Adult-onset Still’s disease with macrophage activation syndrome diagnosed and treated based on cytokine profiling: a case-based review

Goda, Ken; Kenzaka, Tsuneaki; Hoshijima, Masahiko; Yachie, Akihiro; Akita, Hozuka

doi:10.1007/s00296-019-04446-x

Cited by 8 publications

(4 citation statements)

References 17 publications

(22 reference statements)

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“…IL-18 stimulates proinflammatory responses, including the activation of T cells, and shifts the Th-cell balance toward the Th1 response [6]. High levels of IL-18 have been demonstrated in patients with macrophage activation syndrome (MAS), in addition to those with ASD, and it is also believed that IL-18 is implicated in dysregulated innate immunity [7].…”

Section: Introductionmentioning

confidence: 99%

Elevated serum levels of checkpoint molecules in patients with adult Still’s disease

et al. 2020

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Background: The interaction between galectin-9 (Gal-9) and its ligand, T cell immunoglobulin, and mucincontaining-molecule-3 (TIM-3), one of the coinhibitory receptors, transduce the inhibitory signaling to regulate immune responses. The dysregulated expression of checkpoint molecules has been reported under various inflammatory or autoimmune conditions. The aim of this study is to investigate the levels of these checkpoint molecules and their associations between proinflammatory markers in patients with adult Still's disease (ASD). Methods: Serum samples were collected from 47 patients with active ASD, 116 patients with rheumatoid arthritis (RA), and 37 healthy controls (HCs). Serum levels of Gal-9, soluble TIM-3 (sTIM-3), and IL-18 were determined using enzyme-linked immunosorbent assay (ELISA). Results were compared with the clinical features of ASD. Results: Serum Gal-9 levels in patients with ASD (median: 21.57 ng/ml, interquartile range IQR [11.41-39.72]) were significantly higher compared to those in patients with RA (7.58 ng/ml, IQR [5.57-10.20] p < 0.001) as well as those in HCs (4.51 ng/ml, [IQR; 3.58-5.45], p < 0.001). Similarly, serum sTIM-3 levels in patients with ASD were significantly higher than those in patients with RA and HCs. Serum levels of Gal-9 or sTIM-3 showed positive correlations with IL-18 levels (Gal-9; r = 0.90, p < 0.001, sTIM-3; r = 0.78, p < 0.001) in patients with ASD. Serum levels of Gal-9 or sTIM-3 correlated with serum ferritin (Gal-9; r = 0.77, p < 0.001, sTIM-3; r = 0.71, p < 0.001) and ASD disease activity score (Pouchot's score, Gal-9; r = 0.66, p < 0.001, sTIM-3; r = 0.59, p < 0.001), whereas there was no significant correlation between serum Gal-9 or sTIM-3 and CRP. ASD patients with chronic arthritis phenotype had a significantly higher Gal-9/ferritin and sTIM-3/ferritin ratio than those without this phenotype. After immunosuppressive treatment, Gal-9 and sTIM-3 levels showed a significant decline in parallel to the disease activity scores. Conclusions: Serum levels of the coinhibitory checkpoint molecules were elevated and correlated with disease activity in patients with ASD. These coinhibitory checkpoint molecules may be implicated in the autoinflammatory process seen in ASD.

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Section: Introductionmentioning

confidence: 99%

Elevated serum levels of checkpoint molecules in patients with adult Still’s disease

et al. 2020

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“…Furthermore, the sTNF-RⅡ/sTNF-RI ratio was found to be < 5, indicating that the increased neopterin levels were not due to macrophage activation syndrome (Shimizu et al 2018). Only neopterin levels, which were previously reported to decrease along with IL-18 after the initiation of AOSD therapy (Goda et al 2020), were persistently high. This situation suggested the presence of another inflammatory disease, which led to reassessments for potential comorbidities.…”

Section: Discussionmentioning

confidence: 73%

“…Therefore, the measurement of these cytokines may aid in the diagnosis. Cytokine profiling of serum levels of IL-6, IL-18, neopterin, sTNF-RI, and sTNF-RⅡshows specific radar chart patterns which are useful in differentiating between s-JIA/AOSD, Epstein-Barr virus-induced hemophagocytic lymphoistiocytosis, Kawasaki disease and s-JIA with macrophage activation syndrome (Shimizu et al 2010;Goda et al 2020). sTNF-RI and sTNF-RII play an important role as modulators of the biological function of TNF-α (Shimizu et al 2018).…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of Profiling Serum IL-18 and Neopterin in Diagnosis of Adult-Onset Still’s Disease Complicated by Pulmonary Tuberculosis: A Case Report

Kamada

Kenzaka

2020

Tohoku J. Exp. Med.

