Adult Still's disease: New horizons

Still's disease in children (systemic juvenile idiopathic arthritis - JIA) and adult Still's disease (ASD) are considered as systemic autoinflammatory diseases of unknown etiology, which are based on similar immunopathogenetic mechanisms associated with genetically determined disorders of the mechanisms of innate immunity. ASD was first described 50 years ago by the English rheumatologist Eric George Lapthorne Bywaters. The molecular basis of ASD immunopathogenesis is the activation of innate immunity associated with NLRP3 inflammasome-dependent mechanisms of inflammation, characterized by the overproduction of “pro-inflammatory” cytokines - interleukin (IL) 1 and IL-18, inducing the synthesis of other proinflammatory inflammatory mediators. A review of new data concerning the mechanisms of immunopathology, clinical polymorphism, laboratory biomarkers and the possibilities of ASD pharmacotherapy is presented.Particular attention is paid to the prospects for the use of monoclonal antibodies to IL-1β - canakinumab. The problems associated with the generality of clinical and laboratory disorders, pathogenetic mechanisms and pharmacotherapy of ASD and coronavirus disease 2019 (COVID-19) are considered.

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Therapy with canakinumab for adult-onset still's disease

Rheumatology Science and Practice ◽

10.14412/1995-4484-2018-35-40 ◽

2019 ◽

Vol 56 ◽

pp. 35-40

Author(s):

E. L. Nasonov

Keyword(s):

Adult Onset Still’S Disease ◽

Unknown Etiology ◽

Adult Onset ◽

Still’S Disease ◽

First Line ◽

Disease Modifying Drugs ◽

Still's Disease ◽

First Line Therapy ◽

Genetically Determined ◽

Adult Onset Still's Disease

Still's disease in children (systemic-onset juvenile idiopathic arthritis, SoJIA) and in adults (adult-onset Still's disease) are considered as non-familial systemic autoinflammatory diseases of unknown etiology driven by similar immunopathogenetic mechanisms. The adult-onset Still's disease pathogenesis is based on genetically determined innate immunity disturbances and molecular basis of immunopathogenesis consists of NLRP3 inflammasomedependent mechanisms of inflammation characterized by hyperproduction of proinflammatory cytokines interleukin (IL) 1 and IL18. Nonsteroidal anti-inflammatory drugs, glucocorticoids, methotrexate and other disease modifying drugs are considered as «first line» medications for the treatment of adult-onset Still's disease and if they fail biologicals are recommended. A review of the literature data concerning anti-IL1 monoclonal antibodies administration in adult-onset Still's disease is presented, indicating good prospects for the use of canakinumab not only in case of resistance to standard therapy, but also as a «first-line» therapy in the onset of the disease.

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Application of systems biology-based in silico tools to optimize treatment strategy identification in Still’s disease

Arthritis Research & Therapy ◽

10.1186/s13075-021-02507-w ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Cristina Segú-Vergés ◽

Mireia Coma ◽

Christoph Kessel ◽

Serge Smeets ◽

Dirk Foell ◽

...

Keyword(s):

