scholarly journals THU0052 RELATIONSHIP BETWEEN INTERFERON-Γ-PRODUCING IMMUNOCOMPETENT CELLS AND DISEASE ACTIVITY IN ADULT-ONSET STILL’S DISEASE

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 238.1-238
Author(s):  
Y. Shimojima ◽  
D. Kishida ◽  
T. Ichikawa ◽  
Y. Sekijima
Keyword(s):  
T Cells ◽  
Disease Activity ◽  
Nk Cells ◽  
Acute Phase ◽  
Serum Ferritin ◽  
Interferon Γ ◽  
Adult Onset Still’S Disease ◽  
Still’S Disease ◽  
Ifn Γ ◽  
Adult Onset Still's Disease

Background:In the acute phase of adult-onset Still’s disease (AOSD), elevated levels of proinflammatory cytokines including interferon-γ (IFN-γ) are shown. Moreover, IFN-γ impacts on activating macrophages which play a crucial role in the pathogenesis of AOSD. Natural killer (NK) cells and T helper cells are in charge of secreting IFN-γ in the innate and adaptive immune systems of disease, respectively. However, the features of their IFN-γ-producing variation depending on disease activity are still uncertain in AOSD.Objectives:We investigated characteristics of IFN-γ-producing CD4+T cells and NK cells in patients with AOSD.Methods:Twenty-four patients in the acute phase of AOSD (active AOSD), 8 of them after treatment (remission), and 12 healthy controls (HC) were recruited in this study. Peripheral blood mononuclear cells and serum samples were provided from them for the experimental analysis. Flow cytometry was used for analyzing CD4+T cells, CD4+regulatory T cells (Tregs), NK cells, and their intracellular IFN-γ expression levels as well as suppression assay of Tregs. The serum concentration of interleukin-18 (IL-18) was measured using commercially available ELISA kit. Relationship between the analyzed data and clinical findings related to disease activity were statistically evaluated.Results:IFN-γ expression in CD4+T cells was significantly higher in active AOSD than in HC (p < 0.05). Tregs also significantly indicated higher expression of IFN-γ in active AOSD than in HC (p < 0.0001); and moreover, Tregs were significantly impaired in their suppression ability (p < 0.05). In both CD4+T cells and Tregs, expression of IFN-γ was significantly correlated with serum ferritin levels in active AOSD (p < 0.05). IFN-γ expression in CD4+T cells was significantly higher in patients with splenomegaly than those without that (p < 0.05). The proportion of NK cells was significantly lower in active AOSD than in HC (p < 0.005), whereas IFN-γ expression in NK cells was significantly higher in active AOSD than in HC (p < 0.0005). The number of NK cells and IFN-γ-expressing NK cells had inverse relationship with serum ferritin levels in active AOSD (p < 0.05 and p < 0.005, respectively). Increased number of NK cells and their decreased expression of IFN-γ were significantly demonstrated in remission (p < 0.05). In the analyses of NK cell subsets, lower expression of IFN-γ in CD56brightNK cells and higher that in CD56dimNK cells were significantly indicated in active AOSD than HC (p < 0.05). In remission, IFN-γ expression was significantly decreased in CD56dimNK cells (p < 0.05) despite no significant recovery of that in CD56brightNK cells (p = 0.311). Meanwhile, increased expression of IFN-γ in CD56brightNK cells was demonstrated in only patients who were treated with biologics. Although serum levels of IL-18 were significantly higher in active AOSD than in remission and HC; however, they had no significant correlations with any analyzed data.Conclusion:CD4+T cells and NK cells promote IFN-γ expression in the acute phase of AOSD. Meanwhile, increased expression of IFN-γ in CD4+T cells and decreased number of NK cells were correlated with serum ferritin levels, suggesting that they are indicators of disease activity. Furthermore, high disease activity may impact on the alteration of IFN-γ-producing balance in two distinct population of NK cells, and the plasticity of Tregs leading to defect in suppression ability.Disclosure of Interests:None declared

scholarly journals The Role of RIPK1/3 in Adult Onset Still’s Disease Patients With Liver Damage: A Preliminary Study

2020 ◽  
Vol 11 ◽  
Author(s):  
Xuesong Liu ◽  
Ruru Guo ◽  
Xinyu Meng ◽  
Jianchen Fang ◽  
Liangjing Lu
Keyword(s):  
T Cells ◽  
Prospective Study ◽  
Disease Activity ◽  
Liver Damage ◽  
Peripheral Blood ◽  
Adult Onset Still’S Disease ◽  
Adult Onset ◽  
Still’S Disease ◽  
Still's Disease ◽  
Adult Onset Still's Disease

