Search

The interplay of pregnancy, the immune system and its impact on autoimmune disease is an area of growing interest. Adult-onset Still's disease is a rare auto-inflammatory disorder characterised by fever, rash, arthralgia and leucocytosis. We describe a rare case of the disease presenting for the first time in the immediate postpartum period, highlighting pregnancy and birth as possible triggers for this condition. [ABSTRACT FROM AUTHOR]

Adult-onset Still’s disease (AOSD) is a remarkably rare illness. One well-known pathogenic process that results in systemic manifestations is auto-inflammatory disease. We report on a young man who complained of joint pain, sore throat, and a high spiking fever. After a thorough assessment using the Yamaguchi criteria, the patient’s clinical examination, elevated serum ferritin and C-reactive protein (CRP), absence of serologic markers (RA factor, Antinuclear antibody levels), and lymphadenopathy all contributed to the diagnosis of AOSD. He was treated with analgesics, steroids, and disease-modifying anti-rheumatic drugs (DMARDs). Three weeks later, at the follow-up, his symptoms and lab parameters had improved.

Background: Adult‐onset Still's disease (AOSD) is a rare systemic inflammatory disorder that is characterized by quotidian fevers, arthritis, and an evanescent rash. Occurrence of concurrent thrombotic microangiopathy (TMA) in AOSD is rare. The treatment aspects of TMA in AOSD are actively being debated. Methods: Medline search using MeSH terms and snowballing yielded a total of 29 articles with co‐occurrence of AOSD and thrombotic thrombocytopenic purpura (TTP) including our own. Pooled data were synthesized for descriptive analysis. Results: Median age was 35 years with a majority of females (68.96%). A majority of these studies/patients were either Asian (34.48%) or Caucasian (31.03%). Concurrent TMA at the time of AOSD diagnosis was seen in 65.51% patients. Only 3/29 patients had ADAMTS13 level less than 10%, consistent with TTP and 3/29 were diagnosed with hemolytic uremic syndrome (HUS). The remainder were diagnosed clinically. Complication rate was high, and 15/29 (51.72%) patients died or had permanent neurological/renal/vision/gangrenous complications. Median and mean ferritin peak was observed to be higher (7458 and 12 349, respectively) in patients who either died/had partial remission, compared to those who had complete response (3257 and 10 899, respectively), p =.829. Conclusions: A majority of patients with AOSD‐associated TMA either died or had permanent complications. TMA was diagnosed alongside AOSD in 65% patients, while the rest developed TMA during the course of their disease. Blurred vision may precede TMA and could help risk‐stratify high‐risk AOSD patients clinically. Glycosylated ferritin remains low several weeks to months after disease remission and may be used to monitor severity of disease process. Further studies are necessary to confirm the existing vascular endothelial growth factor hypothesis in AOSD‐associated TMA. [ABSTRACT FROM AUTHOR]

Adult-onset Still’s disease (AOSD) is a complex systemic inflammatory disorder, categorized as an ‘IL-1 driven’ inflammasomapathy. Despite this, the interaction between T and B cells remains poorly understood. We conducted a study, enrolling 7 patients with relapsing AOSD and 15 healthy control subjects, utilizing deep flow cytometry analysis to examine peripheral blood T- and B-cell subsets. T-cell and B-cell subsets were significantly altered in patients with AOSD. Within CD4+ T cells, Th2 cells were decreased. Additionally, Th17 cell and follicular Th cell subsets were altered within CD45RA–CD62L+ and CD45RA–CD62L– Th cells in patients with AOSD compared to healthy controls. We identified changes in CD8+ T cell maturation and ‘polarization’ in AOSD patients, with an elevated presence of the TEMRA CD8+ T cell subset. Furthermore, the percentage of Tc1 cells was decreased, while the frequency of CCR6–CXCR3– Tc2 cells was elevated. Finally, we determined that the frequency of CD5+CD27– B cells was dramatically decreased in patients with AOSD compared to healthy controls. Further investigations on a large group of patients with AOSD are required to evaluate these adaptive immunity cells in the disease pathogenesis.

Abstract Currently, the criteria used to classify patients with SJIA are different from those used for AOSD. However, it has been recognized that the existing terms are too narrow, subdividing the Still’s population unnecessarily between pediatric-onset and adult-onset disease and excluding an appreciable group of children in whom overt arthritis is delayed or absent. Government regulators and insurers rely upon the guidance of subject experts to provide disease definitions, and when these definitions are flawed, to provide new and better ones. The classification session at the NextGen 2022 conference helped to serve this purpose, establishing the need for a revised definitional system that transcends the fault lines that remain in existing definitions.

Xiaojing Zhong,* Tongtong Xu,* Tianhao Li,* Nana Luo, Nan Luo, Pingsheng Hao Author Affiliations Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Pingsheng Hao, Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, 39 Shi-Er-Qiao Road, Jinniu District, Chengdu, Sichuan, 610072, People’s Republic of China, Tel +86138 8196 5024, Fax +86-28-87732407, Email hpswl@126.comAbstract: Adult-onset Still’s disease (AOSD) is considered a rare autoimmune inflammatory disorder with an unclear etiology and pathogenesis.The main clinical manifestations of this disease are high fever, joint pain, and transient skin lesions. Physical examination may reveal hepatomegaly, splenomegaly, and lymphadenopathy, while laboratory tests show abnormalities such as elevated white blood cell count (WBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum ferritin (SF). The lack of specific diagnostic markers contributes to a relatively high rate of clinical misdiagnosis and missed diagnoses.In terms of treatment, glucocorticoids have always been the cornerstone medication, but some patients exhibit suboptimal responses to conventional drug therapy, making disease control challenging. However, as our understanding of the pathogenesis continues to grow, novel therapeutic approaches targeting various cytokines have been gradually identified. In this report, we present a case of successful treatment of recurrent AOSD with tocilizumab (TCZ), along with a concise review of innovative treatment strategies for AOSD based on literature retrieval.Keywords: AOSD, tocilizumab, treatment, interleukin-6 inhibitors

