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.

Neutrophil activation biomarker pentraxin 3 for diagnosis and monitoring of macrophage activation syndrome occurrence in adult-onset Still's disease.

Macrophage activation syndrome (MAS) is a potentially fatal consequence of adult-onset Still's disease (AOSD), driven by a cytokine storm. Efficient early diagnosis of AOSD-associated MAS requires a sensitive and specific biomarker. In this study, we demonstrated that pentraxin 3 (PTX3), an acute phase protein, was associated with AOSD disease activity and served as a biomarker for AOSD-MAS. PTX3 levels were significantly increased in AOSD patients compared to other autoimmune diseases and healthy controls. Plasma PTX3 levels showed positive correlations with inflammatory markers, the systemic score and the HScore. In active AOSD with MAS, PTX3 levels were higher compared to those in non-AOSD haemophagocytic lymphohistiocytosis (HLH) patients. Moreover, the PTX3's area under the curve value for distinguishing AOSD with MAS exceeded that of soluble interleukin-2 receptor, ferritin and C-reactive protein. Furthermore, plasma levels of PTX3 were associated with circulating NET-DNA levels. To fully understand the underlying mechanism of PTX3 prompting AOSD and AOSD-MAS progression, we discovered that neutrophils exhibited enhanced NET formation and mitogen-activated protein kinases (MAPK) pathway activation upon PTX3 stimulation. More importantly, PTX3-induced NET formation was effectively dampened by MAPK pathway inhibitors. These findings collectively revealed that PTX3 has a favorable correlation with disease activity and may serve as a potential biomarker to differentiate AOSD patients with MAS. Additionally, PTX3 induces NET release via the MAPK pathway, suggesting a pathogenic role in AOSD-MAS.

Systematic Review and Metaanalysis of Pharmacological Interventions in Adult-Onset Still Disease and the Role of Biologic Disease-Modifying Antirheumatic Drugs.

OBJECTIVE: To conduct a systematic review of the effectiveness and safety of pharmacological treatments for adult-onset Still disease (AOSD). METHODS: Six databases, 2 trial registries, and conference abstracts were searched from January 2012 to February 2023 for studies of pharmacological interventions in people with AOSD. Outcomes were rates of remission and response, discontinuation of concurrent treatments, complications of AOSD, and treatment-related adverse events. Risk of bias was assessed with the Cochrane risk of bias tool and the Joanna Briggs Institute tool for case series. RESULTS: Forty-four studies evaluated treatments, including nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids (CS), conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and biologic DMARDs (bDMARDs). For bDMARDs, tocilizumab (TCZ), anakinra (ANK), and canakinumab (CNK) had the most available data. Although 3 randomized controlled trials did not show statistically significant benefits of bDMARDs, metaanalyses showed high rates of complete remission and CS discontinuation. Complete remission was 80% (95% CI 59-92%, I 2 36%), 73% (95% CI 58-84%, I 2 66%), and 77% (95% CI 29-97%, I 2 82%) and CS discontinuation was 57% (95% CI 29-81%, I 2 66%), 47% (95% CI 18-78%, I 2 79%), and 34% (95% CI 6-81%, I 2 59%), respectively, for TCZ, ANK, and CNK. Studies with a higher proportion of patients previously treated with bDMARDs showed a trend toward lower rates of CS discontinuation (P = 0.05). The analyses had high clinical heterogeneity, largely because treatments were prescribed as different lines of therapy. CONCLUSION: Evidence supports TCZ, ANK, and CNK therapy for AOSD. However, the magnitude of effect and comparative effectiveness of treatments is uncertain.

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.

CRP and sCD25 help distinguish between adult-onset Still's disease and HLH.

