Routine biomarker profile for the prediction of clinical phenotypes of adult-onset Still's disease using unsupervised clustering algorithm.

AIM: This study addresses the challenge of predicting the course of Adult-onset Still's disease (AoSD), a rare systemic autoinflammatory disorder of unknown origin. Precise prediction is crucial for effective clinical management, especially in the absence of specific laboratory indicators. METHODS: We assessed the effectiveness of combining traditional biomarkers with the k-medoids unsupervised clustering algorithm in forecasting the various clinical courses of AoSD-monocyclic, polycyclic, or chronic articular. This approach represents an innovative strategy in predicting the disease's course. RESULTS: The analysis led to the identification of distinct patient profiles based on accessible biomarkers. Specifically, patients with elevated ferritin levels at diagnosis were more likely to experience a monocyclic disease course, while those with lower erythrocyte sedimentation rate could present with any of the clinical courses, monocyclic, polycyclic, or chronic articular, during follow-up. CONCLUSION: The study demonstrates the potential of integrating traditional biomarkers with unsupervised clustering algorithms in understanding the heterogeneity of AoSD. These findings suggest new avenues for developing personalized treatment strategies, though further validation in larger, prospective studies is necessary.

Adult-Onset Still's Disease (AOSD): Advances in Understanding Pathophysiology, Genetics and Emerging Treatment Options.

Adult-onset Still's disease (AOSD) is a multisystemic complex disorder clinically characterised by episodes of spiking fever, evanescent rash, polyarthritis or diffuse arthralgias; multiorgan involvement may develop according to the hyper-inflammatory extent. The pathogenesis of AOSD is not completely recognised. The central role of macrophage activation, which results in T helper 1 (Th1) cell cytokine activation, is well established. Pro-inflammatory cytokines such as interleukin (IL)-1, IL-6 and IL-18 play a fundamental role in disease onset and progression. The disease may develop in both children and adults with overlapping clinical features, and although several subsets depending on the clinical manifestations and the cytokines expressed have been identified, the dichotomy between systemic juvenile idiopathic arthritis (sJIA) and AOSD nowadays has been overcome, and the pathology is considered a disease continuum between ages. Various therapeutic approaches have been evaluated thus far, and different compounds are under assessment for AOSD treatment. Historically, glucocorticoids have been employed for treating systemic manifestations of Still's disease, while conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) demonstrated efficacy in controlling the articular manifestations. Currently, biological (b) DMARDs are widely employed; IL-1 inhibitors such as anakinra and canakinumab have proven to have high efficacy and an excellent safety profile and the anti-IL-6 tocilizumab is approved for sJIA, with several trials and longitudinal studies confirming its efficacy and safety. Moreover, in the light of the 'window of opportunity', new evidence showed that the earlier these treatments are initiated, the sooner clinical inactivity can be achieved. Other treatment options are being considered since several molecules involved in the disease pathophysiology can be targeted through various mechanisms. This review will provide a broad overview of AOSD pathophysiology, insights into specific organ manifestations and the currently available treatments with the identification of potential therapeutic targets involved in AOSD pathogenesis will be outlined.

Optimal time of starting tocilizumab in acute phase of adult-onset Still's disease and comparison of its efficacy with that of methotrexate: a case series and a review of the literature.

Adult-onset still's disease is a rare condition that is generally treated by glucocorticoids. Importantly, due to the limited established treatments, glucocorticoid-refractory cases are particularly difficult to treat. Between December 2009 and August 2022, nine patients with adult-onset Still's disease were treated with tocilizumab (tocilizumab group). The therapeutic efficacy and safety of tocilizumab initiation in the acute phase were evaluated in cases of initial onset and recurrence. We also compared the efficacy of tocilizumab with that of methotrexate (methotrexate group, n = 13), which has been the drug of choice for adjunctive therapy. Tocilizumab demonstrated the expected efficacy in all four patients who received it at relapse and in three of the five patients who received it at the initial onset. However, two patients developed macrophage activation syndrome following treatment. A comparison of treatment effects between the methotrexate and tocilizumab groups revealed that the ferritin and C-reactive protein levels, severity score, and glucocorticoid doses decreased over time in both groups; nonetheless, the tocilizumab group experienced a more stable effect. Tocilizumab is undoubtedly a valuable treatment option for adult-onset Still's disease, especially when administered at relapse. This suggests that it shows both high safety and good efficacy. Nevertheless, a larger sample size is required to validate the efficacy and safety of tocilizumab compared with those of the existing alternatives. Key Points • We examined the significance of TCZ in terms of therapeutic efficacy, reduction in glucocorticoid usage, and safety in patients with AOSD. • We compared the therapeutic efficacy of TCZ with that of MTX, which is often used to treat glucocorticoid-resistant AOSD. • TCZ is undoubtedly a valuable treatment option for AOSD, especially when administered at relapse, suggesting both high safety and good efficacy.