Abstract Objective The differential diagnosis between adult-onset Still’s disease (AOSD) and sepsis has always been a challenge. In this study, a machine learning model for differential diagnosis of AOSD and sepsis was developed and an online platform was developed to facilitate the clinical application of the model. Methods All data were collected from 42 AOSD patients and 50 sepsis patients admitted to Affiliated Hospital of Xuzhou Medical University from December 2018 to December 2021. In addition, 5 AOSD patients and 10 sepsis patients diagnosed in our hospital after March 2022 were collected for external validation. All models were built using the scikit-learn library (version 1.0.2) in Python (version 3.9.7), and feature selection was performed using the SHAP (Shapley Additive exPlanation) package developed in Python. Results The results showed that the gradient boosting decision tree(GBDT) optimization model based on arthralgia, ferritin × lymphocyte count, white blood cell count, ferritin × platelet count, and α1-acid glycoprotein/creatine kinase could well identify AOSD and sepsis. The training set interaction test (AUC: 0.9916, ACC: 0.9457, Sens: 0.9556, Spec: 0.9578) and the external validation also achieved satisfactory results (AUC: 0.9800, ACC: 0.9333, Sens: 0.8000, Spec: 1.000). We named this discrimination method AIADSS (AI-assisted discrimination of Still’s disease and Sepsis) and created an online service platform for practical operation, the website is http://cppdd.cn/STILL1/ . Conclusion We created a method for the identification of AOSD and sepsis based on machine learning. This method can provide a reference for clinicians to formulate the next diagnosis and treatment plan.

Objective: This study aimed to develop nomogram prediction models to differentiate between adult-onset Still's disease (AOSD) and sepsis. Methods: We retrospectively collected laboratory test data from 107 hospitalized patients with AOSD and sepsis at the Affiliated Hospital of Xuzhou Medical University. Multivariate binary logistic regression was used to develop nomogram models using arthralgia, WBC, APTT, creatinine, PLT, and ferritin as independent factors. The performance of the model was evaluated by the bootstrap consistency index and calibration curve. Results: Model 1 had an AUC of 0.98 (95% CI, 0.96–1.00), specificity of 0.98, and sensitivity of 0.94. Model 2 had an AUC of 0.96 (95% CI, 0.93–1.00), specificity of 0.92, and sensitivity of 0.94. The fivefold cross-validation yielded an accuracy (ACC) of 0.92 and a kappa coefficient of 0.83 for Model 1, while for Model 2, the ACC was 0.87 and the kappa coefficient was 0.74. Conclusion: The nomogram models developed in this study are useful tools for differentiating between AOSD and sepsis. Key Points • The differential diagnosis between AOSD and sepsis has always been a challenge • Delayed treatment of AOSD may lead to serious complications • We developed two nomogram models to distinguish AOSD from sepsis, which were not previously reported • Our models can be used to guide clinical practice with good discrimination [ABSTRACT FROM AUTHOR]

Background: Patients with systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) have been under-represented in studies about safety of the COVID-19 immunization. We aimed to inquire about the safety and tolerability of COVID-19 immunization in this population. Methods: An anonymous online survey on closed Facebook groups for patients and parents with self-reported sJIA/AOSD was posted from June 27th until August 30th, 2022. Continuous variables were analyzed using t-tests or the Mann-Whitney U test if non-normally distributed. Fisher's tests were used for categorical variables. Results: Of a total of 167 responses, 17 were excluded. Ninety-nine patients received the COVID-19 immunization, and 51 patients did not. Patients in both immunized and unimmunized groups had a similar history of disease complications such as macrophage activation syndrome (50% vs. 49%), lung disease (17% vs. 29%), arthritis (51% vs. 50%), and pericarditis/myocarditis (10% vs. 8%). Unimmunized patients were younger (median age 8 yo vs. 12 yo, p < 0.001) and had a higher incidence of a history of disease flare or severe side effects with other immunizations (24% vs. 4%, p < 0.001). Thirty-nine patients reported mostly mild immunization side effects. Severe side effects included 6 reports of disease flare and 2 reports of cardiac side effects (pericarditis and atrial fibrillation). Seven patients reported side effects lasting ≥ 8 days. Three patients developed AOSD following COVID-19 immunization, and 2 of them had the only hospital admissions for immunization side effects. Regarding COVID-19 infection, 46 patients were infected without full immunization, and 33 were infected after 2 doses of immunization. There was one hospitalization in the immunized group, compared to one ICU admission leading to death in the non-immunized group. There was a trend (p > 0.05) toward a higher risk of disease flare after COVID-19 infection among non-immunized patients (43%), compared to immunized patients (24%). Conclusions: The COVID-19 immunization was well tolerated by sJIA/AOSD patients even in this group of patients with severe disease. There was a low incidence of disease flare with immunization. Most immunization side effects were mild and lasted < 7 days. The only ICU admission and death from COVID-19 infection occurred in unimmunized subjects. [ABSTRACT FROM AUTHOR]

IntroductionThe effectiveness of canakinumab may change according to the different times it is used after Still’s disease onset. This study aimed to investigate whether canakinumab (CAN) shows differences in short- and long-term therapeutic outcomes, according to its use as different lines of biologic treatment.MethodsPatients included in this study were retrospectively enrolled from the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to Still’s disease. Seventy-seven (51 females and 26 males) patients with Still’s disease were included in the present study. In total, 39 (50.6%) patients underwent CAN as a first-line biologic agent, and the remaining 38 (49.4%) patients were treated with CAN as a second-line biologic agent or subsequent biologic agent.ResultsNo statistically significant differences were found between patients treated with CAN as a first-line biologic agent and those previously treated with other biologic agents in terms of the frequency of complete response (p =0.62), partial response (p =0.61), treatment failure (p >0.99), and frequency of patients discontinuing CAN due to lack or loss of efficacy (p =0.2). Of all the patients, 18 (23.4%) patients experienced disease relapse during canakinumab treatment, 9 patients were treated with canakinumab as a first-line biologic agent, and nine patients were treated with a second-line or subsequent biologic agent. No differences were found in the frequency of glucocorticoid use (p =0.34), daily glucocorticoid dosage (p =0.47), or concomitant methotrexate dosage (p =0.43) at the last assessment during CAN treatment.ConclusionCanakinumab has proved to be effective in patients with Still’s disease, regardless of its line of biologic treatment.

