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.

The amino acid variants in HLA II molecules explain the major association with adult-onset Still's disease in the Han Chinese population.

Adult-onset Still's disease (AOSD) is a rare autoinflammatory disease with systemic involvement, and its pathophysiology remains unclear. Genome-wide association studies (GWAS) in the Chinese population have revealed an association between AOSD and the major histocompatibility complex (MHC) locus; however, causal variants in the MHC remain undetermined. In the present study, we identified independent amino-acid polymorphisms in human leukocyte antigen (HLA) molecules that are associated with Han Chinese patients with AOSD by fine-mapping the MHC locus. Through conditional analyses, we identified position 34 in HLA-DQα1 (p = 1.44 × 10-14) and Asn in HLA-DRß1 position 37 (p = 5.12 × 10-11) as the major determinants for AOSD. Moreover, we identified the associations for three main HLA class II alleles: HLA-DQB1*06:02 (OR = 2.70, p = 3.02 × 10-14), HLA-DRB1*15:01 (OR = 2.44, p = 3.66 × 10-13), and HLA-DQA1*01:02 (OR = 1.97, p = 1.09 × 10-9). This study reveals the relationship between functional variations in the class II HLA region and AOSD, implicating the MHC locus in the pathogenesis of AOSD.

Racial/Ethnic variations in morbidity and mortality in Adult Onset Still's Disease: An analysis of national dataset.

OBJECTIVES: Adult Onset Still's Disease (AOSD) is a rare autoinflammatory disorder. There is relatively little known about the impact of social determinants of health on its outcomes. Our goal is to describe the racial/ethnic variations, morbidity and mortality of AOSD hospitalized patients in the US. MATERIALS AND METHODS: Adult US hospitalized patients between 2009-13 from a nationwide inpatient sample (NIS) database with AOSD were identified using ICD-9 code 714.2. NIS is the largest all-payer US inpatient database with approximately 8 million hospitalizations yearly. Patients with other autoimmune diseases were excluded. We used descriptive statistics to summarize patient and hospital characteristics. We performed survey-weighted logistic regression models adjusting for confounders to study our primary outcome: in-hospital mortality. RESULTS: Between 2009-13, 5,820 AOSD patients were hospitalized with a mean age of 53.6 (SE-0.61) years. 3817 (65.6%) were female, 56% white and 3% Asian. Macrophage Activating Syndrome (1.7%), Disseminated Intravascular Coagulation (DIC-1.1%) and Thrombotic Thrombocytopenic Purpura (0.4%), respectively, complicated the hospital course. There were 154 inpatient deaths in study period (mortality 2.6%). Mean age of patients who died in hospital was higher (62.4 years ± 3.1) and 13.9% were Asians. Patients of Asian origin had significantly higher odds of in-hospital death compared to whites (aOR = 6.39, 95% CI 1.77-23.1, p = 0.005). Mortality was significantly higher for patients whose hospital course was complicated by DIC (aOR = 29.69, 95% CI 5.5-160.41, p = 0.006). CONCLUSIONS: In this national sample of patients hospitalized for AOSD, we found significant variations in In-hospital mortality.

MEFV gene mutations and their clinical significance in Korean patients with adult-onset Still's disease.

OBJECTIVES: Adult-onset Still's disease (AOSD) and periodic fever syndrome share clinical features in some aspects. Familial Mediterranean fever (MEFV) is a typical periodic fever syndrome and MEFV gene mutations may contribute to the clinical features of certain rheumatic diseases. The purpose of this study is to research the incidence and clinical utility of MEFV gene mutations in Korean AOSD patients. METHODS: The study included 96 AOSD patients and 165 healthy controls. In both groups, genomic DNA was isolated and genotyped using restriction fragment length polymorphism for 5 MEFV gene mutations (E148Q, P369S, M680I, V726A and M694V). In the AOSD patients, the clinical significance of MEFV mutation was assessed by the laboratory and clinical features. RESULTS: M680I, V726A and M694V were not found in both groups. P369S was detected in 7 (7.3%) AOSD patients and 10 (6.1%) healthy controls. E148Q mutation was found in 77 (46.7%) among healthy controls with 6 QQ and 44 (45.8%) of AOSD patients with 5 QQ, respectively. The allele frequency of E148Q was 0.25 in AOSD patients, and that of P369S was 0.04. However, there was no significant difference in most clinical manifestations and laboratory findings by the presence and absence of E148Q mutation. CONCLUSIONS: MEFV mutations including E148Q mutation were not associated with the development of AOSD patients in Korea. Although high incidence of E148Q mutation was found, E148Q mutation did not show major effect on the clinical features of AOSD. But we need to look for association with clinical response to certain treatments and long-term prognosis.