Recent advances and evolving concepts in Still's disease.

Still's disease is a rare inflammatory syndrome that encompasses systemic juvenile idiopathic arthritis and adult-onset Still's disease, both of which can exhibit life-threatening complications, including macrophage activation syndrome (MAS), a secondary form of haemophagocytic lymphohistiocytosis. Genetic insights into Still's disease involve both HLA and non-HLA susceptibility genes, suggesting the involvement of adaptive immune cell-mediated immunity. At the same time, phenotypic evidence indicates the involvement of autoinflammatory processes. Evidence also implicates the type I interferon signature, mechanistic target of rapamycin complex 1 signalling and ferritin in the pathogenesis of Still's disease and MAS. Pathological entities associated with Still's disease include lung disease that could be associated with biologic DMARDs and with the occurrence of MAS. Historically, monophasic, recurrent and persistent Still's disease courses were recognized. Newer proposals of alternative Still's disease clusters could enable better dissection of clinical heterogeneity on the basis of immune cell profiles that could represent diverse endotypes or phases of disease activity. Therapeutically, data on IL-1 and IL-6 antagonism and Janus kinase inhibition suggest the importance of early administration in Still's disease. Furthermore, there is evidence that patients who develop MAS can be treated with IFNγ antagonism. Despite these developments, unmet needs remain that can form the basis for the design of future studies leading to improvement of disease management.

The latest advances in the use of biological DMARDs to treat Still's disease.

INTRODUCTION: Currently, the therapeutic management of Still's disease, a multisystemic inflammatory rare disorder, is directed to target the inflammatory symptoms and signs of patients. The treatment varies from glucocorticoids to disease-modifying antirheumatic drugs (DMARDs), both conventional synthetic and biological (bDMARDs). Usually, in refractory patients, bDMARDs are administered. AREAS COVERED: Among bDMARDs, IL-1 and IL-6 inhibitors are frequently used, as data reported from both clinical trials and 'real-life' experiences. Recently, innovative therapeutic strategies have suggested an early administration of bDMARDs to increase the rate of clinical response and drug-free remission. Some new targets have been also proposed targeting IL-18, IFN-γ, and JAK/STAT pathway, which could be applied to Still's disease and its life-threatening evolution. EXPERT OPINION: Many lines of evidence improved the knowledge about the therapeutic management of Still's disease with bDMARDs. However, many unmet needs may be still highlighted which could provide the basis to arrange further specific research in increasing the rate of clinical response. In fact, Still's disease remains a highly heterogeneous disease suggesting possible diverse underlying pathogenic mechanisms, at least partially, and consequent different therapeutic strategies. A better patient stratification may help in arranging specific studies to improve the long-term outcome of Still's disease.

Clinicopathologic Features of Adult-onset Still's Disease Complicated by Severe Liver Injury.

Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder. Severe liver injury has rarely been reported, although liver enzyme elevation is a common complication of AOSD. We herein report four cases of relapsed AOSD with severe liver disorder by tapering or terminating corticosteroids. Liver specimens revealed robust infiltration of inflammatory cells throughout the lobule, especially cluster of differentiation (CD) 8-positive cells. Relapsed AOSD was refractory to corticosteroid reintroduction and required immunosuppressants. Severe liver injury with AOSD is pathologically characterized by extensive lobular infiltration of CD8-positive cells, and we should consider additive immunosuppressive agents on corticosteroids for 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.

BACKGROUND: Adult-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 PRESENTATION: In 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. CONCLUSION: This 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.

Still's disease continuum from childhood to elderly: data from the international AIDA Network Still's disease registry.

