Adult-onset Still's Disease Research Articles

Adult-onset still’s disease with macrophage-activation syndrome presentation in a critically ill woman in the second trimester of pregnancy: A case report

Background: A rare inflammatory illness known as Adult-Onset Still’s Disease (AOSD) is typically characterized by a high fever, arthralgias, and a transient rash of salmon hue. Systemic immune hyperactivation syndrome known as Hemophagocytic Lymphohistiocytosis (HLH) can occur as a primary process in those with a genetic predisposition or it can be brought on by another disease, frequently a viral infection or cancer. When a rheumatologic condition serves as the trigger, secondary HLH is referred to as Macrophage Activation Syndrome (MAS). Reduced natural killer (NK) cell activity, increased soluble interleukin-2 receptor (sIL-2R), and generally, excessive cytokine production appear to be components of both AOSD and MAS pathogenesis.

Treatment of systemic juvenile idiopathic arthritis.

Systemic juvenile idiopathic arthritis (sJIA) is an inflammatory disease with hallmarks of severe systemic inflammation, which can be accompanied by arthritis. Contemporary scientific insights set this paediatric disorder on a continuum with its counterpart, adult-onset Still disease (AOSD). Patients with sJIA are prone to complications, including life-threatening hyperinflammation (macrophage activation syndrome (sJIA-MAS)) and sJIA-associated lung disease (sJIA-LD). Meanwhile, the treatment arsenal in sJIA has expanded markedly. State-of-the-art therapeutic approaches include biologic agents thattarget the IL-1 and IL-6 pathways. Beyond these, a range of novel agents are on the horizon, some of them already being used on a compassionate use basis, including JAK inhibitors and biologic agents thattarget IL-18, IFNγ, or IL-1β and IL-18 simultaneously. However, sJIA, sJIA-MAS and sJIA-LD still pose challenging conundrums to rheumatologists treatingpaediatric and adult patients worldwide. Although national and international consensus treatment plans exist for the treatment of 'classic' sJIA, the treatment approaches for early sJIA without arthritis, and forrefractory or complicated sJIA, are not well defined. Therefore, in this Review we outline current approaches for the treatment of sJIA and provide an outlook on knowledge gaps.

Biallelic mutations in the CFHR genes underlying atypical hemolytic uremic syndrome in a patient with catastrophic adult-onset Still's disease and recurrent macrophage activation syndrome: A case report

We report the fatal case of a 20-year-old woman with refractory adult-onset Still's disease (AOSD) accompanied by fulminant macrophage activation syndrome (MAS) and atypical hemolytic uremic syndrome (aHUS). Anakinra and tocilizumab temporarily controlled AOSD. In 2021, she presented to ICU with generalized tonic-clonic seizure, lymphocytic aseptic meningitis, and acute kidney injury. Despite hemodialysis and methylprednisolone, she developed another seizure, MAS, and disseminated intravascular coagulation (DIC). Following brief control, MAS flares —reflected by increased plasma CXCL9 and CXCL10— re-emerged and were controlled through dexamethasone, etoposide, cyclosporin and tofacitinib. No mutations were detected in haemophagocytic lymphohistiocytosis (HLH)-associated genes, nor in genes associated with periodic fever syndromes. Post-mortem genetic testing revealed loss-of-function biallelic deletions in complement factor H-related proteins (CFHR) genes, predisposing aHUS. This case underscores the importance of prompt genetic assessment of complement-encoding alleles, in addition to HLH-related genes, in patients with severe AOSD with recurrent MAS and features of thrombotic microangiopathy (TMA).

A Case Report on Adult - Onset Still’s Disease

Background: Adult-onset Still's disease (AOSD) is an uncommon systemic inflammatory condition with an unknown cause, presenting with a set of three main symptoms: recurrent high fevers, joint pain (sometimes accompanied by arthritis), and an evanescent skin rash.
 Case Report: We here describe a 38-year-old female patient who presented to the ER with complaints of fever on and off, body pain and swelling of multiple joints for 3 months, and a rash with itching all over the body for 1 month. Fever was associated with chills and rigors, negative rheumatological factors, and infections. Investigations of bone marrow analysis revealed a normal cell count and a slight increase in eosinophil precursors, without any abnormal cells or parasites. Based on the Yamaguchi criteria, the patient was diagnosed with AOSD.