ObjectiveThis study aimed to investigate the distributions of lymphocytes in adult onset Still’s disease (AOSD) with liver dysfunction, and further prospectively explore whether receptor interacting serine/threonine kinases (RIPKs) in lymphocytes play a role in the pathogenesis of AOSD especially liver involvement.MethodsSeventy-two AOSD patients and 19 cases of healthy controls (HCs) were retrospectively reviewed, the AOSD group was then divided into liver damage (LD) group and non-liver damage (NLD) group, and the distributions of lymphocytes in peripheral blood were analyzed. Another independent 24 AOSD patients and 20 HCs were recruited for prospective study of RIPKs; the RIPKs in peripheral blood lymphocytes were detected by flow cytometry. Liver biopsy specimens were obtained from two AOSD patients and underwent immunochemistry analysis with RIPK1 and RIPK3 antibody.ResultsIn the retrospective study, AOSD showed significantly abnormal lymphocytes distributions, and disease activity was positively correlated with percentage of CD3+ T cells. LD patients were younger in age and showed higher disease activity score than NLD patients; they had higher frequencies of CD3+ T cells, especially higher CD8+ T cells (all p&lt;0.05). In the prospective study, RIPKs in lymphocytes were significantly higher in AOSD patients than that of HCs, and LD patients also showed higher RIPKs expression than NLD patients. In addition, RIPKs were positively correlated with erythrocyte sedimentation rate (ESR) and disease activity in AOSD patients and LD and NLD subgroups (all p&lt;0.05). Further, RIPKs expression was confirmed in two AOSD patients’ liver. ROC curve analysis indicated that RIPKs in lymphocytes (%) could be potential biomarkers in the diagnosis of AOSD and liver damage.ConclusionsAbnormal lymphocytes distributions and RIPKs expression were detected in AOSD. Aberrant expression of RIPKs in lymphocytes might be involved in the pathogenesis of AOSD. RIPKs could be candidate markers for AOSD and liver damage.

Natural Killer Cell Cytolytic Function in Korean Patients with Adult-onset Still’s Disease

2012 ◽  
Vol 39 (10) ◽  
pp. 2000-2007 ◽  
Author(s):  
JEONG HA PARK ◽  
HEE-SUN KIM ◽  
JIN SOOK LEE ◽  
JIN JU KIM ◽  
KYONG-HEE JUNG ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Adult Onset Still’S Disease ◽  
Adult Onset ◽  
Still’S Disease ◽  
Cytolytic Function ◽  
Cell Proportion ◽  
Cytotoxic Function ◽  
Adult Onset Still's Disease

Objective.To investigate natural killer (NK) cell proportions, NK cell cytotoxicity, and interleukin 18 (IL-18) expression, in patients with adult-onset Still’s disease (AOSD).Methods.Forty-five patients with AOSD (active = 22, inactive = 23) and 32 healthy controls were included. The proportions of NK cells among peripheral blood mononuclear cells were assessed by flow cytometry. IL-18 and IL-18-binding protein (IL-18BP) concentrations were measured by ELISA. Twenty-four patients with AOSD and 18 controls were examined for cytotoxic activity of NK cells by co-incubating NK cells with NK-sensitive K562 cells. The association of NK cell function with clinical and laboratory measures was investigated.Results.The proportions of NK cells were significantly lower in patients with active AOSD than in patients with inactive disease and controls. NK cell cytotoxic function was significantly lower in patients with AOSD than in controls. NK cell proportions and cytotoxic functions were reexamined in 11 and 6 patients, respectively, after treatment. Low NK cell proportion and cytotoxic dysfunction were improved with clinical improvements of the patients. IL-18 and IL-18BP levels were much higher in patients with active AOSD than in controls. NK cell cytotoxic functions were consistently low and IL-18 and IL-18BP levels were constantly high in patients with AOSD, regardless of disease activity.Conclusion.Low NK cell proportion, defective cytotoxic function, and elevated IL-18 levels may be significant features of AOSD. After resolution of the acute phase, low NK cell proportion was recovered and NK cell cytolytic function was restored along with clinical improvement. These findings possibly contribute to immunologic abnormalities in AOSD.

scholarly journals High Serum Ferritin in Adult-Onset Still's Disease

2010 ◽  
Vol 01 (02) ◽  
pp. 81-83 ◽  
Author(s):  
Peter Jandus ◽  
Wei Wang ◽  
Michael Seitz ◽  
Felix Wermelinger ◽  
Hans-Peter Kohler
Keyword(s):  
Serum Ferritin ◽  
High Serum ◽  
Adult Onset Still’S Disease ◽  
Adult Onset ◽  
Still’S Disease ◽  
Still's Disease ◽  
Adult Onset Still's Disease

scholarly journals Adult-onset Still’s disease, the most internistic of the rheumatic diseases: current concepts and a report of six cases

