Adult-onset Still's disease with concurrent thrombotic microangiopathy: Observations from pooled analysis for an uncommon finding.

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.

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.

Interleukin-18: a biomarker with therapeutic potential in adult-onset Still's disease.

INTRODUCTION: Adult-onset Still's disease (AOSD) is an autoinflammatory disease driven by the innate immune response. Given the ambiguity in clinical presentation and lack of specific diagnostic biomarkers, AOSD diagnosis is usually delayed in the early stage. Because AOSD is a rare disease with clinical heterogeneity, there is no consensus on its treatment currently. This review summarizes the current research evidence regarding the pathogenic role and the diagnostic or therapeutic potential of interleukin (IL)-18 in AOSD. AREAS COVERED: We searched the MEDLINE database using the PubMed interface and reviewed English-language literature from 1971 to 2022. This review focusing on IL-18 discusses its pathogenic role and clinical implications in AOSD. EXPERT OPINION: NLRP3-inflammasome activation with IL-18 overproduction plays a pathogenic role in AOSD. IL-18 is closely linked to the clinical manifestations and disease activity of AOSD and may be a diagnostic biomarker. Given its pathogenic role in AOSD, IL-18 could become a potential therapeutic target. IL-18 binding protein (IL-18BP) negatively regulates the biological activity of IL-18 by inhibiting IL-18 signaling, and a clinical trial revealed that IL-18BP (Tadekinig alfa) treatment was well-tolerated and effective for AOSD. Recently, monoclonal antibodies against IL-18 have been under evaluation in a phase 1b trial.

Expanding the spectrum of the hyperferritinemic syndrome, from pathogenic mechanisms to clinical observations, and therapeutic implications.

From the introduction of hyperferritinemic syndrome concept, a growing body of evidence has suggested the role of ferritin as a pathogenic mediator and a relevant clinical feature in the management of patients with inflammatory diseases. From a pathogenic point of view, ferritin may directly stimulate the aberrant immune response by triggering the production of pro-inflammatory mediators in inducing a vicious pathogenic loop and contributing to the occurrence of cytokine storm syndrome. The latter has been recently defined as a clinical picture characterised by elevated circulating cytokine levels, acute systemic inflammatory symptoms, and secondary organ dysfunction beyond that which could be attributed to a normal response to a pathogen It is noteworthy that the occurrence of hyperferritinemia may be correlated with the development of the cytokine storm syndrome in the context of an inflammatory disease. In addition to adult onset Still's disease, macrophage activation syndrome, catastrophic anti-phospholipids syndrome, and septic shock, recent evidence has suggested this association between ferritin and life-threatening evolution in patients with systemic lupus erythematosus, with anti-MDA5 antibodies in the context of poly-dermatomyositis, with severe COVID-19, and with multisystem inflammatory syndrome. The possible underlying common inflammatory mechanisms, associated with hyperferritinemia, may led to the similar clinical picture observed in these patients. Furthermore, similar therapeutic strategies could be suggested inhibiting pro-inflammatory cytokines and improving long-term outcomes in these disorders. Thus, it could be possible to expand the spectrum of the hyperferritinemic syndrome to those diseases burdened by a dreadful clinical picture correlated with hyperferritinemia and the occurrence of the cytokine storm syndrome. In addition, the assessment of ferritin may provide useful information to the physicians in clinical practice to manage these patients. Therefore, ferritin may be considered a relevant clinical feature to be used as biomarker in dissecting the unmet needs in the management of these disorders. Novel evidence may thus support an expansion of the spectrum of the hyperferritinemic syndrome to these diseases burdened by a life-threatening clinical picture correlated with hyperferritinemia and the occurrence of the cytokine storm syndrome.

[Recommendations of diagnosis and treatment of adult-onset Still's disease in China].

Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disorder. In China, standardized diagnosis and treatment for AOSD is insufficient. Based on the evidence from China and other countries, Chinese Rheumatology Association developed standardization of diagnosis and treatment of AOSD in China. The purpose is to standardize the methods for diagnosis of AOSD, treatment strategies, and reduce misdiagnosis, missed diagnosis and irreversible damage.