Aspect-orieIited programming (AOP) provides better flexibility and maintainability of a system by separating the cross-cutting concerns from the s>·stem and weaving them in at a later stage. However, the actual benefit of adopting AOP is hard to evaluate. Therefore, how to effectively assess the quality of applying aspect-related techniques become an issue that needs further attention. Our previous research, called ABRIDP. proposed to deal with the problem when developers overlook some quality requirements. such as 11exibility and scalability, by weaving design patterns into source code through aspects at the implementation stage. In this paper, as a continuation of our previous work, we propose using GQM (goal, question, and metric) to evaluate the improvement that applies ABRIDP to software systems. That is, to evaluate the system with appropriate metrics that positively answer the questions originating from the goal that indicates the system can benefit from applying ABR]DP. To better evaluate the system quality after refactoring, we further normalize the result and estimate the weight of each metric with fuzzy theory and AHP (analytic hierarchy process). Finally, w·e experiment with the proposed method from three quality perspectives (scalability. flexibility, and readability) to evaluate the improvement after applying ABRIDP. [ABSTRACT FROM AUTHOR]

Adult-onset Still’s disease (AOSD) is a rare complex autoinflammatory disease of unknown etiology. The main problem, practitioners have been facing with when researching AOSD, is the lack of developed approaches to assessing the activity of the disease. Traditionally used standard markers of inflammation do not always reflect the real activity of AOSD, especially when a patient is already receiving anti-inflammatory therapy. The article presents original data on the study of biomarkers: interleukin-1 beta (IL-1b), interleukin-6 (IL-6), interleukin-18 (IL-18), ferritin, glycosylated ferritin, calprotectin, procalcitonin compared with C-reactive protein, leukocyte and neutrophil counts in patients with moderate and high activity of AOSD. The relationship between inflammatory biomarkers and the Pouchot systemic score was evaluated to identify promising laboratory indicators of disease activity.

Paola Galozzi, Sara Bindoli, Andrea Doria, Paolo Sfriso Rheumatology Unit, Department of Medicine DIMED, University of Padova, Padova, ItalyCorrespondence: Paola Galozzi, Rheumatology Unit, Department of Medicine DIMED, University of Padova, via Giustiniani, 2, Padova, 35128, Italy, Tel +39 049 821 8654, Email paola.galozzi@unipd.itAbstract: Adult-onset Still’s disease (AOSD) is a rare multifactorial autoinflammatory disorder of unknown etiology, characterized by an excessive release of cytokines triggered by dysregulated inflammation and articular and systemic manifestations. The clinical spectrum of AOSD ranges from self-limiting forms with mild symptoms to life-threatening cases and presents clinical and biological similarities with the juvenile form (sJIA). Nowadays, the advances in biologic agents no longer limit the treatment to NSAIDs, glucocorticoids, or conventional synthetic DMARDs. The blockade of IL-1 and IL-6 is effective in the treatment of systemic and articular inflammation of AOSD patients; however, novel compounds with different properties and targets are now available and others are being studied. In this review, starting from the pathogenesis of AOSD, we summarized the current and emerging biological therapies, possible effective agents for achieving AOSD control and remission.Keywords: biologics, AOSD, IL-1 inhibitors, IL-6 inhibitors, small molecules, new treatment

Currently, the criteria used to classify patients with SJIA are different from those used for AOSD. However, it has been recognized that the existing terms are too narrow, subdividing the Still's population unnecessarily between pediatric-onset and adult-onset disease and excluding an appreciable group of children in whom overt arthritis is delayed or absent. Government regulators and insurers rely upon the guidance of subject experts to provide disease definitions, and when these definitions are flawed, to provide new and better ones. The classification session at the NextGen 2022 conference helped to serve this purpose, establishing the need for a revised definitional system that transcends the fault lines that remain in existing definitions. [ABSTRACT FROM AUTHOR]

Getting access to specialists for autoinflammatory diseases (AID) can be challenging. Therefore, an increasing number of patients and healthcare professionals are seeking information on AID via the Internet, using the video platform YouTube, for example. However, the quality of such videos has not yet been evaluated. A YouTube search was conducted to assess videos about AID to evaluate the quality and usefulness from both the patient's and healthcare professional´s perspectives. Video duration, number of views, likes, dislikes, comments, and uploading source on various AID were extracted. Video quality was evaluated by the modified global quality scale (GQS). The reliability was assessed by the modified five-point DISCERN score. In total, 140 videos were screened of which 105 videos met the inclusion criteria for further analysis. Based on the GQS, the overall quality of videos for patients was found to be low in 64.8%, intermediate in 27.6%, and high in 7.6% of videos. The quality of videos for professionals was similar (54.3% low, 23.8% intermediate, and 21.9% of high quality). Videos were more often targeting medical professionals (65.7%) and less often patients (34.3%). This analysis demonstrates that the majority of videos regarding AIDs are of limited quality. Available videos more often address users with a professional medical background. Only a small proportion of existing videos provide understandable and useful information for AID patients. Thus, there is a strong need to develop high-quality and audience-oriented videos in the context of educational campaigns for these rare disease groups. [ABSTRACT FROM AUTHOR]

Abstract Background Adult-onset Still's disease (AOSD) is a systemic inflammatory disease of unknown etiology, lacking specific diagnosis and disease activity evaluation indicators. This study will analyze the activity and clinical significance of Adenosine deaminase (ADA) in AOSD patients. Methods Totally 53 AOSD patients, 60 patients with other autoimmune diseases including systemic lupus erythematosus (SLE), sjogren syndrome (SS) and rheumatoid arthritis (RA), as well as 60 healthy subjects were included in this study. AOSD activity was determined by Pouchot score. We analyzed the correlation between ADA activity and clinical parameters. In addition, the correlation between ADA activity and disease activity score was also analyzed. Results This study showed that the activity of ADA in AOSD patients was significantly higher than that of healthy controls, SLE, SS and RA patient groups (p

The deep inferior epigastric artery perforator (DIEP) flap is an excellent option for microsurgical breast reconstruction. In selected cases, e.g. in case of previous abdominoplasty, other autologous options like transverse upper gracilis (TUG) or superior gluteal artery perforator (sGAP) flaps can be considered. The anterolateral thigh (ALT) flap is reported to be used as a salvage procedure in selected cases of breast reconstruction, where other flaps were not available or failed. We present a case of a 41-year-old woman who was undergoing bilateral breast reconstruction after bilateral mastectomies following implant-based mastopexie and multiple infections. She also suffered from an adult onset Still’s disease (AOSD) and was thus immunosuppressed. Microsurgical breast reconstruction was performed in a two-stage procedure. The left breast was reconstructed using a TUG flap. On the right side the TUG reconstruction failed due to vascular anomaly, so an ALT flap was successfully used instead. The whole procedure was accompanied by a multidisciplinary approach including a rheumatological complex treatment and enabled a successful bilateral breast reconstruction in this challenging case.