2013 ◽  
pp. 259-264
Author(s):  
Roberto Boni ◽  
Pier G. Rabitti
Keyword(s):  
Serum Ferritin ◽  
Hemophagocytic Syndrome ◽  
Unknown Origin ◽  
Essential Elements ◽  
Adult Onset Still’S Disease ◽  
Inflammatory Disorder ◽  
Adult Onset ◽  
Still’S Disease ◽  
Still's Disease ◽  
Adult Onset Still's Disease

Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disorder of unknown origin. It is characterized by spiking fever, evanescent rash, arthralgia/arthritis, and leukocytosis. The differential diagnosis includes a number of other conditions, and management is complicated by the lack of course predictors and the risks associated with complications and treatments. This report examines recent advances in our understanding of adult-onset Still’s disease (pathogenesis, diagnosis, complications, treatment). Current research in this field is focused on the significance of serum ferritin in AOSD, mechanisms underlying the hemophagocytic syndrome, and use of biologic therapies in patients who are refractory to conventional treatment. Six cases of AOSD diagnosed by our staff between 2002 and 2009 are also analyzed and compared with other cases reported in the literature. This analysis showed that Still’s rash and serum ferritin levels were not essential elements for diagnosis. In addition, the course of the disease showed little relation to the severity / characteristics of the presenting picture, but the evolution worsened with the age of the patient at diagnosis.

scholarly journals Serum sTREM-1 in adult-onset Still’s disease: a novel biomarker of disease activity and a potential predictor of the chronic course

Rheumatology ◽  
2020 ◽  
Vol 59 (11) ◽  
pp. 3293-3302 ◽  
Author(s):  
Zhihong Wang ◽  
Huihui Chi ◽  
Yue Sun ◽  
Jialin Teng ◽  
Tienan Feng ◽  
...  
Keyword(s):  
Disease Activity ◽  
Multivariate Logistic Regression Analysis ◽  
Soluble Form ◽  
Adult Onset Still’S Disease ◽  
Adult Onset ◽  
Still’S Disease ◽  
Potential Predictor ◽  
Still's Disease ◽  
Chronic Course ◽  
Adult Onset Still's Disease

Abstract Objectives Triggering receptor expressed on myeloid cells-1 (TREM-1) is an amplifier of inflammatory signals. Recently, a soluble form of TREM-1 (sTREM-1) was described. This study aimed to investigate the role of serum sTREM-1 in patients with adult-onset Still’s disease (AOSD). Methods Serum sTREM-1 levels were detected in 108 AOSD patients, 88 RA patients and 112 healthy controls (HC). The correlations of sTREM-1 with disease activity, clinical characteristics and laboratory parameters in AOSD patients were analysed by the Spearman correlation test. Risk factors for the chronic course of AOSD were evaluated by multivariate logistic regression analysis. Results AOSD patients had significantly higher serum sTREM-1 levels than RA patients and HC, and serum sTREM-1 levels were correlated with the systemic score, ferritin, leucocyte count, CRP, IL-1β and IL-6. The elevation in the initial sTREM-1 level by itself could discriminate patients developing the chronic course from patients developing the nonchronic course. Moreover, an elevated sTREM-1 level (&gt; 526.4475 pg/ml) was an independent risk factor for the chronic course in active AOSD patients. Furthermore, interfering with TREM-1 engagement led to reductions in the secretion of pro-inflammatory cytokines, such as IL-1β, IL-6 and TNF-α, in neutrophils and monocytes from active AOSD patients. Conclusion Serum sTREM-1 levels are correlated with disease activity, and an elevation in the initial serum sTREM-1 level is a potential predictor of the chronic course in AOSD patients, which currently provides the best predictive model for identifying patients prone to developing the chronic course of AOSD.

scholarly journals 6. The Stillness after the storm: a challenging diagnostic and therapeutic case of adult-onset Still’s disease

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Owen Cronin ◽  
Euan McRorie
Keyword(s):  
Myasthenia Gravis ◽  
Serum Ferritin ◽  
Previous History ◽  
Adult Onset Still’S Disease ◽  
Recurrent Fever ◽  
Adult Onset ◽  
Still’S Disease ◽  
Still's Disease ◽  
History Of ◽  
Adult Onset Still's Disease