Causes and significance of markedly elevated serum ferritin levels in an academic medical center.

OBJECTIVE: A markedly elevated serum ferritin level has been associated with inflammatory conditions such as adult-onset Still's disease, systemic juvenile idiopathic arthritis, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome. Hyperferritinemia, however, can also be caused by a wide variety of disparate conditions, often with impressively high serum levels. The objective of this analysis was to investigate the underlying etiology of markedly elevated ferritin levels in a large group of patients treated as outpatients and inpatients in a tertiary-care medical center. METHODS: Data of all adult patients from 2008 through 2010 with at least 1 serum ferritin level greater than 1000 µg/L were reviewed. If a patient had multiple qualifying levels, the highest one was used. For each case, the most likely cause of the elevated ferritin was assessed based on the available clinical data using a simple algorithmic approach. RESULTS: Six hundred twenty-seven patients were found. The average serum ferritin level was 2647 µg/L. The most frequent condition was malignancy (153/627), with iron-overload syndromes the second most common (136/627). There were 6 cases of adult-onset Still's disease, systemic juvenile idiopathic arthritis, or hemophagocytic lymphohistiocytosis/macrophage activation syndrome. The average ferritin level in these syndromes was 14242 µg/L. Seven patients appeared to have anemia of chronic inflammation, and in 5 patients, there was no clearly definable cause for hyperferritinemia. CONCLUSIONS: Although extremely elevated ferritin levels may be associated with rheumatologic diseases, more often they are found in patients with other conditions such as malignancy or infection. In addition, extremely high ferritin levels can be found in patients with seemingly indolent disease or levels of chronic inflammation.

'The eyes see what the mind knows.' Adult-onset Still's disease, a case series and review in a south Asian population.

AIM: Adult-onset Still's disease (AOSD) is a rare disease. Very few cases have been reported from the South-Asian region so the aim of this study is to assess the clinical and laboratory aspects of 15 patients with AOSD in a tertiary referral hospital in Karachi. METHODS: Retrospective data was collected from all patients diagnosed using Yamaguchi criteria for AOSD between January 2004 and December 2010 at Jinnah Medical College Hospital, Karachi. RESULTS: Data of 15 patients with AOSD were analyzed. Their ages ranged from 17 to 55 years, the male-to-female ratio being 6:1. The most common clinical features were fever and articular symptoms (100%), sore throat (60%), rash (53.3%), weight loss (93.3%), lymphadenopathy (40%) and elevated erythrocyte sedimentation rate (86.7%). All patients had leukocytosis with counts>20,000/mm 3 were seen in 40%. Elevated liver enzymes were present in 80% of the case series and hyperferritinemia in 100% with a mean of 3,962 ng/mL (range 555-13,865). Ambiguity in presentation and lack of serologic markers make diagnosis of AOSD difficult as 40% of patients were receiving empirical anti-tuberculous therapy prior to final diagnosis. CONCLUSION: It is necessary for physicians to have a high index of suspicion for AOSD in patients with high-grade fever, arthralgia and leukocytosis.

Clinical features and hyperferritinemia diagnostic cutoff points for AOSD based on ROC curve: a Chinese experience.

