A benefit and the prospects of IL-6 inhibitors in idiopathic multicentric Castleman's disease

Abstract

Castleman's disease (CD), a heterogeneous group of lymphoproliferative disorders, is divided into unicentric CD (UCD) and multicentric CD (MCD) based on the number of regions of enlarged lymph nodes with characteristic histopathologic features. The clinical pictures and treatment differ greatly between these UCD and MCD. In MCD, cases of human herpesvirus 8-negative patients with unknown etiology are defined as idiopathic MCD (iMCD). Most cases of UCD are treatable by surgical excision. The prognosis of iMCD varies, and it may be challenging to achieve remission. Glucocorticoids are initiated as the first choice for therapy, but for glucocorticoid-resistant cases, interleukin (IL)-6 inhibition is initiated. However, an IL-6 inhibitor is not effective for all iMCD cases, and refractory cases occur despite these treatments. In this review, we briefly summarize the role of IL-6 in iMCD, and we discuss the efficacy that has been reported for tocilizumab (TCZ), the anti-IL-6 receptor antibody, for patients with iMCD in Japan. Factors predicting the therapeutic response to IL-6 remain to be identified, and the verification of the long-term safety of IL-6 inhibition is needed.

Keywords:

• Idiopathic multicentric Castleman's disease
• interleukin-6
• tocilizumab

Introduction

Castleman's disease (CD) is a rare lymphoproliferative disorder of unknown origin first reported in 1954 by Benjamin Castleman [1,2]. CD presents as two distinct clinical entities: the localized form, unicentric Castleman disease (UCD) and the multicentric form, multicentric Castleman disease (MCD) [3,4]. Individuals with UCD typically have one or more enlarged lymph nodes in a single region and are generally asymptomatic or mildly symptomatic [5–7]. MCD is a systemic disease with multiple regions of lymphadenopathy and systemic symptoms that include fever, night sweats, weight loss, and fatigue [5–7].

Although most of the clinical manifestations observed in MCD patients can be explained by proinflammatory hypercytokinemia through interleukin-6 (IL-6) secretion [8,9], the pathogenesis of MCD remains largely unsolved. Some MCD cases are caused by the human herpesvirus 8 (HHV-8) infection in human immunodeficiency virus (HIV)-positive patients [10], and these cases are referred to as HHV-8-associated MCD. There is also a group of HIV-negative and HHV-8-negative MCD patients with unknown etiology and pathophysiology, which is referred to idiopathic MCD (iMCD) [11,12].

While UCD patients can achieve remission by undergoing surgical excision [13], the treatment of iMCD is sometimes challenging. An IL-6 inhibitor can be used to control symptoms and decrease lymph node size in iMCD [14,15], but refractory cases are encountered despite this treatment. Here we review the present understanding of CD pathogenesis and the efficacy of IL-6 inhibition, and we provide our opinion on therapeutic prospects for iMCD.

Role of IL-6 in the pathogenesis of iMCD

IL-6 is a multifunctional cytokine involved in a number of cellular functions in immune cells, hematopoietic stem cells, osteoclasts, mesangial cells, hepatocytes, and epidermal keratinocytes [16]. Although the etiology and pathogenesis of MCD are poorly understood, a causal association between IL-6 and MCD was demonstrated. An increased amount of IL-6 was observed in the germinal centers of involved lymph nodes from CD patients [8,17], and lymph node excision in UCD patients resulted in the relief of symptoms along with decreased levels of IL-6 and acute-phase reactants such as C-reactive protein [8].

It has been suggested that IL-6 is necessary and sufficient to drive iMCD symptomatology, histopathology, and pathogenesis in some iMCD patients, but the mechanisms underlying the overproduction of IL-6 in iMCD patients have not been fully elucidated. It was proposed that autoimmune mechanisms, autoinflammatory mechanisms, neoplastic mechanisms, and/or infectious mechanisms contribute to an increased level of IL-6 [12]. In addition, immunohistochemical analysis of lymph nodes from iMCD patients indicates that the germinal center of hyperplastic lymph nodes is the production of IL-6 in iMCD [8]. The major sources of IL-6 are suggested as germinal center B cells, follicular dendritic cells [8] but the cells within the lymph node responsible for production of IL-6 have not yet been identified.

Since some iMCD patients during flare have shown low levels of IL-6 in the serum [18], and they did not respond to anti-IL-6 therapy well [19], it appears that other cytokines also play important roles in the pathogenesis of iMCD. IL-1 and tumor necrosis factor-alpha (TNF-α) are proinflammatory cytokines that cause IL-6 production through nuclear factor (NF)-κB signaling. Increased levels of these cytokines have been reported in patients with iMCD [20–22], and the inhibition of IL-1 and TNF-α could be a therapeutic strategy for iMCD.