Abstract Introduction Auto-immune and auto-inflammatory disorders are believed to cause approximately 20% of cases of pyrexia of unknown origin. Rheumatological opinion is often sought when an infectious source has not been detected. Assessment of recurrent fever is challenging for fear of initiating immunosuppression in the presence of undetected infection. This challenge is even greater in patients with a previous history of auto-immune or infectious disorders. Here, we discuss the investigation and management of a challenging case of recurrent fever, ultimately diagnosed as adult-onset Still’s disease, complicated by the previous occurrence of pulmonary tuberculosis and myasthenia gravis. Case description Our 34-year-old female patient, originally from India, had lived in the UK for 8 years. Her background included previous treatment for pulmonary TB in 2011 and myasthenia gravis diagnosed in 2015 with subsequent thoracoscopic thymectomy in 2016. She was admitted to the infectious diseases unit in October 2016 with 3 weeks of recurrent fever and an itchy rash which had commenced 1-week after holidaying in Spain. Pyrexiae were quotidian, occurring nocturnally and would usually last 1 hour with associated malaise and tachycardia. The rash affected the upper arms, buttocks and face but was not consistent in appearance; initially urticarial and later described as maculopapular. Polyarthralgia of the joints of the hands was reported. Extensive infection screening including blood cultures and serology was negative. A CT-CAP revealed changes of old TB and borderline axillary lymphadenopathy. Immunology revealed a negative ANA and ENA screen along with normal levels of anti-PR3, MPO, DsDNA and CCP antibodies. Further investigations included a CRP of 213, ESR of 75 and serum ferritin of 450mcg/l (15-200). A provisional diagnosis of a periodic fever syndrome was made and the patient agreed to a trial of anti-interleukin 1 therapy (Anakinra 100mg SC OD) while awaiting genetic testing. Immediate defervescence of fever occurred with an improvement in the rash and dramatic reduction in inflammatory indices. Two months later the patient represented with malaise, tachycardia, periorbital odema, widespread rash, diarrhoea and a marked peripheral eosinophilia (5.69 x109/L). Skin biopsy demonstrated vacuolar inflammation and prominent eosinophils. A diagnosis of DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome was made and anakinra was withdrawn. However, the patient’s condition deteriorated with a rebound elevation in inflammatory markers, pyrexia and development of synovitis. Repeat serum ferritin during this period was recorded at > 40,000mcg/ml and a diagnosis of adult-onset Still’s disease was made. Discussion This case was challenging on two particular fronts. Firstly, the arrival of a confident and definitive diagnosis was difficult. On initial review and again on deterioration 2 months later, the patient’s previous history of TB, recent travel history and presence of lymphadenopathy led to significant concern of an alternative primary diagnosis. A large number of investigations for occult infection (e.g. TB recurrence) and malignancy (e.g. lymphoma) were conducted. Likewise, the absence of a history of a sore throat, the atypical skin rash, a very modest elevation in serum ferritin, and the absence of synovitis made adult-onset Still’s disease less likely. However, the rapidity and magnitude of the response to Interleukin-1 inhibition with anakinra supported our suspicion of an auto-inflammatory syndrome. The second hurdle in this case was the problematic pharmaceutical management once adult-onset Still’s disease was diagnosed. The occurrence of DRESS syndrome secondary to anakinra is not something we had previously experienced nor does it appear to have been reported in the literature before despite a relatively high incidence of anaphylaxis and localized skin reactions with anakinra. Subsequent interleukin-6 blockade with tocilizumab was partially effective in improving symptoms and clinical parameters but did lead to significant derangement in liver function tests and treatment was stopped. There was an incomplete response to TNF-α inhibition with weekly subcutaneous etanercept injections in combination with high dose oral corticosteroids. Subsequently there was a good response to the monoclonal antibody canakinumab (anti-IL-1β). Our patient remains on 10mg of oral prednisolone but has largely remained in remission for 18 months in combination with canakinumab. Remaining concerns relate to the long-term efficacy of canakinumab for this patient and the limited therapeutic options if recurrent relapses occur. Furthermore, the risk of TB re-activation remains an unavoidable risk with a high degree of clinical suspicion required. Key learning points This was a challenging case complicated by the patient’s past medical history of TB, myasthenia gravis and thymoma, in addition to the occurrence of DRESS syndrome which led to a period of diagnostic uncertainty. While the input of many specialties (i.e., respiratory, infectious diseases, haematology, and dermatology) were required and critical to the overall management of the patient, extensive and prolonged investigation can lead to significant delays in treatment. In such situations, an open discussion with the patient as to the risks and benefits of delaying treatment versus pursuing further investigation is advised. Furthermore, we have learnt from this case to appreciate that focused repetition of some investigations, in the setting of diagnostic uncertainty, can be beneficial. In this case repetition of serum ferritin levels, skin biopsy and cross-sectional CT imaging all led to important diagnostic conclusions and decisions that ultimately resulted in the correct diagnosis and successful management of this patient. Conflict of interest The authors declare no conflicts of interest.

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