OBJECTIVE: Still's disease is more frequently observed in the paediatric context, but a delayed onset is not exceptional both in the adulthood and in the elderly. However, whether paediatric-onset, adult-onset and elderly-onset Still's disease represent expressions of the same disease continuum or different clinical entities is still a matter of controversy. The aim of this study is to search for any differences in demographic, clinical features and response to treatment between pediatric-onset, adult-onset and elderly-onset Still's disease. METHODS: Subjects included in this study were drawn from the International AutoInflammatory Disease Alliance Network registry for patients with Still's disease. RESULTS: A total of 411 patients suffering from Still's disease were enrolled; the disease occurred in the childhood in 65 (15.8%) patients, in the adult 314 (76.4%) patients and in the elderly in 32 (7.8%) patients. No statistically significant differences at post-hoc analysis were observed in demographic features of the disease between pediatric-onset, adult-onset and elderly-onset Still's disease. The salmon-coloured skin rash (p=0.004), arthritis (p=0.009) and abdominal pain (p=0.007) resulted significantly more frequent among paediatric patients than in adult cases, while pleuritis (p=0.015) and arthralgia (p<0.0001) were significantly more frequent among elderly-onset patients compared with paediatric-onset subjects. Regarding laboratory data, thrombocytosis was significantly more frequent among paediatric patients onset compared with adult-onset subjects (p<0.0001), while thrombocytopenia was more frequent among elderly-onset patients although statistical significance was only bordered. No substantial differences were observed in the response to treatments. CONCLUSIONS: Despite some minor difference between groups, overall, demographic, clinical, laboratory and treatments aspects of Still's disease were similarly observed in patients at all ages. This supports that pediatric-onset, adult-onset and elderly-onset Still's disease is the same clinical condition arising in different ages.

Atypical cutaneous presentation of AOSD with persistent itchy urticaria: A case report.

RATIONALE: Adult-onset Still's disease (AOSD) is a rare multisystem disorder considered a complex autoinflammatory syndrome. The clinical and biological features of AOSD typically include a high fever with arthritic symptoms, evanescent skin rash, sore throat, striking neutrophilic leukocytosis, hyperferritinemia, and abnormal liver function. The typical rash and fever are important diagnostic clues for AOSD. Here, we report a case of atypical rash manifesting as persistent itchy urticaria. PATIENT CONCERNS: A 57-year-old female presented with a 6-day history of fever. During her hospital stay, she progressively developed rashes that were not associated with fever, primarily distributed on her back and the distal extremities, and associated with pronounced itching. The rash was initially suspected to be urticaria; however, the patient exhibited a poor response to antihistamines. After malignancies and other rheumatic diseases were excluded, the diagnosis leaned towards AOSD based on diagnostic criteria. The patient's fever was well controlled with the initiation of glucocorticoids, and no further rashes were observed. DIAGNOSES: Although the patient exhibited atypical rashes, after ruling out malignancies and other rheumatic diseases, she met 2 major and 3 minor criteria. Based on Yamaguchi's criteria, the patient was diagnosed with AOSD. INTERVENTIONS: Initially, the patient was administered an intravenous infusion of methylprednisolone at 40 mg once daily. This was later transitioned to oral administration with gradual dose reduction. OUTCOMES: Follow-up at 1 year showed no recurrence of the rash, with a stable condition and no relapse. LESSONS: This case provides valuable insights for the early diagnosis of AOSD, emphasizing the importance of considering this diagnosis even when presenting with atypical skin rash.

Neutrophil extracellular trap-induced intermediate monocytes trigger macrophage activation syndrome in adult-onset Still's disease.