[Still's syndrome-similarities and differences between the juvenile and adult forms]. / Morbus Still ­ Ähnlichkeiten und Differenzen zwischen juveniler und adulter Form.

Still's syndrome includes systemic juvenile idiopathic arthritis (sJIA) and the adult form of Still's disease (adult-onset Still's disease, AOSD). Except for age, there are many similarities between sJIA and AOSD. A biphasic disease model is currently put forth. At disease onset, autoinflammation predominates, which is caused by dysregulation of the innate immune system. Later on, the disease can progress to a chronic-articular form, which is predominantly mediated by the adaptive immune system and is consequently due to autoimmunity. The "window-of-opportunity" hypothesis is based on this biphasic model and supports the assumption that an early, targeted therapy with cytokine blockade can prevent disease progression to chronic destructive arthritis. Macrophage activation syndrome (MAS) is a serious complication of the so-called cytokine storm during the systemic phase of the disease. Clinically, there are many similarities between sJIA and AOSD. Recurrent fever, a fleeting, salmon-colored rash, and arthralgia/arthritis are common signs and symptoms of both sJIA and AOSD. The few differences are mainly related to the therapies and their side effects in children versus adults. In addition, the contribution of genetics to pathogenesis is more pronounced in sJIA compared to AOSD, but there are also smooth transitions in this respect and both diseases are heavily influenced by exogenous factors such as microbial triggers. Future research aspects could include additional investigation of these triggers such as viruses, bacteria, or dysbiosis of the human microbiome.

Circulating regulatory T cells in adult-onset Still's disease: Focusing on their plasticity and stability.

We investigated the characteristics of regulatory T cells in adult-onset Still's disease (AOSD) with a focus on their plasticity, stability and relationship to disease severity. The proportion of circulating CD4+ CD25+ forkhead box protein 3 (FoxP3+ ) cells (Tregs ) and intracellular expression of effector cytokines, including interferon (IFN)-γ, interleukin (IL)-17 and IL-4, was analysed in 27 untreated patients with AOSD (acute AOSD), 11 of the 27 patients after remission and 16 healthy controls (HC) using flow cytometry. The suppressive ability of Tregs was also evaluated. Regression analyses of the results were performed. The proportion of Tregs was significantly lower in patients with acute AOSD than in the HC. The expression levels of IFN-γ, IL-17 and IL-4 in Tregs were significantly increased in patients with acute AOSD. IFN-γ and IL-4 expression levels were inversely correlated with the proportion of Tregs and positively correlated with serum ferritin levels. Decreased expression of FoxP3 in CD4+ CD25+ cells, which was correlated with increased expression of IL-17, and impaired suppressive function were observed in Tregs in acute AOSD. However, these aberrant findings in Tregs , including the reduced circulating proportion and functional ability and altered intracellular expression levels of cytokines and FoxP3, were significantly improved after remission. In acute AOSD, Tregs show plastic changes, including effector cytokine production and reductions in their proportion and functional activity. IFN-γ and IL-4 expression levels in Tregs may be associated with disease severity. Also, down-regulation of FoxP3 may be related to IL-17 expression in Tregs . Importantly, the stability of Tregs can be restored in remission.

Adult-onset Still's disease in Poland - a nationwide population-based study.

INTRODUCTION: Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology, which affects young adults and is associated with multiple organ involvement and life-threatening complications. The aim of the study was to establish the incidence and prevalence of AOSD in Poland, and factors related to this disease among hospitalized patients. MATERIAL AND METHODS: A retrospective, population-based study was conducted, using data from hospital discharge records compiled by the National Institute of Public Health in 2009-2018. RESULTS: Based on hospitalization records and census data in a group of the 1,050 patients included in the study, women were predominant (60%) and patients' mean and median ages at hospitalization were 42 (95% CI: 40.8-42.8) and 38 years, respectively. The average annual incidence rate of AOSD during the 10-year period was established at the level of 0.32/100,000 (95% CI: 0.30-0.34), and the point prevalence at the end of 2018 was 2.7/100,000. The most common comorbidities were: cardiovascular diseases (14%), diseases of the musculoskeletal system and connective tissue (14%), endocrine, nutritional and metabolic diseases (9%). CONCLUSIONS: AOSD is a rare disease Poland with gender and territorial differences in incidence ratek, and predominance of cardiovascular diseases among comorbidities. The presented data may be useful for comparisons of the Polish population with other geographical regions. Predominance of patients from urban regions and predominance of women may suggest environmental and personal factors in AOSD development; however, further research seems to be necessary.

