Tocilizumab masks the clinical symptoms of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome: The diagnostic significance of interleukin-18 and interleukin-6

Abstract

Macrophage-activation syndrome (MAS) is a potentially life-threatening complication of systemic juvenile idiopathic arthritis (s-JIA). Tocilizumab (TCZ), a humanized anti-IL-6 receptor monoclonal antibody, is an effective cytokine inhibitor for the treatment of s-JIA. We described the clinical courses of five cases of MAS during TCZ therapy and demonstrated the need for monitoring serum interleukin (IL)-18 and IL-6 concentrations. Clinical symptoms of patients with s-JIA receiving TCZ were apparently mild compared to those not receiving TCZ. Furthermore, serum CRP concentrations never increased during TCZ therapy, even in MAS. Serum IL-6 concentrations increased during s-JIA flare-up and with the complication of infection. Serum IL-18 concentrations increased persistently before the other measures of disease activity. The clinical symptoms of MAS and s-JIA could be masked during TCZ therapy; hence, monitoring serum concentrations of IL-18 and IL-6 is recommended for the evaluation of disease activity in s-JIA and to detect the complication of infection.

Introduction

Systemic juvenile idiopathic arthritis (s-JIA), a systemic inflammatory disorder of unknown etiology characterized by arthritis and systemic features such as spiking fever, skin rash, generalized lymphadenopathy, hepatosplenomegaly, and serositis was first described by a British pediatrician George F. Still in 1897 [1], [2]. Recent studies have shown that inflammatory cytokines, including interleukin (IL)-1, IL-6, and IL-18, play pathogenic roles in the disease processes of s-JIA [3]. Thus, inhibition of these cytokines can be considered as an appropriate therapeutic strategy for s-JIA. On the other hand, it is unknown whether the blockade of a single cytokine pathway in the setting of a cytokine storm, if any, causes an unfavorable imbalance in the cytokine system or whether the blockade is sufficient to suppress the inflammatory condition.

Tocilizumab (TCZ), a humanized anti-IL-6 receptor monoclonal antibody, is an effective cytokine inhibitor for the treatment of JIA [4], [5]. A recent clinical trial demonstrated the therapeutic efficacy of TCZ for treating s-JIA [6]. Furthermore, several reports on adult-onset Still’s disease (AOSD), an adult form of s-JIA, have suggested that TCZ therapy is also effective for AOSD [7], [8], [9]. However, macrophage-activation syndrome (MAS) has been observed as a complication in a case of AOSD during TCZ therapy [10].

MAS is a severe, potentially life-threatening complication of s-JIA. It is clinically characterized by fever, hepatosplenomegaly, lymphadenopathy, profound depression of all three blood cell lines, deranged liver function, intravascular coagulation, and central nervous system dysfunction [11], [12]. The excessive activation and proliferation of T lymphocytes and macrophages are observed in MAS [13]. Massive hypercytokinemia is strongly associated with the pathogenesis of MAS [14]. MAS bears a close resemblance to a group of hemophagocytic lymphohistiocytosis (HLH) syndromes and could be considered among the secondary causes of HLH [15], [16].

Interleukin (IL)-18 was originally described as an interferon-γ-inducing factor mainly produced by activated macrophage lineage cells [17], [18]. IL-18 stimulates a variety of inflammatory responses, enhances proliferation and activity of T cells and natural killer cells, and shifts helper T cell balance towards Th1 response [19], [20]. IL-18 has been reported to enhance production of Th2 cytokines and IgE and recruitment of eosinophils, suggesting that IL-18 can also regulate allergic inflammation [21]. Some reports have recently shown that serum levels of IL-18 are highly elevated in patients with s-JIA [22], [23], [24]. We previously reported that the cytokine release pattern in MAS/HLH differs among patients with different etiologies and that IL-18 is a promising indicator of disease activity in s-JIA [25].

Here, we describe five cases of MAS associated with s-JIA (MAS/s-JIA) with TCZ and show that clinical symptoms of patients with MAS/s-JIA receiving TCZ were apparently mild compared to those not receiving TCZ. We also demonstrate that cytokine profile monitoring, including that of IL-18 and IL-6, is useful for evaluating s-JIA disease activity during TCZ therapy.