OBJECTIVE: Adult-onset Still's disease (AOSD) and secondary hemophagocytic lymphohistiocytosis (sHLH) are both hyperferritinemic cytokine storm syndromes that can be difficult to distinguish from each other in hospitalized patients. The objective of this study was to compare the inflammatory markers ferritin, D-dimer, C-reactive protein (CRP), and soluble CD25 (sCD25) in patients with AOSD and sHLH. These four markers were chosen as they are widely available and represent different aspects of inflammatory diseases: macrophage activation (ferritin); endothelialopathy (D-dimer); interleukin-1/interleukin-6/tumour necrosis factor elevation (CRP) and T cell activation (sCD25). METHODS: This was a single-center retrospective study. Patients diagnosed by the Hematology service at Vancouver General Hospital for AOSD or sHLH from 2009 to 2023 were included. RESULTS: There were 16 AOSD and 44 sHLH patients identified. Ferritin was lower in AOSD than HLH (median 11 360 µg/L vs. 29 020 µg/L, p = .01) while D-dimer was not significantly different (median 5310 mg/L FEU vs. 7000 mg/L FEU, p = .3). CRP was higher (median 168 mg/L vs. 71 mg/L, p <.01) and sCD25 was lower (median 2220 vs. 7280 U/mL, p = .004) in AOSD compared to HLH. The combined ROC curve using CRP >130 mg/L and sCD25< 3900 U/mL to distinguish AOSD from HLH had an area under the curve (AUC) of 0.94 (95% confidence interval 0.93-0.97) with sensitivity 91% and specificity 93%. CONCLUSIONS: These findings suggest that simple, widely available laboratory tests such as CRP and sCD25 can help clinicians distinguish AOSD from HLH in acutely ill adults with extreme hyperferritinemia. Larger studies examining a wider range of clinically available inflammatory biomarkers in a more diverse set of cytokine storm syndromes are warranted.

Adult-onset Still's disease: analysis of a monocentric cohort of patients.

OBJECTIVE: Adult-onset Still's disease (AOSD) is a multigenic autoinflammatory disease with a severe systemic involvement. Because of the rarity of the disease, most published cohorts are multicentric. The aim of this report is to describe a monocentric cohort of AOSD patients, reporting clinical features and response to therapy in a long follow-up. METHOD: Thirty-eight patients, attending the Clinical Immunology Unit and fulfilling Yamaguchi, Fautrel, or Daghor-Abbaci classification criteria for AOSD, were recruited for this study. In all patients, clinical and serological data were collected at diagnosis and every 6 months thereafter. The Pouchot score was calculated at every visit. RESULTS: Fever, arthromyalgia, and skin rash were the most frequent manifestations, followed by lymphadenopathy, sore throat, arthritis, splenomegaly, hepatic involvement, pleuropericarditis, and weight loss. As far as the disease course is concerned, 25% presented a monocyclic and 35% a polycyclic pattern, and 40% developed chronic articular involvement. Severe complications were observed at disease onset in 21% of the patients. All of the patients were treated with steroids; 74% also received conventional synthetic disease-modifying anti-rheumatic drugs (methotrexate in most cases) and 71% biological disease-modifying anti-rheumatic drugs (interleukin-1 inhibitors in most cases). Therapeutic switching for lack/loss of efficacy or adverse drug reactions was necessary in 66%. CONCLUSION: The analysis of this cohort confirms that AOSD is a complex, severe, and heterogeneous disease. However, despite long-term treatment and comorbidities, therapies are effective and well tolerated. The therapeutic armamentarium now available allows long-lasting remission with low immunosuppression to be achieved in most patients.

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

BACKGROUND: Environmental factors play an important role in the pathogenesis of rheumatic diseases. Smoking is thought to be a risk factor for autoimmune rheumatic diseases. AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Smoking probably is not a risk factor for AOSD and did not affect the response to treatment.

Renal manifestations in adult-onset Still's disease: a systematic review.

OBJECTIVE: We aimed to review the literature on the clinical presentation, renal pathology, treatment, and outcome of renal manifestations in adult-onset Still's disease (AOSD). METHODS: We used PRISMA guidelines for our systematic review and included all English-language original articles from inception till September 15, 2023, on AOSD and kidney involvement in any form. Data on patient demographics, diagnostic criteria, clinical presentation, renal pathology, treatment employed including dialysis, outcome, cause of death were collected and analyzed. RESULTS: The median age at the diagnosis of renal issues was 37, with a higher prevalence among females (58.1%). Among the cases, 28 experienced renal problems after being diagnosed with AOSD, 12 had simultaneous diagnoses of renal issues and AOSD, and in 4 cases, renal problems appeared before AOSD diagnosis. Out of the 44 cases, 36 underwent renal biopsy, revealing various pathology findings including AA amyloidosis (25%), collapsing glomerulopathy (11.4%), thrombotic microangiopathy (TMA) (11.4%), IgA nephropathy (9.1%), minimal change disease (6.8%), and others. Some cases were clinically diagnosed with TMA, proximal tubular dysfunction, or macrophage activation syndrome-related acute kidney injury. Treatment approaches varied, but glucocorticoids were commonly used. Renal involvement was associated with increased mortality and morbidity, with 6 out of 44 patients passing away, 4 progressing to end-stage renal disease (ESRD), and data on 2 cases' outcomes not available. CONCLUSION: Renal manifestations in AOSD are diverse but rarely studied owing to the rarity of the disease. Studies with larger data would be essential to study further on the pathogenesis and implications.