Current and emerging biological therapy in adult-onset Still's disease.

Adult-onset Still's disease (AOSD) is a rare, but characteristic non-familial, multi-genic systemic auto-inflammatory disorder, characterized by high spiking fever, salmon-like evanescent skin rash, polyarthritis, sore throat, hyperferritinemia and leucocytosis. The hallmark of AOSD is a cytokine storm triggered by dysregulation of inflammation. Nowadays, with advances in anti-cytokine biologic agents, the treatment of AOSD is no longer limited to NSAIDs, glucocorticoids or conventional synthetic DMARDs. In this review, we focussed on the roles of these cytokines in the pathogenesis of AOSD and summarized the current and emerging biological therapy.

The clinical heterogeneity of adult onset Still's disease may underlie different pathogenic mechanisms. Implications for a personalised therapeutic management of these patients.

Adult-onset Still's disease (AOSD) is a rare inflammatory disease of unknown aetiology usually affecting young adults and manifesting with a clinical triad of spiking fever, arthritis, and evanescent cutaneous rash. AOSD may be considered a highly heterogeneous disease, despite a similar clinical presentation, the disease course may be completely different. Some patients may have a single episode of the disease whereas others may evolve toward a chronic course and experience life-threatening complications. On these bases, to dissect the clinical heterogeneity of this disease, four different subsets were identified combining the manifestations at the beginning with possible diverse outcomes over time. Each one of these derived subsets would be characterised by a prominent different clinical feature from others, thus proposing dissimilar underlying pathogenic mechanisms, at least partially. Consequently, a distinct management of AOSD may be suggested to appropriately tailor the therapeutic strategy to these patients, according to principles of the precision medicine. These findings would also provide the rationale to recognise a different genetic and molecular profile of patients with AOSD. Taking together these findings, the basis for a precision medicine approach may be suggested in AOSD, which would drive a tailored therapeutic approach in these patients. A better patient stratification may also help in arranging specific designed studies to improve the management of patients with AOSD. Behind these different clinical phenotypes, distinct endotypes of AOSD may be suggested, probably differing in pathogenesis, outcomes, and response to therapies.

Adult macrophage activation syndrome-haemophagocytic lymphohistiocytosis: 'of plasma exchange and immunosuppressive escalation strategies' - a single centre reflection.

OBJECTIVE: In the context of systemic autoimmunity, that is systemic lupus erythematosus (SLE) or adult-onset Still's disease (AOSD), secondary haemophagocytic lymphohistiocytosis (HLH; also referred to as macrophage activation syndrome (MAS) or more recently MAS-HLH) is a rare and potentially life-threatening complication. Pathophysiological hallmarks are aberrant macrophage and T cell hyperactivation and a systemic cytokine flare, which generate a sepsis-like, tissue-damaging, cytopenic phenotype. Unfortunately, for adult MAS-HLH we lack standardized treatment protocols that go beyond high-dose corticosteroids. Consequently, outcome data are scarce on steroid refractory cases. Aside from protocols based on treatment with calcineurin inhibitors, etoposide, cyclophosphamide and anti-IL-1, favourable outcomes have been reported with the use of intravenous immunoglobulin (IvIG) and plasma exchange (PE). METHODS: Here we report a retrospective series of steroid refractory MAS-HLH, the associated therapeutic regimes and outcomes. RESULTS: In this single-centre experience, 6/8 steroid refractory patients survived (median follow-up: 54.4 (interquartile range: 23.3-113.3) weeks). All were initially treated with PE, which induced partial response in 5/8 patients. Yet, all patients required escalation of immunosuppressive therapies. One case of MAS-HLH in new-onset AOSD had to be escalated to etoposide, whereas most SLE-associated MAS-HLH patients responded well to cyclophosphamide. Relapses occurred in 2/8 cases. CONCLUSION: Together, early use of PE is at most a supportive measure, not a promising monotherapy of adult MAS-HLH. In refractory cases, conventional cytoreductive therapies (i.e. cyclophosphamide and etoposide) constitute potent and reliable rescue approaches, whereas IvIG, anti-thymoglobulin, and biologic agents appear to be less effective.

