21 publications

Systemic IgG4-related lymphadenopathy: a clinical and pathologic comparison to multicentric Castleman's disease

Systemic IgG4-related lymphadenopathy: a clinical and pathologic comparison to multicentric Castleman's disease

In vivo effects of the anti–interleukin‐6 receptor inhibitor tocilizumab on the B cell compartment

Developmental Therapeutics Implications of Next-Generation Sequencing in Human Herpesvirus 8–Negative Castleman Disease

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