ObjectiveInterleukin (IL)-1 inhibitors are largely employed in patients with Still’s disease; in cases with refractory arthritis, IL-6 inhibitors have shown to be effective on articular inflammatory involvement. The aim of the present study is to assess any difference in the effectiveness of the IL-1β antagonist canakinumab prescribed as first-line biologic agent between the systemic and the chronic-articular Still’s disease.MethodsData were drawn from the retrospective phase of the AutoInflammatory Disease Alliance (AIDA) international registry dedicated to Still’s disease. Patients with Still’s disease classified according to internationally accepted criteria (Yamaguchi criteria and/or Fautrel criteria) and treated with canakinumab as first-line biologic agent were enrolled.ResultsA total of 26 patients (17 females, 9 males; 18 patients developing Still’s disease after the age of 16 years) were enrolled; 16 (61.5%) patients suffered from the systemic pattern of the disease; 10 (38.5%) patients suffered from the chronic-articular type. No differences were observed between the systemic and the chronic-articular Still’s disease in the frequency of complete response, of flares after the start of canakinumab (p = 0.701) and in the persistence in therapy (p = 0.62). No statistical differences were observed between the two groups after 3 months, 12 months and at the last assessment in the decrease of: the systemic activity score (p = 0.06, p = 0.17, p = 0.17, respectively); the disease activity score on 28 joints (p = 0.54, p = 0.77, p = 0.98, respectively); the glucocorticoid dosage (p = 0.15, p = 0.50, and p = 0.50, respectively); the use of concomitant disease modifying anti-rheumatic drugs (p = 0.10, p = 1.00, and p = 1.00, respectively). No statistically significant differences were observed in the decrease of erythrocyte sedimentation rate (p = 0.34), C reactive protein (p = 0.48), and serum ferritin levels (p = 0.34) after the start of canakinumab.ConclusionCanakinumab used for Still’s disease has been effective in controlling both clinical and laboratory manifestations disregarding the type of disease course when used as first-line biotechnological agent. These excellent results might have been further enhanced by the early start of IL-1 inhibition.

Background: Adult-onset Still’s disease (AOSD) is a clinical syndrome whose etiology and pathogenesis remain unclear. The clinical symptoms of AOSD mainly include fever, erythema, arthralgia and muscle pain, which cannot be diagnosed by specific auxiliary examination and can initially attack during pregnancy. The identification of the disease is revealed by a diagnosis of exclusion. Currently, the relationship between pregnancy and AOSD remains unclear. Here, we report on one case of AOSD during pregnancy that was admitted to the Beijing Anzhen Hospital affiliated to Capital Medical University. A 24-year-old woman was admitted to hospital due to intermittent fever, a history of pain and swelling of the large joints at 33 weeks gestation. After the diagnosis of AOSD, the symptoms relieved with medication. The patient delivered a premature, 3450 g baby successfully. Conclusions: The diagnostic criteria of pregnancy complicated by AOSD mainly depends on a diagnosis of exclusion. The literature both at home and abroad shows that the onset of AOSD is closely related to pregnancy, and that pregnancy is one of its predisposing factors. Its clinical manifestations are arthritis, arthromyalgia, fever, pharyngitis and so on, which involve multiple systems. There is no highly specific approach available in the laboratory examination and imaging for this disease.

Vaccination against the virus responsible for COVID-19 has become key in preventing mortality and morbidity related to the infection. Studies have shown that the benefits of vaccination outweigh the risks. However, there are concerns regarding serious adverse events of some vaccines, although they are fortunately rare. Here, we report a case of a 47-year-old female from Kathmandu who presented with high grade fever, dry cough and erythematous rash a week after exposure to the Oxford-AstraZeneca vaccine. She had hepatosplenomegaly, persistent leucocytosis, anaemia and thrombocytosis along with markedly raised inflammatory markers. Her tests for infectious causes and haematological malignancies were negative and she showed no response to multiple antibiotics. Finally, she had a dramatic response to steroids with disappearance of fever and normalization of other laboratory parameters. Hence, she was diagnosed with Adult-onset Still’s Disease (AOSD). She was under methotrexate and prednisolone tapering dose and doing well as of the time of writing. The trigger for the disease was hypothesized to be the vaccine because of the strong temporal association.

We report the case of an 18-year-old male with Still's disease for the last 3 years, in remission, who developed two flares of his disease after receiving two doses of the ChAdOX1 nCoV-19 vaccine. While the first flare was mild requiring steroid initiation and resolved rapidly, the second flare after the second dose was much severe, requiring pulse steroid and tocilizumab. We also review three reported cases of flares of Still's disease after COVID-19 vaccination. The temporal association of the flares with both vaccine doses strengthens the association between the vaccine administration and the flare. The proposed mechanism may be due to activation of the innate immune system by the vaccine adjuvants. This review serves to inform the medical community regarding a possible role of the vaccine in producing a systemic inflammatory response. Early detection and treatment can help reduce morbidity in these cases. [ABSTRACT FROM AUTHOR]

Adult-onset Still's disease (AOSD) and Schnitzler syndrome (SchS) are rare, not fully understood, multisystemic and autoinflammatory disorders, with a challenging differential diagnosis. The authors report the case of an elderly man with unexplained fever, arthralgia, weight loss, spleen enlargement, lymphadenopathy, anemia, hyperferritinemia and IgG monoclonal gammopathy. Autoimmunity, infection, haematological disease and malignancy were excluded. The clinical spectrum fulfilled both AOSD diagnostic criteria and IgG-variant SchS Strasbourg criteria. Symptom resolution was achieved with immunosuppressive therapy, supporting the diagnosis of an autoinflammatory disorder, a diagnostic challenge for the medical team emerging as an unexpected cause of fever in the elderly. [ABSTRACT FROM AUTHOR]