An unusual case of adult-onset still's disease complicated with anti-complement factor H antibodies associated atypical haemolytic uraemic syndrome.

BACKGROUND: Atypical haemolytic uremic syndrome (aHUS) is an uncommon form of thrombotic microangiopathy (TMA). However, it remains difficult to diagnose the disease early, given its non-specific and overlapping presentation to other conditions such as thrombotic thrombocytopenic purpura and typical HUS. It is also important to identify the underlying causes and to distinguish between primary (due to a genetic abnormality leading to a dysregulated alternative complement pathway) and secondary (often attributed by severe infection or inflammation) forms of the disease, as there is now effective treatment such as monoclonal antibodies against C5 for primary aHUS. However, primary aHUS with severe inflammation are often mistaken as a secondary HUS. We presented an unusual case of adult-onset Still's disease (AOSD) with macrophage activation syndrome (MAS), which is in fact associated with anti-complement factor H (anti-CFH) antibodies related aHUS. Although the aHUS may be triggered by the severe inflammation from the AOSD, the presence of anti-CFH antibodies suggests an underlying genetic defect in the alternative complement pathway, predisposing to primary aHUS. One should note that anti-CFH antibodies associated aHUS may not always associate with genetic predisposition to complement dysregulation and can be an autoimmune form of aHUS, highlighting the importance of genetic testing. CASE PRESENTATION: A 42 years old man was admitted with suspected adult-onset Still's disease. Intravenous methylprednisolone was started but patient was complicated with acute encephalopathy and low platelet. ADAMTS13 test returned to be normal and concurrent aHUS was eventually suspected, 26 days after the initial thrombocytopenia was presented. Plasma exchange was started and patient eventually had 2 doses of eculizumab after funding was approved. Concurrent tocilizumab was also used to treat the adult-onset Still's disease with MAS. The patient was eventually stabilised and long-term tocilizumab maintenance treatment was planned instead of eculizumab following haematology review. Although the aHUS may be a secondary event to MAS according to haematology opinion and the genetic test came back negative for the five major aHUS gene, high titre of anti-CFH antibodies was detected (1242 AU/ml). CONCLUSION: Our case highlighted the importance of prompt anti-CFH antibodies test and genetic testing for aHUS in patients with severe AOSD and features of TMA. Our case also emphasized testing for structural variants within the CFH and CFH-related proteins gene region, as part of the routine genetic analysis in patients with anti-CFH antibodies associated aHUS to improve diagnostic approaches.

Nationwide Analysis of Adult-Onset Still Disease With and Without Hemophagocytic Lymphohistiocytosis.

INTRODUCTION: Adult-onset Still disease (AOSD) is a rare inflammatory condition with a monophasic, intermittent, or chronic clinical course, and a subset may experience life-threatening complications such as hemophagocytic lymphohistiocytosis (HLH). This study aims to characterize concurrent AOSD and HLH and identify variables independently associated with in-hospital death. METHODS: We performed a medical records review of AOSD with and without HLH from the 2016-2019 National Inpatient Sample database. We performed a multivariable logistic regression analysis for in-hospital death. Results were reported as adjusted odds ratios (OR adj ). RESULTS: There were 5495 hospitalizations with AOSD, of which 340 (6.2%) had HLH. Thirty (9.0%) of the combined AOSD and HLH group died in the hospital compared with 75 (1.5%) of those without HLH. Multivariable analysis in AOSD inpatients showed that disseminated intravascular coagulation (OR adj 6.13), hepatic failure (OR adj 7.16), infection (OR adj 3.72), respiratory failure (OR adj 6.89), and thrombotic microangiopathy (OR adj 14.05) were associated with higher odds of death. However, HLH itself was not an independent predictor of mortality in AOSD population. CONCLUSIONS: HLH occurred in a small minority of inpatients with AOSD. HLH itself was not an independent risk factor for in-hospital death. Disseminated intravascular coagulation, hepatic failure, infection, respiratory failure, and thrombotic microangiopathy were associated with higher odds of in-hospital death in AOSD. Better awareness of these life-threatening complications may improve hospital outcomes.

Case Report: Adult Onset Still Disease in a 26-year-old Male.