Adult-onset Still's disease with Acute Kidney Injury Requiring Hemodialysis: A Case Report and Literature Review.

Adult-onset Still's disease (AOSD) is characterized by high spiking fever, evanescent rash, and arthritis. However, AOSD rarely presents with severe acute kidney injury (AKI). We herein present the case of a 56-year-old woman with new-onset AOSD who rapidly developed AKI. A physical examination and laboratory data revealed spiking fever, evanescent rash, thrombocytopenia, hyperferritinemia, and azotemia. The patient was diagnosed with AOSD complicated by AKI and macrophage activation syndrome. Treatment with high-dose steroids, hemodialysis, and plasma exchange successfully resolved her AKI. In this report, we review previously published reports on AOSD accompanied by AKI and discuss this rare complication in AOSD.

The landscape of innate and adaptive immune cell subsets in patients with adult-onset Still's disease.

Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disorder. The understanding of the changes in adaptive immune cells and the crosstalk between innate and adaptive immune systems in AOSD is limited. This study aimed to examine the peripheral immune cell composition and inflammatory protein levels in AOSD patients. Twenty-nine active AOSD patients were enrolled. Flow cytometry was used to analyze the cell populations in peripheral blood. Antibody chips were utilized to detect the protein expression profile in serum. In active AOSD patients, there was an increase in the percentage of classical and non-classical monocytes among peripheral blood mononuclear cells. The proportion of natural killer (NK) cells decreased, with an increase in CD56dim NK1 cells and a decrease in CD56bright NK2 cells compared with healthy controls (HC). The percentage of naïve central memory T cells was decreased, while the percentage of effector and effector memory T cells was increased among adaptive lymphocytes. The proportion of naïve B and memory B cells was decreased, while plasma cells were increased in AOSD patients, indicating activation of the adaptive immune system. Additionally, the serum levels of 40 proteins were elevated in AOSD patients, primarily involved in cytokine-cytokine receptor interaction, inflammatory response, and regulation of MAPK cascade. Our findings showed the activation of the innate and adaptive immune system in AOSD. The protein-protein interaction analysis suggested potential communication between innate and adaptive cell subsets. These findings provide new insights into the pathogenesis of the disease and the development of targeted therapies.

Care pathway analysis and evidence gaps in adult-onset Still's disease: interviews with experts from the UK, France, Italy, and Germany.

Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disease of unknown etiology. Published AOSD data are limited, and clinical guidelines were lacking until recently. Managing AOSD remains largely empirical with uncertainties and high variability about the optimal care pathway. Therefore, we used a qualitative approach to collect clinical judgments from the UK, Italy, France and Germany to inform the development of an agreed care pathway. Our work aimed to decrease the uncertainty associated with clinical practice, inform future research in AOSD, and help identify standardized definitions and outcomes in this population. Semi-structured interviews and thematic analysis were conducted. Eleven clinicians were interviewed between May and July 2022: four were based in Italy, three in the UK, two in France, and two in Germany. In this work, we identified the structure of the typical care pathway for AOSD patients, which can be used to inform future economic models in AOSD. The general structure of the pathway was similar across countries. Non-steroidal anti-inflammatory drugs are prescribed during the diagnostic workup while an additive approach is commonly used in confirmed cases: corticosteroids, conventional synthetic disease-modifying antirheumatic drugs, then biologic disease-modifying antirheumatic drugs (bDMARDs) (dose increased before switching). For severe presentations, more aggressive approaches with higher doses and early use of bDMARDs are used. The main elements of variation among countries and clinicians were the criteria used for diagnosis; order of bDMARDs and preferential treatments for articular and systemic patients; and tests for patient monitoring. There is also a lack of standardized outcome measures making comparisons and evidence synthesis challenging. We identified important evidence gaps for clinical practice, e.g., reliable tests or scores predictive of disease progression and treatment outcome, and recommendations for research, e.g., reporting of compliance rates and use of the Yamaguchi criteria for clinical study inclusion. Consensus is needed around the use of the Systemic score in clinical practice and the clinical utility of this score. A standardized definition of remission is also required in AOSD, and further research should look to identify and validate the specific laboratory markers to be considered when assessing remission.