Background: Adult-onset Still's disease (AOSD) is a systemic inflammatory disease of unknown etiology, lacking specific diagnosis and disease activity evaluation indicators. This study will analyze the activity and clinical significance of Adenosine deaminase (ADA) in AOSD patients. Methods: Totally 53 AOSD patients, 60 patients with other autoimmune diseases including systemic lupus erythematosus (SLE), sjogren syndrome (SS) and rheumatoid arthritis (RA), as well as 60 healthy subjects were included in this study. AOSD activity was determined by Pouchot score. We analyzed the correlation between ADA activity and clinical parameters. In addition, the correlation between ADA activity and disease activity score was also analyzed. Results: This study showed that the activity of ADA in AOSD patients was significantly higher than that of healthy controls, SLE, SS and RA patient groups (p < 0.0001). The ADA activity of AOSD patients decreased significantly after systemic treatment (p < 0.0001). Correlation analysis showed that ADA activity was positively correlated with ALT(r = 0.54, p < 0.0001), AST (r = 0.82, p < 0.0001) and serum ferritin (r = 0.67, p < 0.001). ADA activity was negatively correlated with white blood cell (r = − 0.42, p = 0.002) and platelet counts (r = − 0.44, p = 0.001). We also found a significant positive correlation between the activity of ADA and Pouchot score in AOSD patients (r = 0.51, p = 0.001). Receiver operating characteristic (ROC) curve analysis showed that ADA activity had a sensitivity of 93.3%, and a specificity of 83% for the diagnosis of AOSD, with an area under the curve of 0.93. Conclusion: This study showed that serum ADA activity can be used as a potential biomarker for AOSD diagnosis and disease activity assessment. [ABSTRACT FROM AUTHOR]

• Seventeen studies published between 2012 and 2021 were identified, mostly case reports (11) and observational studies (4), and only one RCT and one analysis of pooled sJIA data. • Of a total of 99 patients treated with canakinumab, 68.7% of these presented a complete remission of the symptoms, while 16.2% of the patients showed a partial improvement, and the remaining (15.1%) did not show clinical improvement or were excluded. • Canakinumab was also associated with an acceptable safety profile, similar to expected in IL-1 inhibitor therapy. • The current use of canakinumab is encouraged by the increasing favorable results reported and the efficacy of other IL-1 inhibitors. Adult-onset Still's disease (AOSD) is a rare inflammatory disease, typically characterized by spiking fever, skin rash, and arthralgia or arthritis. Its conventional treatment includes NSAIDs and corticosteroids, and DMARDs as second-line therapy. Frequently, IL-1 inhibitors are also required, mainly in patients refractory to traditional therapy. Canakinumab is a monoclonal antibody that binds IL-1β with high affinity and specificity, making it appropriate for therapeutic purposes in AOSD. The aim of this systematic review was to identify and compile the current data on the efficacy and safety of canakinumab in the treatment of AOSD. Following the guidelines established by the PRISMA statement, we searched Scopus, Web of Science, Pubmed, and Cochrane Library for relevant literature up to March 2021. The inclusion criteria comprised: randomized controlled trials, pooled analyses, observational studies, case series, and case reports. Seventeen studies published from 2012 to 2021 were evaluated; 11 of these correspond to case series or case reports, four observational studies, one placebo-controlled phase II trial, and one analysis of pooled systemic juvenile idiopathic arthritis data. In general, out of a total of 99 patients, 68.7% of these presented a complete remission of the systemic and arthritic manifestations at the end of the observation period, while 16.2% of the patients showed a partial improvement of the symptoms and the remaining (15.1%) did not show clinical improvement or were excluded. Moreover, 210 adverse events were reported in 69 patients during canakinumab treatment, of which the majority correspond to respiratory tract infections, arthralgia, disease flares, abdominal pain, nausea, and diarrhea, whereas the most common severe adverse events included macrophage activation syndrome and serious infections. Also, a corticosteroid-sparing effect was observed in a large percentage of patients. More studies with solid evidence are needed to support the efficacy of canakinumab in AOSD, although its use is encouraged by the increasing favorable results reported and the efficacy of other IL-1 inhibitors. It was also associated with an acceptable safety profile, similar to expected in IL-1 inhibitor therapy. However, future studies with well-defined endpoints are warranted to examine further the usefulness of canakinumab in AOSD. [Display omitted] [ABSTRACT FROM AUTHOR]

Objectives Adult-onset Still's disease (AOSD) is a multifactorial systemic autoinflammatory disease. Neurological damage has been rarely reported in AOSD. We aimed to characterize the clinical features of AOSD patients with neurological involvement. Methods A total of 187 AOSD patients were admitted to Peking Union Medical College Hospital from January 2015 to August 2019. The complete medical records were reviewed in this retrospective study. Clinical features of 14 AOSD patients with neurological involvement were collected and compared with those without. Results The prevalence of neurological involvement in AOSD inpatients was 7.5%. The median disease duration was 4.5 months, with a range of 1–15 months. The frequent symptoms were fever [14 (100%)], rash [13 (92.9%)], liver dysfunction [11 (78.6%)], arthralgia/arthritis [10 (71.4%)] and lymphadenopathy [10 (71.4%)]. Four (28.6%) patients had macrophage activation syndrome (MAS). Aseptic meningitis was the most common presentation (64.3%) when the nervous system was involved. Other rare manifestations included cranial nerve palsy, encephalitis and cerebral infarction. The rate of MAS, serum levels of lactate dehydrogenase and ferritin were significantly higher in AOSD patients with neurological involvement than in those without. All patients received high-dose corticosteroid therapy and immunosuppressive agents and two were given tocilizumab. Clinical remission was achieved in all 14 AOSD patients with neurological involvement. Conclusion Neurological involvement, particularly aseptic meningitis, is not a rare complication of AOSD. It is frequently complicated by MAS. There may be a potential relationship between the neurological damage of AOSD and MAS. [ABSTRACT FROM AUTHOR]

