Successful control of juvenile dermatomyositis-associated macrophage activation syndrome and interstitial pneumonia: distinct kinetics of interleukin-6 and -18 levels

Background Macrophage activation syndrome (MAS) is the secondary hemophagocytic lymphohistiocytosis associated with rheumatic diseases. Recently, the different cytokine profiles between systemic juvenile idiopathic arthritis (sJIA)-associated MAS (sJIA-MAS) and juvenile systemic lupus erythematosus (JSLE)-associated MAS (JSLE-MAS) were reported. However, there is little information about juvenile dermatomyositis (JDM)-associated MAS (JDM-MAS). Case presentation A 4-year-old girl with JDM was hospitalized because of fever, erythema, hepatosplenomegaly, cytopenia, liver dysfunction and coagulopathy. Bone marrow aspiration revealed appreciable numbers of activated and hemophagocytosing macrophages. She was diagnosed as having JDM–MAS complicated with interstitial pneumonia (IP) based on the findings of the elevation of serum Krebs von den Lungen-6 (KL-6) levels and chest computed tomography findings. We analyzed circulating levels of interleukin (IL)-2,4,6,10,18, tumor necrosis factor-α and interferon-γ in the patient. Hypercytokinemia occurred at the diagnosis of MAS and IP, showing with the prominent elevations of IL-6 and IL-18 levels. The cytokine profiles were distinct from those reported in patients with sJIA-MAS or JSLE-MAS. High-dose corticosteroid and cyclosporine therapy led to a drastic improvement of MAS with decreased IL-6 levels. Subsequent cyclophosphamide therapy successfully controlled IP, paralleled with the declining pattern of IL-18 and KL-6 levels. Conclusion This is the first report to describe a successful treatment and the cytokine profile of JDM-MAS and IP. Serum IL-6 and IL-18 levels may be useful for predicting the disease activity of JDM-MAS and IP, respectively.


Background
Macrophage activation syndrome (MAS) is the secondary hemophagocytic lymphohistiocytosis (HLH) associated with rheumatic diseases, which is a life-threatening complication of systemic inflammatory disorders [1]. It is clinically characterized by fever, hepatosplenomegaly, lymphadenopathy, cytopenia, intravascular coagulation and organ failure [1]. Juvenile dermatomyositis (JDM) is a multisystem disease of uncertain origin that results in chronic inflammation of the striated muscle and skin [2]. Although MAS has been reported to develop in various rheumatic diseases, it is most often complicated in the children with systemic juvenile idiopathic arthritis (sJIA) [1]. Juvenile systemic lupus erythematosus (JSLE) is also one of the underlying rheumatic diseases in which MAS occurs more frequently seen than in the others [3]. On the other hand, MAS is a quite rare complication in JDM patients [4].
Recently, the difference in the serum cytokine profiles between sJIA-associated MAS (sJIA-MAS) and JSLEassociated MAS (JSLE-MAS) was reported [5]. However, there have been no reports about the cytokine profiles in JDM-associated MAS (JDM-MAS) with interstitial pneumonia (IP). We present the first report about successful treatment and analysis of cytokine profile in a case with JDM complicated MAS and IP.

A B C D
The clinical courses and the results of cytokine expressions in our patient with JDM-MAS and IP are shown in Fig. 2a, b. There was hypercytokinemia before the treatment and during the acute phase of JDM-MAS with IP. Fig. 2 Sequential changes of the laboratory data and serum cytokine levels during the initial (a), and the overall treatment courses (b). IL-6 (♦), IL-18 (□) and KL-6 (■) were at higher levels at the onset of JDM-MAS and IP. Pearson correlation coefficient test indicated positive correlation of KL-6 with IL-18 (r = 0.997, P <0.01), but not IL-6 or the other cytokine levels. CsA cyclosporine A, DP dexamethasone palmitate, MPT methylprednisolone pulse therapy, PSL prednisolone, IVCY intravenous cyclophosphamide, U-β 2 MG urinary β 2 -microglobulin, IL interleukin, TNF-α tumor necrosis factor-α, IFN-γ interferon-γ IL-6 and IL-18 were at prominent high levels compared with the elevated levels of IL-10, TNF-α and IFN-γ. IL-6 levels promptly decreased after the initial therapy. IL-18 levels sustained to be high after the start of effective treatments during the acute and subacute phases of JDM-MAS. On the other hand, the IL-18 levels decreased after IVCY therapy, in concert with the declining KL-6 levels and the clinical and radiographical improvement of IP (Fig. 2b).