Innate Immunity ◽

Systems Biology ◽

Treatment Strategy ◽

In Silico ◽

Systemic Juvenile Idiopathic Arthritis ◽

Treat To Target ◽

Molecular Characteristics ◽

Expression Data ◽

Still’S Disease ◽

Still's Disease

Abstract Background Systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD) are manifestations of an autoinflammatory disorder with complex pathophysiology and significant morbidity, together also termed Still’s disease. The objective of the current study is to set in silico models based on systems biology and investigate the optimal treat-to-target strategy for Still’s disease as a proof-of-concept of the modeling approach. Methods Molecular characteristics of Still’s disease and data on biological inhibitors of interleukin (IL)-1 (anakinra, canakinumab), IL-6 (tocilizumab, sarilumab), and glucocorticoids as well as conventional disease-modifying anti-rheumatic drugs (DMARDs, methotrexate) were used to construct in silico mechanisms of action (MoA) models by means of Therapeutic Performance Mapping System (TPMS) technology. TPMS combines artificial neuronal networks, sampling-based methods, and artificial intelligence. Model outcomes were validated with published expression data from sJIA patients. Results Biologicals demonstrated more pathophysiology-directed efficiency than non-biological drugs. IL-1 blockade mainly acts on proteins implicated in the innate immune system, while IL-6 signaling blockade has a weaker effect on innate immunity and rather affects adaptive immune mechanisms. The MoA models showed that in the autoinflammatory/systemic phases of Still’s disease, in which the innate immunity plays a pivotal role, the IL-1β-neutralizing antibody canakinumab is more efficient than the IL-6 receptor-inhibiting antibody tocilizumab. MoA models reproduced 67% of the information obtained from expression data. Conclusions Systems biology-based modeling supported the preferred use of biologics as an immunomodulatory treatment strategy for Still’s disease. Our results reinforce the role for IL-1 blockade on innate immunity regulation, which is critical in systemic autoinflammatory diseases. This further encourages early use on Still’s disease IL-1 blockade to prevent the development of disease or drug-related complications. Further analysis at the clinical level will validate the findings and help determining the timeframe of the window of opportunity for canakinumab treatment.

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Adult onset Still’s disease: a diagnostic challenge

International Journal of Research in Dermatology ◽

10.18203/issn.2455-4529.intjresdermatol20180119 ◽

2018 ◽

Vol 4 (1) ◽

pp. 87

Author(s):

Rahul Jain ◽

V. K. Joglekar ◽

Kriti Jain

Keyword(s):

Disease Diagnosis ◽

Adult Onset Still’S Disease ◽

Unknown Etiology ◽

Inflammatory Disorder ◽

Adult Onset ◽

Still’S Disease ◽

Diagnostic Challenge ◽

Still's Disease ◽

Adult Still's Disease ◽

Adult Onset Still's Disease

<p class="abstract"><span lang="EN-IN">Adult Still’s disease (ASD) is a systemic inflammatory disorder of unknown etiology, typically characterized by a clinical triad of daily spiking high fevers, evanescent rash, and arthritis. This report described a 26-year-old male who presented with these symptoms along with raised liver enzymes and hyperferritinemia. After ruling out systemic infections, localized infections, malignancies and other rheumatological diseases, Adult onset Still’s disease diagnosis was made according to Yamaguchi criteria (having 4 major features and 3 minor features). AOSD is a heterogeneous and rare disease and the lack of serologic markers as a true gold standard makes diagnosis difficult.</span></p>

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AB0660 COVID-19 SHARES CLINICAL FEATURES WITH ANTI-MELANOMA DIFFERENTIATION ASSOCIATED PROTEIN 5 POSITIVE DERMATOMYOSITIS AND ADULT STILL’S DISEASE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.1031 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1362.1-1362

Author(s):

Y. Kondo ◽

Y. Kaneko ◽

H. Takei ◽

H. Tamai ◽

T. Takeuchi

Keyword(s):