• AOSD is a rare multisystem inflammatory disease characterized by spiking high fevers, arthritis or arthralgia, maculopapular salmon-colored rash, neutrophilic leukocytosis, and hyperferritinemia. • Emerging evidence suggest that AOSD and SJIA are part of the same disease continuum with different ages of onset. • Owing to an increased awareness about AOSD, incidence and prevalence rates have increased over time. • AOSD may present with different phenotypes, one with prominent systemic features and one with chronic arthritis. • There is no specific test for diagnosis of AOSD, but classification criteria are available. • In the absence of timely diagnosis and appropriate management, AOSD can lead to irreversible joint damage with functional impairment and potentially life-threatening complications. • There are no internationally recognized guidelines for the management of AOSD, although local guidelines have been developed recently in Japan and Italy. • Currently, biologic drugs are usually reserved for patients who do not respond to conventional DMARDs. Further studies are needed to assess if early treatment with biologics leads to better patient outcomes and a change in the natural history of AOSD. • Treatment with IL-1 inhibitors in AOSD patients refractory to conventional treatment can lead to clinical remission. • Canakinumab is the only FDA-approved biologic for AOSD in the USA; canakinumab and anakinra are approved in Europe. Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology, characterized by a clinical triad of high spiking fever, arthralgia (± arthritis), and evanescent skin rash. Management of AOSD poses several challenges, including difficulty in diagnosis and limited therapeutic options. In this review, we examined whether AOSD and systemic juvenile idiopathic arthritis (SJIA) represent a continuum of the same disease. We also explored the latest available evidence related to prevalence, clinical and laboratory manifestations, complications, diagnostic challenges, novel biomarkers, and treatment options in the era of biologics and identified the unmet needs of patients with AOSD. A comprehensive systematic literature search was performed in the Embase and MEDLINE (via PubMed) literature databases. The search was limited to human studies published in English from inception up to March 2020. Additionally, abstracts presented at various conferences were screened and hand searches were performed. Publications were processed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 123 publications were identified through the literature search, majority of which were case series and retrospective observational studies. AOSD and SJIA are widely considered part of the same disease spectrum owing to similarities in their clinical and biological features. The clinical presentation of AOSD is highly variable, accompanied by a broad spectrum of disease manifestations. Recent evidence suggests that the AOSD disease course can be classified into two distinct categories: "systemic" and "articular." Furthermore, AOSD patients may experience various life-threatening complications, such as macrophage activation syndrome — reported in as high as 23% of AOSD patients and considered to be the most severe complication characterized by a high mortality rate. The ambiguity in presentation and lack of serologic markers make the diagnosis of AOSD difficult, often leading to a delay in diagnosis. Given these limitations, the Yamaguchi and Fautrel criteria are the most widely used diagnostic tools in clinical practice. It has been observed that a clinical diagnosis of AOSD is generally reached by exclusion while investigating a patient with fever of unknown origin. Recent advances have demonstrated a major role of proinflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-18, and IL-37, and other biomarkers in the pathogenesis and management of AOSD. Owing to the rarity of the disease, there are very limited clinical trials evaluating management strategies for AOSD. The current AOSD treatment paradigm includes non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids initially, conventional synthetic disease-modifying anti-rheumatic drugs in steroid-refractory patients, and biologics in those resistant to conventional treatment. Only a few country-specific guidelines for the management of AOSD have been published, and a treat-to-target approach, as previously recommended for SJIA, is still lacking. Canakinumab is the only FDA–approved biologic for the treatment of AOSD. Emerging evidence supports that AOSD and SJIA represent a continuum of the same disease entity. Despite advancements in the understanding of AOSD, it continues to pose a substantial burden on patients and the healthcare systems, and substantial unmet needs exist across key domains such as the pathway to diagnosis, use of biomarkers in clinical practice, and standardized treatment strategies. Further research and collaboration is crucial for optimizing the diagnosis and management of AOSD patients. [ABSTRACT FROM AUTHOR]

Abstract Adult‐onset Still's disease (AOSD) is a rare inflammatory autoimmune disorder characterized by fever, skin rash, and arthralgia. Pulmonary artery hypertension (PAH) rarely occurs with AOSD and has not been reported in the absence of typical symptoms of AOSD. A 33‐year‐old woman was admitted to our hospital with dyspnoea on exertion. Although she had not had symptoms of AOSD for 18 months before her admission, she presented with gradually progressing PAH. Because she had no typical symptoms of AOSD, she was treated with pulmonary vasodilators. However, her PAH did not improve. At one month after vasodilator treatment, she developed a high fever with elevation of ferritin. We determined that her AOSD had relapsed. Immunosuppressants were started and both her AOSD and PAH quickly improved. PAH may develop in the absence of typical symptoms of AOSD and immunosuppressants may be effective in such a case.

Objective: The purpose of this study was to explore the value of 18F-FDG PET/CT in monitoring the disease activity and predicting the prognosis of the Adult-onset Still's disease (AOSD).Methods: We retrospectively analyzed the electronic medical records of 45 AOSD patients who underwent 18F-FDG PET/CT in the Second Xiangya Hospital. PET/CT imaging and clinical information were retrospectively reviewed and analyzed. 18F-FDG uptake was assessed by measuring standard uptake value (SUV) in the spleen, liver, bone marrow, and lymph nodes. The spleen-to-liver ratio of the SUVmax (SLRmax) and SUVmean (SLRmean), the bone-to-liver ratio of the SUVmax (BLRmax), and SUVmean (BLRmean), and the lymph nodes-to-liver ratio of the SUVmax (LyLRmax) were calculated. Clinical and laboratory information were collected and evaluated for association with metabolic parameters of 18F-FDG PET/CT. The influencing factors for recurrence within 1 year were analyzed to determine whether 18F-FDG PET/CT can predict the prognosis of AOSD patients.Results: Elevated 18F-FDG uptake could be observed in bone marrow, spleen, and lymph nodes of AOSD patients. Correlation analysis between 18F-FDG uptake of organs and laboratory examinations showed that SLRmean positively correlated with LDH, AST, ferritin, and the systemic score (r = 0.572, 0.353, 0.586, and 0.424, P < 0.05). The SLRmean had the highest correlation with ferritin (r = 0586, P < 0.001). All metabolic parameters in spleen, including SUVmax, SUVmean, SLRmax, and SLRmean, are positively correlated with LDH level (r = 0.405, 0.539, 0.481, and 0.572, P < 0.05). Bone marrow SUVmax, BLRmax, and BLRmean were correlated with C-reactive protein (CRP) level (r = 0.395, 0.437, and 0.469, P < 0.05). Analysis of the influencing factors of recurrence within 1 year showed that the spleen SUVmax, spleen SUVmean, SLRmax, SLRmean, ferritin, and the systemic score of the recurrence group was significantly higher than the non-recurrence group (P < 0.05). The SLRmean cutoff of 1.66 with a sensitivity of 72.7% and specificity of 80.0% had the highest performance in predicting recurrence.Conclusion: The glucose metabolism of the liver, spleen, and bone marrow of AOSD patients were correlated with laboratory inflammatory indicators and system score, suggesting that 18F-FDG PET/CT could be applied to evaluate disease activity. Moreover, spleen 18F-FDG uptake may be a potential biomarker for predicting clinical prognosis of AOSD patients.