The efficacy of IL-6 inhibition in iMCD

iMCD patients with mild symptoms may not need treatment, but most iMCD patients require treatment to alleviate symptoms such as fever and fatigue. Glucocorticoids have frequently been used as a systemic therapy in patients with MCD [5,23,24], but approx. 50% of iMCD patients are resistant to the glucocorticoid prednisolone (PSL) [25], and its discontinuation may result in disease recurrence; long-term maintenance therapy with low-dose PSL is usually required. According to research conducted in Japan, treatment with a glucocorticoid was performed in 77% of mild cases, 89% of middle-severity cases, and 95% of severe cases of iMCD [26].

In addition to glucocorticoid, immunosuppressants such as cyclosporine can be an option for treatment of iMCD, but a long-term oral administration of these drugs is concerned about side effects. Considering the pathology of iMCD, anti-IL-6-directed treatment may be more clinically beneficial than these conventional treatments to control the disease activity of iMCD.

IL-6 is produced by the enlarged lymph nodes of MCD patients, and most of the symptoms (fever, general fatigue, weight loss, and lymphadenopathy) and blood test abnormalities (anemia, hypoalbuminemia, hypergammaglobulinemia, elevated CRP) presenting in iMCD can be explained by overproduction of IL-6. Accordingly, the improvement of most symptoms and laboratory findings are normalized by IL-6 inhibition (Figure 1). For glucocorticoid-resistant iMCD patients, monoclonal antibodies targeted at IL-6 (siltuximab) or the IL-6 receptor (tocilizumab; TCZ) have demonstrated clinical efficacy leading to a resolution of systemic symptoms along with an improvement of hypergammaglobulinemia [15,27–30]. TCZ was approved for the treatment of iMCD only in Japan in 2005, and siltuximab was approved in 2014 for the treatment of iMCD in other countries, including the U.S. and all of Europe.

Figure 1 Effect of IL-6 inhibition on clinical symptoms and findings in multicentric Castleman's disease.

The efficacy of siltuximab and TCZ in iMCD was evaluated by two small clinical trials. A randomized, double-blind, phase II trial of siltuximab in 79 patients with symptomatic iMCD demonstrated significant benefits including improvements in anemia, inflammatory markers, and systemic symptoms compared to placebo [31]. The safety and efficacy of TCZ were evaluated in an open-label clinical trial of 28 symptomatic patients with iMCD [32]. After the 16-week treatment with intravenous TCZ at 8 mg/kg every 2 weeks, the patients' nutritional status, fatigue scores, lymphadenopathy, inflammatory markers, and anemia were significantly improved. In addition, the average daily doses of PSL decreased by ∼50% over the course of the TCZ therapy. Collectively, these results established IL-6 inhibition as a standard treatment option for iMCD. However, further follow-up study is needed to determine whether these high response rates contribute to the improvement of the patients' survival rate.

In the Japanese cohort established by a nationwide research group on CD, TCZ was widely used regardless of the level of disease activity: iMCD patients were treated with TCZ in 42% of the mild cases, 40% of the middle-severity cases, and 57% of the severe cases [26]. We need to identify predictive factors of response to IL-6 inhibition and establish the long-term safety of IL-6 inhibition.

We finally describe the future prospective of iMCD treatment. Since the precise molecular mechanisms of its etiology of iMCD are not yet well understood well, the current therapy is a systematic administration of glucocorticoids, immunosuppressive agents and biologics targeting IL-6. However, there are not only differences in the efficacy of these therapies but also severe side effects. Appropriate and effective treatment according to the disease condition is thus desired. Among the currently available drugs, mTOR inhibitors have been suggested to be effective for iMCD [33]. Since mTOR regulates VEGF expression, T cell activation, and cellular proliferation [34,35], it may be candidates for the treatment of severe MCD. Further clinical research with a larger number of cases is needed to determine whether this drug is beneficial for the treatment of iMCD.

Conclusion

We have briefly reviewed the pathogenesis of CD and the efficacy of IL-6 inhibitors. The current therapy for iMCD is a systematic administration of glucocorticoids, immunosuppressive agents, and biologics targeting IL-6. However, there are not only differences in the efficacy of this therapy but also severe adverse effects in some cases. Appropriate and effective treatment according to the disease condition is thus desired.

Conflict of interest

K. Yoshizaki holds a patent on the applied patent for Tocilizumab therapy. The other authors declare that there are no conflicts of interest related to this report.