Interstitial Lung Disease ◽

Lung Disease ◽

Clinical Features ◽

Serum Ferritin ◽

Rheumatic Diseases ◽

Macrophage Activation ◽

Cytokine Storm ◽

Still’S Disease ◽

Still's Disease ◽

Adult Still's Disease

Background:The coronavirus disease 2019 (COVID-19), caused by a novel corona virus named SARS-CoV-2, has emerged as a global pandemic. Severe inflammatory process is one of main pathogenesis of COVID-19 and this involves cytokine storm along with overactivation of macrophage. On another front, cytokine storm with macrophage activation is frequently observed in various connective tissue diseases including dermatomyositis with positive antimelanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies and adult Still’s disease. Macrophage activation during inflammatory states is partially characterized by an increased serum ferritin levels and hyperferritinaemia and characteristics shared by the three diseases are a topic of interest to rheumatologists, however, no study has evaluated anti-MDA5-positive dermatomyositis and adult Still’s disease in comparison to COVID-19.Objectives:The aim of this study was to highlight the homology and heterogeneity of COVID-19, anti-MDA5 dermatomyositis, and adult Still’s disease by comparing clinical pictures of each disease in order to discuss their respective pathogeneses.Methods:We reviewed consecutive, newly diagnosed, untreated patients with COVID-19, anti-MDA5 dermatomyositis, or adult Still’s disease. We compared their clinical, laboratory, and radiological characteristics, including the prevalence of macrophage activation syndrome and lung involvement in each disease.Results:The numbers of patients with COVID-19, anti-MDA5 dermatomyositis, and adult-onset Still’s disease with hyperferritinaemia (serum ferritin ≥ 500ng/dL) who were included for main analysis were 22, 14, and 59, respectively. COVID-19 and adult Still’s disease both featured hyperinflammatory status, such as high fever and elevated serum C-reactive protein, whereas COVID-19 and anti-MDA5 dermatomyositis both presented with severe interstitial lung disease and hypoxaemia. While two-thirds of the patients in each group met the criteria for macrophage-activated syndrome that is used in systemic juvenile idiopathic arthritis, the HScore, an indicator of haemophagocytic lymphohistiocytosis, was low in anti-MDA5 dermatomyositis and COVID-19 even in severe or critical cases. The findings of chest computed tomography were similar between COVID-19 and anti-MDA5 dermatomyositis (Figure 1).Conclusion:COVID-19 shared clinical features with rheumatic diseases characterised by hyperferritinaemia, including anti-MDA5 dermatomyositis and adult Still’s disease. These findings should be investigated further in order to shed light on the pathogenesis of not only COVID-19 but also the aforementioned rheumatic diseases.References:[1]Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. (2020) 395: 1033-4.[2]Gono T, Sato S, Kawaguchi Y, et al. Anti-MDA5 antibody, ferritin and IL-18 are useful for the evaluation of response to treatment in interstitial lung disease with anti-MDA5 antibody-positive dermatomyositis. Rheumatology (Oxford). 2012; 51(9):1563-70.Figure 1.Imaging characteristics of chest CT scans in patients with COVID-19, anti-MDA5 dermatomyositis, and adult Still’s disease A)Bilateral ground-glass and consolidative opacities with peripheral distribution in COVID-19. B)Bilateral ground-glass opacities with peripheral consolidations in anti-MDA5 dermatomyositis. C)Pleural effusion with pleural thickening on the left side in adult Still’s disease.Disclosure of Interests:Yasushi Kondo: None declared., Yuko Kaneko: None declared., Hisoshi Takei: None declared., Hiroya Tamai: None declared., Tsutomu Takeuchi Grant/research support from: received research grants outside the submitted work from Abbvie, Astra Zeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eisai Pharmaceutical, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Novartis, Takeda Pharmaceutical, Abbott Japan Co., Ltd., Astellas Pharma, Ltd., Daiichi Sankyo, Pfizer, Sanofi–Aventis, Santen Pharmaceutical, Teijin Pharma Ltd., Asahikasei Pharma Corp., SymBio Pharmaceuticals Ltd., Celtrion, Nipponkayaku Co. Ltd., Eli Lilly Japan, and Taisho Toyama Pharmaceutical.