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Adult-onset Still's Disease (AOSD) is a systemic inflammatory disorder characterized by high fever, skin rashes, and joint pains, and is extremely rare in patients over 80 years of age. An 88-year-old woman was admitted with high fever lasting for > 2 weeks and arthritis of the right knee and bilateral wrists. Further examination revealed that the patient fulfilled the Yamaguchi criteria, the most sensitive and extensively used classification criteria for AOSD. After ruling out other causes and considering a greatly raised serum interleukin-18 (IL-18) level, the patient was diagnosed with AOSD. Before prednisolone therapy, active tuberculosis was excluded using chest computed tomography (CT) and an interferon-gamma release assay (IGRA). After starting the treatment, serum levels of IL-18 and acute-phase reactants were decreased gradually. However, during prednisolone tapering, fever relapsed along with increasing serum acute phase reactant levels. Her serum IL-18 level was decreased but remained at a high level, and the neopterin level was further increased. These findings suggested the onset of another disease, but not AOSD recurrence. A chest CT scan revealed new lung infiltrates. Despite the initial negative IGRA result, cultures and polymerase chain reaction tests of bronchoalveolar lavage and sputum were positive for Mycobacterium tuberculosis. She was placed on a 9-month course of anti-tuberculosis therapy and continued prednisolone tapering. She showed steady improvement and her cytokine profile showed a decrease in the IL-18 and neopterin levels. In conclusion, cytokine profiling is useful in making the diagnosis of AOSD and subsequent pulmonary tuberculosis developed during steroid therapy.

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“…IL-18 stimulates proin ammatory responses, including the activation of T cells, and shifts the Th-cell balance toward the Th1 response [6]. High levels of IL-18 have been demonstrated in patients with macrophage activation syndrome (MAS), in addition to those with ASD, and it is also believed that IL-18 is implicated in dysregulated innate immunity [7].…”

Section: Introductionmentioning

confidence: 99%

Elevated serum levels of checkpoint molecules in patients with adult Still’s disease

Fujita¹,

Asano²,

Matsumoto³

et al. 2020

Preprint

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Background: The interaction between galectin-9 (Gal-9) and its ligand, T cell immunoglobulin and mucin-containing-molecule-3 (TIM-3), one of the coinhibitory receptors, transduce the inhibitory signaling to regulate immune responses. The dysregulated expression of checkpoint molecules has been reported under various inflammatory or autoimmune conditions. The aim of this study is to investigate the levels of these checkpoint molecules and their associations between proinflammatory markers in patients with adult Still’s disease (ASD). Methods: Serum samples were collected from 47 patients with active ASD, 116 patients with rheumatoid arthritis (RA), and 37 healthy controls (HCs). Serum levels of Gal-9, soluble TIM-3 (sTIM-3), and IL-18 were determined using enzyme-linked immunosorbent assay (ELISA). Results were compared with clinical features of ASD. Results: Serum Gal-9 levels in patients with ASD (median: 21.57 ng/ml, interquartile range IQR [11.41–39.72]) were significantly higher compared to those in patients with RA (7.58 ng/ml, IQR [5.57–10.20] p < 0.001) as well as those in HCs (4.51 ng/ml, [IQR; 3.58–5.45], p < 0.001). Similarly, serum sTIM-3 levels in patients with ASD were significantly higher than those in patients with RA and HCs. Serum levels of Gal-9 or sTIM-3 showed positive correlations with IL-18 levels (Gal-9; r = 0.90, p< 0.001, sTIM-3; r = 0.78, p< 0.001) in patients with ASD. Serum levels of Gal-9 or sTIM-3 correlated with serum ferritin (Gal-9; r = 0.77, p< 0.001, sTIM-3; r = 0.71, p< 0.001) and ASD disease activity score (Pouchot’s score, Gal-9; r = 0.66, p< 0.001, sTIM-3; r = 0.59, p< 0.001). Whereas there was no significant correlation between serum Gal-9 or sTIM-3 and CRP. ASD patients with chronic arthritis phenotype had a significantly higher Gal-9/ferritin and sTIM-3/ferritin ratio than those without this phenotype. After immunosuppressive treatment, Gal-9 and sTIM-3 levels showed a significant decline in parallel to the disease activity scores. Conclusions: Serum levels of the coinhibitory checkpoint molecules were elevated and correlated with disease activity in patients with ASD. These coinhibitory checkpoint molecule may be implicated in the autoinflammatory process seen in ASD.

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Adult-onset Still’s disease with macrophage activation syndrome diagnosed and treated based on cytokine profiling: a case-based review

Cited by 8 publications

References 17 publications

Elevated serum levels of checkpoint molecules in patients with adult Still’s disease

Elevated serum levels of checkpoint molecules in patients with adult Still’s disease

Effectiveness of Profiling Serum IL-18 and Neopterin in Diagnosis of Adult-Onset Still’s Disease Complicated by Pulmonary Tuberculosis: A Case Report

Elevated serum levels of checkpoint molecules in patients with adult Still’s disease

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