Acute severe hepatitis is a rare complication of adult-onset Still's disease (AOSD). This condition is poorly characterized. We performed a review of the medical literature to describe clinical, biological, pathological, and treatment characteristics from AOSD patients with acute severe hepatitis. Their characteristics were compared with AOSD patients without severe hepatitis. Twenty-one cases were collected including a new case reported here. Patients with severe hepatitis were mostly young adults with a median age of 28 years (range: 20 to 55 years). Overall, patients with severe hepatitis had less arthritis, macular rash, sore throat, lymphadenopathy, or splenomegaly than patients without severe hepatitis. Cytopenia was more frequent in case of severe hepatitis. Most patients were treated with steroids, and the use of biotherapies has increased over the last decade. Despite treatment, 49% of patients required liver transplantation and 24% died. Key Points • Acute severe hepatitis in adult-onset Still's disease (AOSD) is associated with liver transplantation and/or death in, respectively, 43% and 24% of cases. • Severe hepatitis is the inaugural manifestation of AOSD in half of cases. Diagnosis is difficult when extra-hepatic clinical manifestations are lacking. • The mechanism of hepatic necrosis in AOSD with severe hepatitis is unknown. Liver biopsy is not specific and should not delay treatment initiation. [ABSTRACT FROM AUTHOR]

Objective: The objective of the study was to assess the advantages of 18F-fluorodeoxyglucose (FDG) positron emission tomography and computed tomography with magnetic resonance (PET/CT-MR) in diagnosing and monitoring patients with adult-onset Still's disease (AOSD).Methods: Participants in this retrospective case-control study underwent whole-body 18F-FDG-PET/CT-MR imaging. All PET scans were qualitatively and semiquantitatively analyzed using standardized uptake values (SUVs) normalized to liver uptake, i.e., we calculated the ratio (SUVr) between the minimum, maximum, and mean SUVs for different organs and tissues and the mean SUV for the liver. Disease activity scores were assessed using Pouchot's criteria.Results: Eighteen patients diagnosed with AOSD and 24 controls (non-AOSD patients diagnosed with solid tumors, excluding lymphomas) were considered. A total of 38 PET/MR and nine PET/CT scans were analyzed. AOSD patients had higher SUVr than controls. All SUVr differed significantly between the patient and control group for bone marrow, and for the spleen, the only difference lacking statistical significance concerned the ratio of the minimum SUV for spleen to the mean SUV for liver. Though limited in number, AOSD responders to therapy showed lower uptakes during the period monitored. No correlations were found between Pouchot's scores and SUVr.Conclusion: Our data revealed higher spleen and bone marrow 18F-FDG uptakes on PET/CT and PET/MR images in AOSD patients than in controls. Together with clinical examinations and laboratory data, PET/CT and PET/MR seemed more reliable than Pouchot's score in assessing disease activity.

Objective: To analyze the clinical characteristics, laboratory indexes, treatments and outcome of the adult-onset Still's disease(AOSD). Methods: Retrospective analysis of clinical data was made in 26 cases of AOSD from Jan. 2010 up to present. Results: The main features of AOSD included high fever, skin rash, polyarthralgia, sore throat, lymphadenopathy, hepatosplenomegaly and elevated circulating levels of liver enzymes. Other changes in laboratory tests were elevations in white blood cell counts, neutrophils, erythrocyte sedimentation rate and serum ferritin, along with decreased hemoglobin. In addition to the treatment with nonsteroidal anti-inflammatory drugs, 24 cases were also treated with glucocorticoids, while 4 and 2 cases were given methotrexate and thunder god vine, respectively. One case died. Conclusions: The main manifestations of AOSD are fever, skin rash, arthralgia, sore throat, splenomegaly and lymphadenopathy. There is no specific criteria for the diagnosis of AOSD. Therapeutic regimens of AOSD include nonsteroidal anti-inflammatory drugs, glucocorticoids and immunosuppressants.

Objective: Adult-onset Still's disease (AOSD) is an autoinflammatory disorder leading to multiorgan involvements. We sought to investigate mood status and the health-related quality of life (HRQoL) in these patients. Methods: In this study, 82 AOSD patients and 82 age- and sex-matched healthy controls were included. Demographic and clinical data of recruited patients were collected. The Hospital Anxiety and Depression Scale (HADS) and Medical Outcomes Survey Short Form-36 (SF-36) were used to evaluate the mood status and quality of life, respectively. Spearman correlation and multivariable linear regression analyses were used to assess the disease-related risk factors associated with anxiety and depression. Results: Forty-four active and thirty-eight relieved patients were enrolled. We found that scores of both HADS anxiety (HADS-A) and depression (HADS-D) subscales in active AOSD were significantly higher than inactive patients, which were significantly higher than controls. Moreover, the HADS-A was positively correlated to the patient's global assessment (PGA), pain, and dosage of prednisone, and the HADS-D was positively correlated to systemic score, PGA, and pain. Female, high dosage of corticosteroids, and PGA more than 50 had a significant association with HADS-A score, while the sore throat and PGA more than 50 had a significant association with HADS-D score. Furthermore, AOSD patients' anxiety and depression had a negative impact on HRQoL. Conclusion: Active AOSD patients tended to be anxious and depressed, suffering from poorer HRQoL compared to patients in remission. Therefore, the evaluation of mental health and HRQoL should be included in AOSD patients' long-term management. Key Points • Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder leading to multiorgan involvement. This study was so far the first published research focuses on AOSD patients' mental involvement and health-related quality of life (HRQoL). • Active AOSD patients were more tended to be anxious and depressive and suffered from poorer HRQoL compared to inactive patients. • Patients' anxiety and depression were associated with impaired HRQoL. [ABSTRACT FROM AUTHOR]