BACKGROUND: Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disease characterized by innate immune system activation, with a high risk for macrophage activation syndrome (MAS). MAS development is associated with monocyte/macrophage activation and cytokine storm. Monocytes consist of three different subsets, classical monocytes (CMs, CD14brightCD16 -), intermediate monocytes (IMs, CD14brightCD16 +), and non-classical monocytes (NCMs, CD14dimCD16 +), each has distinct roles in inflammatory regulation. However, the frequencies and regulatory mechanism of monocyte subsets in AOSD patients have not been identified. METHODS: We performed flow cytometry, RNA sequencing, phagocytosis analysis, and enzyme-linked immunosorbent assay to evaluate monocyte subsets, cell functions, and potential biomarkers. The effect of neutrophil extracellular traps (NETs) on monocytes was determined by evaluating mRNA levels of DNA sensors, surface CD16 expression, and inflammasome pathway activation. RESULTS: Higher proportions of intermediate monocytes (IMs) were identified in active AOSD patients. IMs displayed higher expression of CD80, CD86, HLA-DR, and CD163 than CMs and NCMs. CD163 upregulation was noted on AOSD IMs, accompanied by increased phagocytic activity and elevated cytokine/chemokine production, including IL-1ß, IL-6, CCL8, and CXCL10. The frequencies of IMs were correlated with disease activity and higher in AOSD patients with MAS (AOSD-MAS). CCL8 and CXCL10 were highly expressed in RNA sequencing of monocytes from AOSD-MAS patients and plasma CXCL10 level could serve as a potential biomarker for AOSD-MAS. Moreover, DNA-sensing pathway was activated in monocytes from AOSD-MAS patients. Stimulation with NETs derived from AOSD induced DNA sensor expression, the expansion of IMs, and inflammasome pathway activation. These effects can be abrogated by DNase I treatment. CONCLUSIONS: Our results demonstrated that the proportions of IMs were elevated in AOSD and associated with MAS. The DNA component in NETs from AOSD plays an important role in the formation of IMs, shedding new light for the therapeutic target.

Efficacy and safety of 5-aminolevulinic acid in adult-onset Still's disease: A preclinical study in mice and a pilot study in humans.

The study aimed to investigate the therapeutic effects of 5-aminolevulinic acid/sodium ferrous citrate (5-ALA/SFC) on adult-onset Still's disease (AOSD), specifically focusing on arthritis and macrophage activation syndrome (MAS). We used mouse models to assess the impact of 5-ALA/SFC on collagen-induced arthritis (CIA) and MAS induced by synthetic oligonucleotides containing CpG motifs (CpG-S-ODN). Additionally, we conducted a pilot study with AOSD patients receiving prednisolone (PSL) treatment and 5-ALA/SFC administration to evaluate its efficacy and safety. The 5-ALA/SFC group exhibited significantly lower joint scores in CIA mice. In CpG-S-ODN-treated mice, 5-ALA/SFC administration led to reduced hemophagocytosis and splenomegaly. The anti-inflammatory properties of 5-ALA/SFC were attributed to the suppression of CCL4 and CXCL10 production in monocytes and the induction of M2 macrophages. AOSD patients treated with 5-ALA/SFC demonstrated successful PSL tapering without adverse events. Collectively, the administration of 5-ALA/SFC showed promising potential in ameliorating arthritis and MAS in AOSD patients.

Expert consensus on the treatment of patients with adult-onset still's disease with the goal of achieving an early and long-term remission.

We performed a comprehensive systematic targeted literature review and used the Delphi method to formulate expert consensus statements to guide the treatment of adult-onset Still's disease (AOSD) to achieve an early and long-term remission. Seven candidate statements were generated and reached consensus in the first round of voting by the panel of experts. We postulate: (i) In patients with AOSD with predominant arthritis at onset who achieved no disease control with glucocorticoids (GCs), the use of methotrexate can be considered, whereas the use of cyclosporin A and low-dose GCs should not (Statements 1-3); (ii) In patients with AOSD with poor prognostic factors at diagnosis, an IL-1 inhibitor (IL-1i) in addition to GCs should be taken into consideration as early as possible (Statement 4); (iii) A switch to an IL-6 inhibitor (IL-6i) may be considered in patients with AOSD with prevalent joint involvement, who are unresponsive or intolerant to IL-1i (Statement 5); (iv) Drug tapering or discontinuation may be considered in patients who achieved a sustained clinical and laboratory remission with IL-1i (Statement 6); (v) In patients with AOSD who failed to attain a good clinical response with an IL-1i, switching to an IL-6i may be considered in alternative to a different IL-1i. TNF-inhibitors may be considered as a further choice in patients with a prominent joint involvement (Statement 7). These statements will help clinicians in treatment decision making in patients with AOSD.

Persistent Pancytopenia as a Long-COVID Manifestation in a Patient with Adult-Onset Still's Disease: A Case Report.