Management of adult-onset Still's disease: evidence- and consensus-based recommendations by experts.

Adult-onset Still's disease (AOSD) is a rare condition characterized by fevers, rash, and arthralgia/arthritis; most doctors treating AOSD in the Netherlands treat <5 patients per year. Currently, there is no internationally accepted treatment guideline for AOSD. The objectives of this study were to conduct a Delphi panel aimed at reaching consensus about diagnostic and treatment strategies for patients with AOSD and to use the outcomes as a basis for a treatment algorithm. The Delphi panel brought together 18 AOSD experts: rheumatologists, internists and paediatricians. The Delphi process consisted of three rounds. In the first two rounds, online lists of questions and statements were completed. In the third round, final statements were discussed during a virtual meeting and a final vote took place. Consensus threshold was set at 80%. Two targeted literature searches were performed identifying the level of evidence of the consensus-based statements. Consensus was reached on 29 statements, including statements related to diagnosis and diagnostic tests, definition of response and remission, the therapy, the use of methotrexate and tapering of treatment. The panel consented on reduction of the use of glucocorticoids to avoid side effects, and preferred the use of biologics over conventional treatment. The role of IL-1 and IL-6 blocking agents was considered important in the treatment of AOSD. In this Delphi panel, a high level of consensus was achieved on recommendations for diagnosis and therapy of AOSD that can serve as a basis for a treatment guideline.

A Case of Adult-onset Still’s Disease Complicated with Macrophage Activation Syndrome and Diffuse Alveolar Hemorrhage

Adult-onset Still’s Disease (AOSD) is a rare inflammatory disease of unknown etiology characterized by high fever, skin rash, arthritis, elevated ferritin and organ involvement. Macrophage Activation Syndrome (MAS) can be seen as a rare, potentially fatal complication in AOSD. Here, we presented a case who was diagnosed with MAS due to general condition disorder, increased ferritin and cytopenia while being followed up with the diagnosis of chronic articular form ESH, and then developed diffuse alveolar hemorrhage (DAH) after a short time. We aimed to draw attention to rare complications after AOSD with this case report that showed a dramatic response to corticosteroid and tocilizumab treatment.

Successful complementary therapy with traditional Chinese medicine in a patient with Qi and Jin deficiency symptoms from adult-onset Still's disease: A case report

BackgroundAdult-onset Still's disease (AOSD) is a rare yet well-documented polygenic and systemic autoinflammatory disease characterized by recurrent spiking fever, transient skin rash, arthralgia, and sore throat. Traditional Chinese medicine (TCM) holds a significant role in complementary and alternative medicine. This study presents a unique case of a female AOSD patient with concurrent Qi and fluid deficiency syndrome who received combined treatment with formulated Zhu Ye Shi Gao Decoction (ZYSGD). Case presentationIn this case, a 28-year-old female patient presented with a 15-day history of fever and skin rash accompanied by sore throat, fatigue, myalgia, and arthralgia. Additionally, leucocytosis, aminotransferase abnormalities, and elevated inflammatory factor levels were observed. Infectious diseases, solid tumors, and hematological disorders were all ruled out. Anti-infective treatments proved ineffective, leading to the final diagnosis of AOSD. Glucocorticoid therapy provided only partial relief. Consequently, formulated ZYSGD and hepatoprotective drugs were added to the glucocorticoid treatment. Subsequently, the patient's symptoms and inflammatory biomarkers showed improvement. After discharge, the patient's condition remained stable while continuing the formulated ZYSGD in combination with 4 mg of Medrolol (qd) during a 10-month follow-up period. ConclusionThis case report suggests that formulated ZYSGD could be a viable option for complementary and alternative therapy for late-stage AOSD, especially in cases involving both Qi and body fluid imbalances.

Adult Onset Still’s Disease Revealed by a Cardiac Tamponade: A Case Report

Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disease of unknown origin with various clinical manifestations. In this article, we describe a case of 57-year-old presenting with Still's disease complicated by cardiac tamponade.&#x0D; This case highlights the importance of a prompt diagnosis of cardiac involvement in inflammatory diseases, as it can be fatal, and underlines the utility of echocardiographic evaluation not only in symptomatic patients, but also for the systematic detection of pericardial effusions. The case of hemodynamic compromise, it allows the provider to determine the timing, approach, and method of pericardial drainage due to cardiac tamponade being a very rare complication that requires an invasive approach.