[Adult-onset Still's disease complications]. / Complications de la maladie de Still de l'adulte.

Adult-onset Still's disease (AOSD), first described in 1971 by Bywaters, is a rare systemic auto-inflammatory disorder of unknown etiology, characterized by a symptomatic triad associating prolonged fever, polyarthritis and rash. The management of this disease has significantly improved since its first description, and, although the overall prognosis of the AOSD is good, with a low attributable mortality, below 3% (but up to 18% depending on the series), some rare complications are still possible, can be life-threatening and change the prognosis of the disease. A literature search was performed to review AOSD's complications: reactive hemophagocytic lymphohystiocytosis, coagulation disorders, fulminant hepatitis, cardiovascular (pericarditis, myocarditis, HTAP) or pulmonary complications, neurologic, renal complications, and AA amyloidosis. For most of AOSD-related complications, corticosteroids remain the first-line treatment, in association with supportive care measures in case of severe complications. In case of inadequate response, multidisciplinary care with concil from a referral center is advised, and IL-1 or IL-6 blockers, but also ciclosporine, are the molecule to use in second intention.

Autoinflammatory Pathogenesis and Targeted Therapy for Adult-Onset Still's Disease.

Adult-onset Still's disease (AOSD) is a rare multisystem autoinflammatory disorder of unknown etiology. AOSD is generally characterized by high spiking fever, arthralgia or arthritis, skin rash, leukocytosis, and hyperferritinemia. Traditionally, AOSD has been treated with non-steroidal anti-inflammatory drugs, corticosteroids, and immunosuppressants. An increasing number of studies have shown that proinflammatory cytokines, such as interleukin-1ß, -18, -6, and tumor necrosis factor-α, play key roles in AOSD and may serve as therapeutic targets. In the current review, we provided insights into the roles of these cytokines in the pathogenesis of AOSD and also provided a commentary on the clinical studies of biologic therapy against AOSD.

Managing Adult-onset Still's disease: The effectiveness of high-dosage of corticosteroids as first-line treatment in inducing the clinical remission. Results from an observational study.

To assess the effectiveness of the treatment with high dosage of corticosteroids (CCSs), as first-line therapy, in inducing remission in naïve Adult-onset Still's disease (AOSD) patients compared with low dosage of CCSs, after 6 months. To further evaluate the rate of patients maintaining the remission and the rate of CCSs discontinuation, after additional 12 months of follow-up.A retrospective evaluation of patients prospectively followed was designed to compare the rate of clinical remission in naïve AOSD patients treated with high dosages of CCSs (0.8-1 mg/kg/day of prednisone-equivalent) or low dosage of CCSs (0.2-0.3 mg/kg/day of prednisone-equivalent), after 6 months. An additional analysis was performed to compare the rate of monocyclic pattern between these groups, after further 12 months of follow-up.The clinical remission was achieved in a higher percentage of patients treated with the first-line treatment with high dosage of CCSs than treated the first-line treatment with low dosage of CCSs. At the end of 18 months of follow-up, a larger percentage of patients treated the first-line treatment with high dosage of CCSs was classified as monocyclic pattern and discontinued CCSs when compared with patients treated the first-line treatment with low dosage of CCSs. Patients defined as CCSs non-responder were treated with methotrexate (MTX)+CCSs or with combination therapy CCSs+MTX+biologic drug. The clinical remission was observed in a percentage of these patients.We showed the effectiveness of the first-line treatment with high dosage of CCSs in inducing clinical remission in naïve AOSD patients when compared with the first-line treatment with low dosage of CCSs. The first-line treatment with high dosage of CCSs was also associated with the achievement of monocyclic pattern and CCSs discontinuation, after 18 months of follow-up.