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FRI0505 TOCILIZUMAB DISCONTINUATION AFTER REMISSION ACHIEVEMENT IN PATIENTS WITH ADULT STILL’S DISEASE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3491 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 851.2-851

Author(s):

H. Tamai ◽

Y. Kaneko ◽

T. Takeuchi

Keyword(s):

Laboratory Data ◽

Good Control ◽

Still’S Disease ◽

Median Dose ◽

Chugai Pharmaceutical ◽

Still's Disease ◽

Adult Still's Disease ◽

The Mean ◽

Recurrence Group ◽

Observation Period

Background:The efficacy of tocilizumab, an interleukin (IL)-6 receptor inhibitor, has been proved in patients with adult Still’s disease on suppressing systemic inflammation and decreasing glucocorticoid dose. However, whether tocilizumab can be discontinued after remission achievement is unclear.Objectives:To clarify the possibility of tocilizumab discontinuation in patients with adult Still’s disease who achieved remission with tocilizumab.Methods:Consecutive patients with adult Still’s disease diagnosed according to the Yamaguchi’s criteria in our hospital from April 2012 until September 2019 were retrospectively reviewed. Patients who were in good control with tocilizumab were included in the analysis, and their clinical courses were collected from their medical charts. Patients were divided according to the presence of recurrence after tocilizumab discontinuation and compared.Results:Among 42 patients with adult Still’s disease who had a history of intravenous tocilizumab of 8mg/kg use, 13 patients discontinued tocilizumab following a good disease control. During the mean observation period of 26.4 months, six patients (46%) remained in remission while seven patients (54%) developed recurrence after tocilizumab discontinuation. The sex and the mean observation period were not different between the patients with recurrence and those without (71% vs 50%, p=0.43; 27.3 months vs 25.4 months, p=0.93, respectively), but the age at tocilizumab discontinuation tended to be higher in the recurrence group than the non-recurrence group (64.0 years vs 46.5 years, p=0.08). The disease activity including swollen joint counts and laboratory data at tocilizumab discontinuation were comparable between the two groups (serum ferritin levels, 88 ng/mL vs 122 ng/mL, p=0.67). While the duration of tocilizumab use was not different between the two groups (29.4 months vs 39.5 months, p=0.40), the mean interval of tocilizumab infusion at tocilizumab discontinuation in the recurrence group was 3.6 weeks, shorter than the 6.7 weeks in the non-recurrence group (p=0.03). The median dose of prednisolone at tocilizumab discontinuation was 5.0 mg/day in the recurrence group and 0.0 mg/day in the non-recurrence group (p=0.06). In the recurrence group, the duration from the last tocilizumab administration to recurrence was 7.8 months, and the median dose of prednisolone at recurrence was 5.0 mg/day.Conclusion:Patients with adult Still’s disease remaining in remission with a longer interval of tocilizumab administration and a lower dose of prednisolone was likely to succeed in withdrawal of tocilizumab.Disclosure of Interests:Hiroya Tamai: None declared, Yuko Kaneko Speakers bureau: Dr. Kaneko reports personal fees from AbbVie, personal fees from Astellas, personal fees from Ayumi, personal fees from Bristol-Myers Squibb, personal fees from Chugai, personal fees from Eisai, personal fees from Eli Lilly, personal fees from Hisamitsu, personal fees from Jansen, personal fees from Kissei, personal fees from Pfizer, personal fees from Sanofi, personal fees from Takeda, personal fees from Tanabe-Mitsubishi, personal fees from UCB, Tsutomu Takeuchi Grant/research support from: Eisai Co., Ltd, Astellas Pharma Inc., AbbVie GK, Asahi Kasei Pharma Corporation, Nippon Kayaku Co., Ltd, Takeda Pharmaceutical Company Ltd, UCB Pharma, Shionogi & Co., Ltd., Mitsubishi-Tanabe Pharma Corp., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co. Ltd., Consultant of: Chugai Pharmaceutical Co Ltd, Astellas Pharma Inc., Eli Lilly Japan KK, Speakers bureau: AbbVie GK, Eisai Co., Ltd, Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co Ltd, Bristol-Myers Squibb Company, AYUMI Pharmaceutical Corp., Eisai Co., Ltd, Daiichi Sankyo Co., Ltd., Gilead Sciences, Inc., Novartis Pharma K.K., Pfizer Japan Inc., Sanofi K.K., Dainippon Sumitomo Co., Ltd.

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