Therapeutic outlook for Castleman’s disease: prospects for the next decade

ABSTRACT

Introduction: Castleman disease (CD) is a rare and heterogeneous cluster of disorders, characterized by lymphadenopathy and systemic symptoms. Although most cases of unicentric CD (UCD) are treatable by surgical excision, the prognosis of multicentric CD (MCD) is varied, and it may be challenging to achieve remission. Current treatments of MCD have advanced dramatically with the advent of the novel biologic therapies including interleukin-6 (IL-6) inhibition, but refractory cases occur despite these treatments.

Areas covered: We review the etiology and pathogenesis of CD, summarize the current MCD treatments, and discuss the possibilities of a new therapeutic target in severe MCD.

Expert opinion: The disease type, the presence of human immunodeficiency virus (HIV) and human herpesvirus 8 (HHV-8), and the progression of organ involvement determines the optimal therapeutic interventions for CD. IL-6 inhibition by tocilizumab or siltuximab has shown effectiveness for HIV/HHV­8-negative patients. Rituximab, alone or in combination with chemotherapy has been used for HIV/HHV-8 negative patients as well as HIV/HHV-8-positive MCD. Antiviral agents are indicated in HIV/HHV-8 positive cases. Novel agents modulating inflammatory pathways such as JAK-STAT signaling and PIK3-Akt-mTOR signaling involved in the pathogenesis of MCD may be candidates for the treatment of severe MCD.

KEYWORDS:

• Castleman disease
• human herpesvirus 8
• multicentric Castleman disease
• siltuximab
• tocilizumab

Article highlights

• The pathogenesis and symptoms of CD are associated with excessive release of IL-6 from affected lymph nodes.

• In a subset of MCD, HHV-8 infection and vIL-6 also play important roles in its pathogenesis.

• The choice of treatment for MCD depends upon whether the patient is HIV/HHV-8-positive, and upon whether the clinical course is aggressive with organ involvement or not.

• Treatment with IL-6 inhibitors (tocilizumab or siltuximab) has been shown to be effective for treating symptomatic, HIV/HHV­8 negative MCD patients.

• Novel agents modulating inflammatory pathways such as JAK-STAT signaling and PI3K/Akt/mTOR signaling may be candidates for treating severe MCD.

This box summarizes key points contained in the article.

Declaration of interest

K Yoshizaki and H Kawabata report grants from the Ministry of Health, Labour and Welfare, Japan. He has also received royalties from Chugai Pharmaceutical Co. Y Masaki disclose grants from Astellas, Eisai, MSD, Ono, Kyowa Hakko Kirin, Shionogi, Daiichi Sanyko, Taisho Toyama, Taiho, Takeda, Tanabe Mitsubishi, Chugai, Teijin, Novartis and Japan Blood Products Organization. T Kishimoto is patent holder of Tocilizumab. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This study was supported in part by a grant from the Ministry of Health, Labor and Welfare, Japan (H27-28 Nanchi, etc. (Nan)- General-002).