INTRODUCTION: Adult onset still's disease (AOSD) is a systemic inflammatory disease of unknown etiology. It is partially a diagnosis of exclusion, which is why making the diagnosis can be difficult. CASE REPORT: A previously healthy 26-year-old male presented to the clinic following a five-day course of generalized body pain and daily spiking fevers up to 101˚ F. Of note, he reported similar symptoms along with a pink rash on his lower extremities four months prior. These previous symptoms were less severe and lasted one month before spontaneously resolving. Over the span of the next two weeks, his symptoms worsened and he was hospitalized. Physical exam showed a patient in moderately acute distress due to pain. He had generalized abdominal tenderness with questionable hepatomegaly. He had decreased range of motion and strength due to pain in his bilateral upper and lower extremities. His large joints (bilateral shoulders, hips, and knees) were tender to palpation. He also had a new salmon-colored maculopapular rash on his left thigh. PMH, PSH, and FH was noncontributory. He had no known drug allergies and took no medications. Lab work revealed leukocytosis, elevated ESR, elevated haptoglobin, and elevated CRP. All other lab values were within normal limits. Patient met diagnostic criteria for AOSD and was started on high dose prednisone with good response. He was discharged from the hospital, to follow up with rheumatology and his PCP. At a follow up visit with rheumatology, the patient tapered off of prednisone and started on Canakinumab 4 mg/kg (240 mg) subcutaneous injections every 4 weeks. He continued this treatment for five months and had no recurrent symptoms, and injections were discontinued. CONCLUSION: In conclusion, AOSD is a rare disease, but should be considered for patients that present with salmon colored maculopapular rash, pharyngitis, arthralgias or arthritis, and fevers.

Cluster analysis defines four groups of Japanese patients with adult-onset Still's disease.

OBJECTIVES: To define groups and characterize differences in the prognosis of patients with adult-onset Still's disease (AOSD). METHODS: We performed a retrospective cohort study. Patients with AOSD were grouped using hierarchical unsupervised cluster analysis according to age, sex, clinical features, and laboratory data. The primary endpoints were overall survival and drug-free remission rate. RESULTS: A total of 153 patients with AOSD were placed into four clusters. Those in Cluster 1 had a young onset, tended to be female, and had fewer complications and moderate ferritin concentrations. Those in Cluster 2 had a young onset and had more complications and higher ferritin concentrations. Those in Cluster 3 had a young onset, tended to be male, and had no lymphadenopathy and fewer complications. Those in Cluster 4 had an older onset, tended to be female, and had more complications and higher ferritin concentrations. Overall survival tended to be lower (P = .0539) in Cluster 4, and drug-free remission was higher in Clusters 1, 2, and 3 [hazard ratios (HRs) 2.19, 3.37, and 3.62 vs. Cluster 4, respectively]. CONCLUSIONS: Four groups of AOSD that have distinct clinical manifestations, ferritin concentrations, severity, and drug-free remission rate were identified, which were lowest in Cluster 4.

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.

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).

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 emapalumab in macrophage activation syndrome.

OBJECTIVES: Macrophage activation syndrome (MAS) is a severe, life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD). The objective of this study was to confirm the adequacy of an emapalumab dosing regimen in relation to interferon-γ (IFNγ) activity by assessing efficacy and safety. The efficacy outcome was MAS remission by week 8, based on clinical and laboratory criteria. METHODS: We studied emapalumab, a human anti-IFNγ antibody, administered with background glucocorticoids, in a prospective single-arm trial involving patients who had MAS secondary to sJIA or AOSD and had previously failed high-dose glucocorticoids, with or without anakinra and/or ciclosporin. The study foresaw 4-week treatment that could be shortened or prolonged based on investigator's assessment of response. Patients entered a long-term (12 months) follow-up study. RESULTS: Fourteen patients received emapalumab. All patients completed the trial, entered the long-term follow-up and were alive at the end of follow-up. The investigated dosing regimen, based on an initial loading dose followed by maintenance doses, was appropriate, as shown by rapid neutralisation of IFNγ activity, demonstrated by a prompt decrease in serum C-X-C motif chemokine ligand 9 (CXCL9) levels. By week 8, MAS remission was achieved in 13 of the 14 patients at a median time of 25 days. Viral infections and positive viral tests were observed. CONCLUSIONS: Neutralisation of IFNγ with emapalumab was efficacious in inducing remission of MAS secondary to sJIA or AOSD in patients who had failed high-dose glucocorticoids. Screening for viral infections should be performed, particularly for cytomegalovirus. TRIAL REGISTRATION NUMBER: NCT02069899 and NCT03311854.