Association between CCR2 and CCL2 expression and NET stimulation in adult-onset Still’s disease

Adult-onset Still’s disease (AOSD) is a systemic inflammatory disease characterized by the activation of monocyte-derived cells and the release of neutrophil extracellular traps (NET). C–C motif ligand (CCL) 2 is a chemoattractant that interacts with the C–C motif chemokine receptor (CCR) 2, resulting in monocyte recruitment and activation. CCL2 and CCR2 were measured with enzyme-linked immunosorbent assay (ELISA) at the serum level, and using immunohistochemical staining at the skin and lymph node tissues levels. THP-1 cell lysates were analyzed using western blot and ELISA after NET stimulation in patients with AOSD. Serum CCL2 level was higher in patients with AOSD than in patients with rheumatoid arthritis and healthy controls (HCs). In patients with AOSD, the percentage of CCL2-positive inflammatory cells in the skin tissues and CCR2-positive inflammatory cells in the lymph nodes increased, compared to that in HCs and in patients with reactive lymphadenopathy, respectively. NET induced in patients with AOSD enhanced the secretion of CCR2, higher CCR2 expression in monocytes, and the levels of interleukin (IL)-1β, IL-6, and IL-18 from THP-1 cells. Our findings suggest that upregulation of the CCL2–CCR2 axis may contribute to the clinical and inflammatory characteristics of AOSD.

Cigarette smoking and risk of adult-onset Still disease: a propensity score matching analysis.

Environmental factors play an important role in the pathogenesis of rheumatic diseases. Smoking is thought to be a risk factor for autoimmune rheumatic diseases. The purpose of the present study was to assess the association between smoking and adult-onset Still disease (AOSD) and the effect of smoking on outcomes of this disease. In this case-control study, patients with AOSD who met the Yamaguchi criteria, were older than 16 years at the disease onset and were in follow-up for at least 12 months were consecutively enrolled in the study. The outcome of AOSD was assessed by acquiring remission on treatment, remission off treatment, time to remission and rate of flare. The smoking status of participants was defined by direct or phone interviews. Individuals who had smoked daily for at least 6 months were defined as a smoker. We performed propensity score matching analyses by using four parameters, including age, sex, educational status and marital status. Propensity score matching resulted in 72 patients with AOSD and 216 matched controls. The number of ever smokers in the AOSD and control groups were 11 (15.3%) and 25 (11.6%) respectively. There was no significant increase in the risk of AOSD in multivariate analysis after adjustment for age, sex, marital status and educational level. There were no significant differences in the outcomes of AOSD between ever and never smokers. Smoking probably is not a risk factor for AOSD and did not affect the response to treatment.

Adult-Onset Still's Disease in Pregnancy: Lessons Learned and an Approach to Subsequent Pregnancies.

Adult-onset Still's disease (AOSD) is a rare autoinflammatory disorder with potential for life-threatening complications in pregnancy. Recently, biologic therapeutics have been increasingly used for treatment of AOSD, but there is little available data on the treatment of AOSD in pregnancy. Here we report a 23-year-old primigravid patient with a history of AOSD who presented at 20 weeks of gestation with fever, arthralgias, rash, fatigue, and highly elevated ferritin, concerning for AOSD flare. She was treated with tocilizumab, an interleukin-6 receptor antagonist, with rapid clinical and laboratory improvement; however, she underwent iatrogenic preterm delivery at 34 weeks of gestation for fetal distress, which was attributed to placental injury. In a subsequent pregnancy, she was treated with tocilizumab throughout and had an uncomplicated term delivery with normal labs and no AOSD flare. This case highlights that the use of tocilizumab may be effective to reduce the risk of AOSD flare during pregnancy.

Pyroptosis: the potential eye of the storm in adult-onset Still's disease.