Hyperferritinemia has been reported in adult-onset Still's disease (AOSD). This study aims to investigate clinical features of AOSD in Chinese population and diagnostic value of different hyperferritinemia cutoff points based on ROC curve. A total of 48 patients from October 2002 to February 2007 diagnosed AOSD in the department of rheumatology, the first affiliated hospital of Sun Yat-set University were enrolled. A total of 86 patients mainly complaining fever >39°C for over one week and meeting Yamaguchi criteria but confirmed as non-AOSD by other serological or pathological tests were obtained from the same department as controls. Total serum ferritin levels were determined at the time of admission. Clinical features of AOSD in Chinese population were similar to previous studies. Significantly higher levels of total serum ferritin were presented in patients with AOSD (8100.7 ± 13678.5) compared with non-AOSD controls (448.3 ± 539.4) (P < 0.01). No differences were found in serum ferritin level between different categories of non-AOSD patients (P > 0.05). High value of area under receiver operating characteristic curve (ROC curve) suggested that ferritin was very predictive in AOSD diagnosis. Three cutoff points were picked based on clinical practice and ROC curve. Ferritin level ≥2,500 µg/L appeared to be highly specific for a diagnosis of AOSD, yet the low sensitivity may falsely ruled out patients with true AOSD. Hyperferritinemia ≥750 µg/L was seldom observed in inflammatory diseases or solid tumor. Hyperferritinemia ≥1,250 µg/L could mostly rule out other autoimmune diseases and hematologic diseases. Combined Yamaguchi criteria and hyperferritinemia gave better prediction for AOSD. In conclusion, different hyperferritinemia cutoff points observed in ROC curve help to optimize diagnostic and therapeutic strategy.

Adult onset Still's disease: clinical presentation in a large cohort of Italian patients.

OBJECTIVES: To characterise the clinical phenotype of Italian patients with adult-onset Still's disease (AOSD). METHODS: Sixty-six subjects who received a definite diagnosis of AOSD were seen and followed-up at our institution from 1991 to 2009. The diagnosis was made by a senior rheumatologist and confirmed by Yamaguchi's criteria for AOSD. Data regarding clinical manifestations, laboratory and radiographic features, and disease course were collected and compared with those reported in other published series of different ethnicity. RESULTS: The most frequent features were: articular pain (100%), acute phase reactants elevation (100%), elevated serum ferritin (97%), high fever (95%), negative RF and ANA (92%), neutrophilia (82%), skin rash (79%), and overt arthritis (79%). Forty-percent of patients showed a chronic articular disease. Five subjects (8%) experienced severe, life-threatening complications, and 1 patient died. As compared to other North American, North European, Middle Eastern, and Far Eastern cohorts, Italian patients showed significant differences in several epidemiologic, clinical and laboratory features. CONCLUSIONS: Our data show that AOSD is rare in the Italian population, and that its clinical presentation appears to be significantly influenced by the ethnicity of the affected patients. Given its broad differential diagnosis, early recognition of this condition is challenging, but it could become crucial in the setting of severe complications. Beyond the protean manifestations of this disease, a clinical picture of seronegative febrile arthritis and skin rash, concurrent with a marked elevation in serum ferritin should always be mindful of AOSD.

Liver abnormalities in adult onset Still's disease: a retrospective study of 77 Chinese patients.

OBJECTIVE: Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder of unknown etiology, characterized by high fever, transient cutaneous rash, arthralgia/arthritis, and leukocytosis. Liver involvement in AOSD has been described, but few reports have described it in depth. The present study analyzed clinical and laboratory features in a series of Chinese AOSD patients. METHODS: Data of 77 patients with AOSD (fulfilling Yamaguchi's diagnostic criteria) were retrospectively reviewed and compared with other series. RESULTS: The characteristics of our patients are similar to those reported in the literature. Hepatomegaly occurred in 11.7% of the cases; abnormal liver enzymes in 62.3% mild cytolysis (level of transaminases <2 N) (23.4%), moderate cytolysis (between 2 and 5 N) (23.4%), severe cytolysis (>5 N) (15.6%), and increase in the level of alkaline phosphatase (32.9%), gamma-glutamyltransferase (48.1%), lactic dehydrogenase (69.0%). Complete recovery occurred in all patients, except for 1 who died of severe liver failure and complications. CONCLUSION: AOSD is a systemic disease, and the present study reemphasizes the high frequency of liver involvement. Although it was slight to moderate in most cases, severe cytolytic hepatitis has been described. Treatment for AOSD patients with liver involvement aimed mainly at AOSD itself and most of the patients with liver involvement got complete remission with systemic corticosteroid therapy.