Consensus statement on blocking interleukin-6 receptor and interleukin-6 in inflammatory conditions: an update.

BACKGROUND: Targeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the specific receptor using anti-IL-6Rα antibodies or by directly inhibiting the IL-6 cytokine. This paper is an update of a previous consensus document, based on most recent evidence and expert opinion, that aims to inform on the medical use of interfering with the IL-6 pathway. METHODS: A systematic literature research was performed that focused on IL-6-pathway inhibitors in inflammatory diseases. Evidence was put in context by a large group of international experts and patients in a subsequent consensus process. All were involved in formulating the consensus statements, and in the preparation of this document. RESULTS: The consensus process covered relevant aspects of dosing and populations for different indications of IL-6 pathway inhibitors that are approved across the world, including rheumatoid arthritis, polyarticular-course and systemic juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, Castleman's disease, chimeric antigen receptor-T-cell-induced cytokine release syndrome, neuromyelitis optica spectrum disorder and severe COVID-19. Also addressed were other clinical aspects of the use of IL-6 pathway inhibitors, including pretreatment screening, safety, contraindications and monitoring. CONCLUSIONS: The document provides a comprehensive consensus on the use of IL-6 inhibition to treat inflammatory disorders to inform healthcare professionals (including researchers), patients, administrators and payers.

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.

OBJECTIVES: To 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. METHODS: We 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. RESULTS: The 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] CONCLUSION: AOSD 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.

Comprehensive description of adult-onset Still's disease after COVID-19 vaccination.

Cases of adult-onset Still's disease (AOSD) have been reported after COVID-19 vaccination. Here we provide a comprehensive description and analysis of all cases of AOSD reported in the literature and in pharmacovigilance databases through April 2022. Disproportionality analyses of pharmacovigilance data were performed in order to further explore the association between vaccination and AOSD. We included 159 patients, 144 from the World Health Organization pharmacovigilance database and 15 from the literature. Detailed clinical characteristics were described for the cases from the literature and from the French pharmacovigilance database (n = 9). The cases of AOSD after COVID-19 vaccination concerned women in 52.2% of cases. The median age was 43.4 years. More than 80% of AOSD reports occurred during the first three weeks and concerned mostly the BNT162b2 mRNA vaccine. We identified 14.5% of disease flare with a median time-to-onset of AOSD flare-up significantly shorter than for the new onset form. More than 90% patients received steroids. Although all cases were considered serious and required hospitalization, most cases presented a favorable outcome (67.1%) with a good response to corticosteroid therapy with a mean time to recovery of 7.2 days. Disproportionality analyses suggested that AOSD was associated with COVID-19 vaccines as well as other vaccines. AOSD was nearly five times more frequently reported with COVID-19 vaccines than with all other drugs. Clinicians should be informed about the potential risk of AOSD onset or flare following COVID vaccines and the importance of its early detection to optimize its management.

AOSD endotypes based on immune cell profiles: patient stratification with hierarchical clustering analysis.

OBJECTIVES: This study aimed to analyse the immune cell profiles of adult-onset Still's disease (AOSD) and to stratify disease-associated endotypes. METHODS: We included 95 cases of treatment-naïve patients with AOSD and 66 cases of healthy controls. Patients with AOSD were classified via an unbiased hierarchical cluster analysis based on circulating immune cells. Their clinical and laboratory characteristics, treatment management, systemic scores and outcomes were then analysed. RESULTS: The proportions of neutrophils and CD8+ T cells were significantly higher while monocytes and natural killer and CD4+ T cells were decreased in patients with AOSD (all P < 0.005). Unbiased hierarchical cluster analysis classified 95 AOSD into three endotype-based groups: group 1 had the highest percentage of neutrophils (neu-dominant group), group 2 had the highest percentage of monocytes (mono-dominant group) and group 3 had the highest percentage of CD8+ T cells (CD8-dominant group). Patients in group 3 had the highest systemic score at diagnosis and were more likely to have pulmonary infiltrates, pericarditis, splenomegaly and poorer treatment responses. A correlation study revealed that the CD4 to CD8 ratio was negatively correlated with the systemic score and positively correlated with treatment response in patients with AOSD (P = 0.001 and P = 0.0091). During the 24.6 (15.2) months of follow-up, the highest total number of disease flares occurred in group 3 (P < 0.0001). CONCLUSION: Hierarchical cluster analysis of peripheral immune cells classified AOSD into three disease-related endotypes. Group 3 showed higher systemic score and poorer treatment responses.