Adult‐onset Still's disease (AOSD) is a rare inflammatory autoimmune disorder characterized by fever, skin rash, and arthralgia. Pulmonary artery hypertension (PAH) rarely occurs with AOSD and has not been reported in the absence of typical symptoms of AOSD. A 33‐year‐old woman was admitted to our hospital with dyspnoea on exertion. Although she had not had symptoms of AOSD for 18 months before her admission, she presented with gradually progressing PAH. Because she had no typical symptoms of AOSD, she was treated with pulmonary vasodilators. However, her PAH did not improve. At one month after vasodilator treatment, she developed a high fever with elevation of ferritin. We determined that her AOSD had relapsed. Immunosuppressants were started and both her AOSD and PAH quickly improved. PAH may develop in the absence of typical symptoms of AOSD and immunosuppressants may be effective in such a case.We report a patient previously diagnosed with adult‐onset still's disease (AOSD) who presented with pulmonary artery hypertension (PAH) but without typical symptoms of AOSD. Immunosuppressive agents rapidly improved PAH. [ABSTRACT FROM AUTHOR]

Adult-onset Still's disease (AOSD) is a systemic inflammatory disease characterized by cytokine storm. However, a diagnostic test for AOSD in clinical use is yet to be validated. The aim of our study was to identify non-invasive biomarkers with high specificity and sensitivity to diagnosis of AOSD. MicroRNA (miRNA) profiles in PBMC from new-onset AOSD patients without any treatment and healthy controls (HCs) were analyzed by miRNA deep sequencing. Plasma samples from 100 AOSD patients and 60 HCs were used to validated the expression levels of miRNA by qRT-PCR. The correlations between expression levels of miRNAs and clinical manifestations were analyzed using advanced statistical models. We found that plasma samples from AOSD patients showed a distinct miRNA expression profile. Five miRNAs (miR-142-5p, miR-101-3p, miR-29a-3p, miR-29c-3p, and miR-141-3p) were significantly upregulated in plasma of AOSD patients compared with HCs both in training and validation sets. We discovered a panel including 3 miRNAs (miR-142-5p, miR-101-3p, and miR-29a-3p) that can predict the probability of AOSD with an area under the receiver operating characteristic (ROC) curve of 0.8250 in training and validation sets. Moreover, the expression levels of 5 miRNAs were significantly higher in active AOSD patients compared with those in inactive patients. In addition, elevated level of miR-101-3p was found in AOSD patients with fever, sore throat and arthralgia symptoms; the miR-101-3p was also positively correlated with the levels of IL-6 and TNF-α in serum. Furthermore, five miRNAs (miR-142-5p, miR-101-3p, miR-29c-3p, miR-29a-3p, and miR-141-3p) expressed in plasma were significantly higher in AOSD patients than in sepsis patients (P < 0.05). The AUC value of 4-miRNA panel (miR-142-5p, miR-101-3p, miR-29c-3p, and miR-141-3p) for AOSD diagnosis from sepsis was 0.8448, revealing the potentially diagnostic value to distinguish AOSD patients from sepsis patients. Our results have identified a specific plasma miRNA signature that may serve as a potential non-invasive biomarker for diagnosis of AOSD and monitoring disease activity.

TNFAIP3 encodes the NF-κB regulatory protein A20. High-penetrance heterozygous mutations in TNFAIP3 cause a haploinsufficiency of A20 (HA20), inadequate inhibition of NF-κB pathway, and an early onset autoinflammatory disorder. However, the clinical phenotype of patients with HA20 varies greatly and clinical diagnoses prior to establishing the genetic cause, included both autoimmune and autoinflammatory conditions. Here, we present the first patient with HA20, who was previously diagnosed with AOSD but was later found to have a novel heterozygous variant in TNFAIP3 and who was successfully treated with anti-IL6 receptor biologic tocilizumab (RoActemra). We discovered a novel heterozygous mutation in TNFAIP3 c.1906C>T, not previously found in ExAC database. Further analysis shows that this single-nucleotide variant at the terminal residue of TNFAIP3 exon 7 produces an alternatively spliced mRNA resulting in p.His636fsTer1. Additional genetic analysis of family members shows that this variant does segregate with the inflammatory clinical phenotypes. Subsequent functional test show that NF-κB activation, measured as intracellular phosphorylation of p65 in CD14 + monocytes, was more enhanced in the patient compared with healthy controls (HC) following stimulation with LPS. This was associated with higher production of inflammatory cytokines by the patients PBMC in response to LPS and ATP and enhanced activation of NLRP3 inflammasome complex. Furthermore, increased activation of NLRP3 inflammasome was evident systemically, since we detected higher levels of ASC specks in patients’ sera compared with HC. Finally, we used population genetics data from GnomAD to construct a map of both genetic conservation and most probable disease-causing variants in TNFAIP3 which might be found in future cases of HA20.

TNFAIP3 encodes the NF-κB regulatory protein A20. High-penetrance heterozygous mutations in TNFAIP3 cause a haploinsufficiency of A20 (HA20), inadequate inhibition of NF-κB pathway, and an early onset autoinflammatory disorder. However, the clinical phenotype of patients with HA20 varies greatly and clinical diagnoses prior to establishing the genetic cause, included both autoimmune and autoinflammatory conditions. Here, we present the first patient with HA20, who was previously diagnosed with AOSD but was later found to have a novel heterozygous variant in TNFAIP3 and who was successfully treated with anti-IL6 receptor biologic tocilizumab (RoActemra). We discovered a novel heterozygous mutation in TNFAIP3 c.1906C>T, not previously found in ExAC database. Further analysis shows that this single-nucleotide variant at the terminal residue of TNFAIP3 exon 7 produces an alternatively spliced mRNA resulting in p.His636fsTer1. Additional genetic analysis of family members shows that this variant does segregate with the inflammatory clinical phenotypes. Subsequent functional test show that NF-κB activation, measured as intracellular phosphorylation of p65 in CD14 + monocytes, was more enhanced in the patient compared with healthy controls (HC) following stimulation with LPS. This was associated with higher production of inflammatory cytokines by the patients PBMC in response to LPS and ATP and enhanced activation of NLRP3 inflammasome complex. Furthermore, increased activation of NLRP3 inflammasome was evident systemically, since we detected higher levels of ASC specks in patients’ sera compared with HC. Finally, we used population genetics data from GnomAD to construct a map of both genetic conservation and most probable disease-causing variants in TNFAIP3 which might be found in future cases of HA20. [ABSTRACT FROM AUTHOR]