Discussion
There has been no report about the cytokine profile in JDM-MAS with IP. To our knowledge, only 5 patients with JDM-MAS were reported [4,[7][8][9][10]. There were 4 boys and 1 girl, the median age of whom was 12 years ranging from 7 to 14. MAS is a life-threatening condition, and the reported mortality rates reach 20 % [11]. On the other hand, all 6 patients including ours survived JDM-MAS after immunosuppressive therapy. The distinct changes between IL-6 and IL-18 levels during the treatment come of our patient may indicate the unique pathophysiology of JDM-driven complications.
Serum IL-18 concentrations in sJIA-MAS patients were reportedly higher than those seen in EBV-associated HLH (EBV-HLH) [12]. Monitoring the cytokine profile, including IL-18, may be useful for the differential diagnosis of sJIA-MAS from the other MAS/HLH. Although various proinflammatory cytokines are overexpressed in MAS patients, the prodominant elevations of TNF-α levels might be characteristic as shown in a patient with JSLE-MAS, compared to sJIA-MAS and EBV-HLH patients [5]. The cytokine profiles in MAS patients are considered to depend on the underlying rheumatic diseases. In the present case, both levels of IL-6 and IL-18 were prominently increased during the acute phase of JDM-MAS with IP before treatment. The serum levels of IL-18 may be associated with the disease activity of IP, but not JDM-MAS. Because Pearson correlation coefficient test indicated the positive correlation between serum KL-6 and IL-18 levels (r = 0.997, P <0.01) (Fig. 2b), we speculated that the leading cytokine may be IL-18 in sJIA-MAS, TNF-α in JSLE-MAS, and IL-6 in JDM-MAS, respectively. Serum IL-18 and TNF-α levels were dominantly elevated in patients with sJIA-MAS (average of 5 cases) and JSLE-MAS (one case), respectively (sJIA-MAS IL-18: >100,000, TNF-α: 0-10, IL-6: 10-50 pg/mL, JSLE-MAS, IL-18: 1,000-3,000, TNF-α: > 1,000, IL-6: 100-500 pg/mL) [5,12]. Our results suggest that IL-6 and IL-18 may play differential roles in the pathophysiology of JDM-MAS and IP, respectively. It has been reported that activated macrophages and monocytes produce proinflammatory cytokines, such as IL-6, TNF-α in MAS patients. On the other hand, IL-18 is produced not only from tissueresident macrophages and bone marrow macrophages, but also from dendritic cells in the muscle, and lungs in patients with JDM [13]. In the present case, there was a positive correlation between serum IL-18 and KL-6 levels (Fig. 2b). In IP complicated with JDM, IL-18 is mainly produced from activated alveolar macrophages, and KL-6 is produced from type II pneumocytes and bronchial epithelial cells during regeneration of lung tissues [13]. The kinetics of these biomarkers may represent the tissues injury and regeneration occurring in the lungs of IP patients.

Conclusion
This is the first report to describe the successful treatment and the cytokine profile in JDM-MAS with IP patient. Our results suggest that the elevations of serum IL-6 and IL-18 levels are associated with disease activity of JDM-MAS and IP, respectively. These results indicate that IL-6 and IL-18 may be useful for predicting treatment responsiveness in the pathophysiology of JDM-MAS with IP. However, the limitation of the present study is a single case analyzed. Therefore, the accumulation of further case reports is necessary for identifying the pathophysiology of JDM-MAS.

Consent
Provided informed consent was obtained from the patient's guardian for publication of this case report.