Pyroptosis, a form of programmed cell death with a high pro-inflammatory effect, causes cell lysis and leads to the secretion of countless interleukin-1β (IL-1β) and IL-18 cytokines, resulting in a subsequent extreme inflammatory response through the caspase-1-dependent pathway or caspase-1-independent pathway. Adult-onset Still's disease (AOSD) is a systemic inflammatory disease with extensive disease manifestations and severe complications such as macrophage activation syndrome, which is characterized by high-grade inflammation and cytokine storms regulated by IL-1β and IL-18. To date, the pathogenesis of AOSD is unclear, and the available therapy is unsatisfactory. As such, AOSD is still a challenging disease. In addition, the high inflammatory states and the increased expression of multiple pyroptosis markers in AOSD indicate that pyroptosis plays an important role in the pathogenesis of AOSD. Accordingly, this review summarizes the molecular mechanisms of pyroptosis and describes the potential role of pyroptosis in AOSD, the therapeutic practicalities of pyroptosis target drugs in AOSD, and the therapeutic blueprint of other pyroptosis target drugs.

Adult-Onset Still’s Disease after COVID-19 Vaccination: A Case Report and Review

To overcome the global pandemic of coronavirus disease 2019 (COVID-19), COVID-19 vaccination has been developed and distributed. Many people have received the vaccination worldwide. However, there are some vaccinated individuals who complain of side effects due to COVID-19 vaccination. We report the case of a patient who developed adult-onset Still’s disease (AOSD) after receiving the messenger RNA COVID-19 vaccine. A 21-year-old male patient without a previous medical history developed a fever on the day of the first dose of the vaccine. He had persistent fever, arthralgia of the knee and wrist, hyperferritinemia, transient skin rash, and negative test results for rheumatoid factor or antinuclear antibody. Positron emission tomography-computed tomography scan showed lymphadenopathies with reactive patterns and no malignancy. His symptoms and laboratory abnormalities gradually improved with glucocorticoid, cyclosporine, methotrexate, and tocilizumab treatment. Although its causality is still not confirmed, AOSD should be considered in a case that meets the diagnostic criteria after COVID-19 vaccination.

Epidemiology, characteristics, treatments, and outcomes of adult-onset Still's disease in Afro-Caribbeans: Results from a population-based study in Martinique, French West Indies

ObjectivesTo describe the epidemiology, characteristics, response to initial treatment, and outcomes of Adult-Onset Still's disease (AOSD) in the Afro-Caribbean population of Martinique with free and easy access to specialised care. MethodsWe conducted a retrospective study from 2004 to 2022 in the island of Martinique, French West-Indies which total population was 354 800 in 2021. Patients were identified from multiple sources including standardised databases. To be included, patients had to be residents of the island and fulfilled Yamaguchi and/or Fautrel's criteria for AOSD, or have a compatible disease course, without a diagnosis of cancer, auto-immune disease or another auto-inflammatory disorder. Date of diagnosis, clinical and biological characteristics, treatments, and outcomes were collected. ResultsThe prevalence was 7.6/100 000 inhabitants in 2021. The mean incidence was 0.4/100 000 during study period. Thirty-three patients (70.6% females) with a median follow-up of 35 months [7.5 to 119] were included. Twenty-six patients (78.8%) had a systemic pattern. Patients with a systemic monocyclic pattern had significantly more polyarticular involvement than patients with systemic polycyclic pattern (p = 0.016). Pulmonary involvement occurred in 51.5% of patients at diagnosis and systemic Pouchot score has been identified as an independent predictive factor for pulmonary involvement; OR of 3.29 [CI 95% 1.20; 9.01]. At first flare, all patients but one received oral glucocorticoids, 11 patients (32.4%) received intravenous glucocorticoids pulse and 12 patients (33%) received anti-IL1 therapy. Nineteen patients (57%) relapsed in a median time of 9 months [6 to 12] Three patients (9%) developed hemophagocytosis lymphohistiocytosis, fatal in 1 case. All deceased patients (n = 4, 11.76%) belonged to the systemic polycyclic pattern, with an event-free survival of 13.6 months [IQR 5.7; 29.5] ConclusionAOSD in the Afro-Caribbean population of Martinique shares some similarities with other ethnic groups, but exhibit differences, such as a high proportion of lung involvement. Comparative studies are needed to confirm these results.

Tocilizumab-induced mucosal injury in the terminal ileum mimicking intestinal Behçet's disease: A case report.