Background: Adult-onset Still's disease (AOSD) is a rare rheumatic inflammatory condition with an extremely heterogeneous clinical presentation and systemic impairment. Uncommon manifestations may be challenging to manage, especially in patients with previous severe acute SARS-CoV-2 infection. For the first time, we report the case of a patient affected by refractory AOSD presenting with severe pancytopenia as a long-COVID manifestation. The purpose of this case report is to illustrate the clinical presentation, diagnostic and therapeutic management of this unusual manifestation. Moreover, we examine the mechanisms that are potentially responsible for the onset of the pancytopenia observed in our patient. Case presentation: We describe the case of a 40-year-old male who presented with a history of fever for 2 years, arthralgia, maculopapular salmon-pink rash and a previous SARS-CoV-2 infection which required admission to intensive care. The patient's laboratory results revealed elevated inflammatory markers levels (erythrocyte sedimentation rate and C-reactive protein), hyperferritinemia and severe pancytopenia that needed multiple transfusions. A diagnosis of AOSD was made based on clinical and laboratory presentation after excluding neoplastic, infectious and other rheumatic diseases. The previous empirical treatment was not adequate to control the condition; therefore, treatment with high-dose steroids, canakinumab and epoetin alfa was started and led to the resolution of the man's symptoms and a reduction in inflammatory marker levels, whereas blood cell count remained stable without a need for further blood transfusions. The patient is currently under rheumatologic and hematologic follow-up every month. Conclusions: Neither AOSD nor SARS-CoV-2 infection usually manifests with pancytopenia, except in hemophagocytic syndrome or immunodeficient patients, respectively. Identifying the underlying etiology of pancytopenia is mandatory to establish a prompt treatment that generally resolves the disorder. However, in our case, all common causes of pancytopenia were excluded, suggesting a potential manifestation of the long-COVID syndrome. Despite the resolution of the acute infection and the remarkable treatment of AOSD, pancytopenia persists. Herein, we propose for refractory AOSD patients with previous SARS-CoV-2 infection a novel approach to the diagnosis and treatment of pancytopenia.

IL-18 in Autoinflammatory Diseases: Focus on Adult Onset Still Disease and Macrophages Activation Syndrome.

Interleukin-18 (IL-18) is a potent pro-inflammatory cytokine that is involved in various innate and adaptive immune processes related to infection, inflammation, and autoimmunity. Therefore, it is described as a key mediator of autoinflammatory diseases associated with the development of macrophage activation syndrome (MAS), including systemic juvenile idiopathic arthritis and adult-onset Still's disease. This review focuses on the role of IL-18 in inflammatory responses, placing emphasis on autoinflammatory diseases associated with chronic excess of serum IL-18, which correlate with clinical and biological signs of the disease. Therefore, it is useful for the diagnosis and monitoring of disease activity. Researchers are currently investigating IL-18's role as a therapeutic target for the treatment of inflammatory diseases. The inhibition of IL-18 signaling through recombinant human IL-18BP (IL-18 binding protein) seems to be an effective therapeutic strategy, though further studies are necessary to clarify its importance as a therapeutic target.

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.

The administration of methotrexate in patients with Still's disease, "real-life" findings from AIDA Network Still Disease Registry.

OBJECTIVES: To describe clinical characteristics of patients with Still's disease treated with methotrexate (MTX) and to assess drug effectiveness evaluating change in disease activity, reduction of inflammatory markers, and glucocorticoid (GC)-sparing effect. METHODS: Patients with Still's disease treated with MTX were assessed among those included in AIDA Network Still Disease Registry. RESULTS: In this registry, 171 patients with Still's disease were treated with MTX (males 43.3%, age 37.1 ± 16.0 years). They were mainly characterised by joint features and fever without a prominent multiorgan involvement. MTX was administered with GCs in 68.4% of patients, with other conventional synthetic DMARDs in 6.4%, and with biologic DMARDs in 25.1%. A significant reduction of the modified systemic score was observed, and 38.6% patients were codified as being in clinical remission at the end of follow-up. The concomitant administration of a biologic DMARD resulted a predictor of the clinical remission. Furthermore, a reduction of inflammatory markers and ferritin levels was observed following the administration of MTX. Additionally, a marked reduction of the dosage of concomitant GCs was identified, while 36.7% discontinued such drugs. Male gender appeared as a predictor of GC discontinuation. MTX was discontinued in 12.3% of patients because of adverse effects, and in 12.3% for lack of efficacy. CONCLUSIONS: Clinical characteristics of patients with Still's disease treated with MTX were described, mainly joint features and fever without a prominent multiorgan involvement. The clinical usefulness of MTX was reported in reducing the disease activity, decreasing the inflammatory markers, and as GC-sparing agent.