Tocilizumab, a humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody, is used for the treatment of adult-onset Still disease (AOSD). Despite its efficacy in many clinical situations, concerns have been raised regarding intestinal mucosal injury in patients receiving tocilizumab. A 64-year-old woman with a history of AOSD was admitted to our hospital with hematochezia. She had AOSD for 15 years and underwent treatment with biweekly tocilizumab 9 months prior to admission. Colonoscopy revealed a large punched-out ulcer in the terminal ileum. On pathological evaluation, nonspecific enteritis with lymphocytes and eosinophils were seen. Based on the location and shape of the lesion, we suspected intestinal Behçet's disease. However, the ulcer reduced in size over time by discontinuation of tocilizumab without additional drug treatment, indicating that it was a drug-induced ulcer. The patient was diagnosed with tocilizumab-induced small intestinal ulcer. The patient treated with the discontinuation of tocilizumab. The discontinuation of tocilizumab resulted in ulcer scarring. There was no recurrence of hematochezia. Tocilizumab can cause deep ulcerative lesions in the terminal ileum, which may resemble intestinal Behçet's disease. It is important to continuously monitor abdominal symptoms during tocilizumab therapy and aggressively perform colonoscopy when hematochezia or abdominal pain is observed.

The role of interleukin-18 and interleukin-18 binding protein in K/BxN serum transfer-induced arthritis.

Interleukin-18 is a proinflammatory cytokine, the activity of which is regulated by its natural inhibitor, IL-18 binding protein (IL-18BP). Elevated circulating levels of IL-18 have been observed in patients with systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD), two conditions associated with dysregulated innate immune responses. This study examines the expression and function of IL-18 and IL-18BP in K/BxN serum transfer arthritis (STA), a model that is uniquely dependent on innate immune responses. Naïve and serum transfer-induced arthritis (STA) wild-type (WT) mice were used to examine the articular levels of IL-18 and IL-18BP mRNA by RT-qPCR. The cellular sources of IL-18BP in the joints were determined by using Il18bp-tdTomato reporter knock-in mice. The incidence and severity of arthritis, including mRNA levels of different cytokines, were compared in IL-18BP or IL-18 knock-out (KO) mice and their WT littermates. IL-18 and IL-18BP mRNA levels were significantly increased in arthritic as compared to normal joints. Synovial neutrophils, macrophages, and endothelial cells represented the cellular sources of IL-18BP in arthritic joints, whereas IL-18BP production was limited to endothelial cells in non-inflamed joints. The incidence and severity of arthritis were similar in IL-18BP KO and IL-18 KO compared to their WT littermates. Transcript levels of different inflammatory cytokines were not different in the two KO mouse lines compared to WT mice. Although IL-18 and IL-18BP levels were increased in arthritic joints, our results show that the IL-18/IL-18BP balance is not involved in the regulation of STA.

Fulminant myocarditis with adult-onset Still's disease: case-based review.

Myocarditis has been reported as a life-threatening complication of adult-onset Still's disease (AOSD), but fulminant myocarditis with AOSD is very rare. We hereby report a case of a 43-year-old female with fulminant myocarditis with AOSD. She had a refractory AOSD and cardiogenic shock with markedly elevated ferritin level up to 67,370 ng/mL. She was successfully treated with canakinumab and mechanical circulatory support (MCS) such as venoarterial extracorporeal membrane oxygenation and Impella CP. We also reviewed the previous cases of fulminant myocarditis with AOSD published from 1976 to December 2022, and only 8 cases of fulminant myocarditis with AOSD have been reported. The characteristics of these cases showed that the average age at presentation was 37.6 years (range 24-47 years). The time to myocarditis from the onset of AOSD ranged from 2 weeks to 2 years; however, most cases developed myocarditis within 1 year. Initial presenting symptoms included fever, dyspnea, chest pain, myalgia, rash, and sore throat. The median peak ferritin was 13,000 ng/mL. Left ventricular ejection fractions were not greater than 35%. Our case was the first reported case successfully treated with canakinumab and MCS. This review suggests that myocarditis may be an early phase of the complication in patients with AOSD, and the severity of AOSD may correlate with the severity of myocarditis. Canakinumab for AOSD and MCS for fulminant myocarditis may be one of the choices for overcoming the comorbidities.