Functional association of interleukin 18 gene -607 (C/A) promoter polymorphisms with disease course in Chinese patients with adult-onset Still's disease.

OBJECTIVE: Interleukin 18 (IL-18) has a central role in the pathogenesis of adult-onset Still's disease (AOSD). We investigated the functional association of -607 (C/A) IL-18 promoter polymorphisms with disease course in Chinese patients with AOSD. METHODS: Sequence-specific primer polymerase chain reaction and the restriction fragment-length polymorphism method were used to analyze the genotypes of IL-18 promoter polymorphism at position -607 in 96 unrelated patients with AOSD and 164 ethnically-matched healthy controls. Serum IL-18 levels were determined using ELISA in patients with active untreated AOSD. RESULTS: Significantly lower frequencies of single-nucleotide polymorphism -607/AA were observed in patients with AOSD compared to healthy controls (18.8% vs 31.1%, respectively; p < 0.05). Median levels of serum IL-18 were significantly lower in AOSD patients with AA genotype compared to those with CA genotype or CC genotype (147.5 pg/ml vs 410.5 pg/ml or 262.4 pg/ml, respectively; both p < 0.05). Significantly lower IL-18 levels were demonstrated in AOSD patients with a monocyclic systemic course than in those with a polycyclic systemic course or a chronic articular course. The AA genotype was more frequently observed in patients with monocyclic systemic course, which had the best prognosis, than in those with the other 2 disease courses. In contrast, a lower frequency of the AA genotype than the CA or the CC genotype was observed in patients with chronic disabling arthritis (5.5% vs 25.0% or 19.2%, respectively). CONCLUSION: The SNP -607/AA genotype with lower IL-18 levels might be a genetically protective factor for the occurrence of AOSD in the Chinese population, against progression of chronic disabling arthritis.

Thrombotic thrombocytopenic purpura and adult onset Still's disease.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) has a high mortality rate if undiagnosed and untreated. Although recent literature supports the role of ADAMTS13 (a disintegrin-like metalloproteinase with thrombospondin type 1 repeats), the von Willebrand factor cleaving protease, in the pathogenesis of the disease, many aspects of the disease remain a mystery. Various drugs and autoimmune conditions, such as systemic lupus erythematosus and the antiphospholipid syndrome, have been observed in association with TTP. Adult onset Still's disease (AOSD) has been reported less frequently in association with TTP. PRESENTATION: We report the case of a 43-year-old African American man who initially presented with fever and joint pain and was later diagnosed with TTP. He responded initially to plasma exchange, but never achieved complete remission. He eventually required splenectomy for complete resolution of symptoms of TTP, but the arthritis never resolved, resulting in several admissions for joint pain. The arthritis was eventually diagnosed as AOSD. DISCUSSION: Literature review shows that the autoimmune diseases usually associated with TTP include systemic lupus erythematosus and the antiphospholipid syndrome. Eight reports of AOSD with TTP have been reported, but our case is unique in several aspects. Previous case reports have described TTP occurring in patients with known AOSD; here, we describe TTP preceding or coinciding with the onset of AOSD. Interestingly, the patient's AOSD-associated arthritis responded to plasma exchange, but did not resolve after splenectomy. The coincident onset of AOSD and TTP in this patient lead us to suspect a common pathophysiologic pathway in the pathogenesis for both of these diseases.

Association of Fcgamma receptor polymorphisms with adult onset Still's disease in Korea.

OBJECTIVE: Fcgamma receptors (FcgammaR) have important functions in the regulation of immune response and clearance of immune complex. High levels of immunoglobulins have been observed in patients with the active stage of adult onset Still's disease (AOSD), and high-dose intravenous immunoglobulin treatment has decreased the disease activity of AOSD. We investigated polymorphisms of FcgammaR as genetic factors influencing susceptibility or disease course of AOSD in Korea. METHODS: We genotyped the FcgammaRIIA H/R131, IIIA F/V176, and IIIB NA1/NA2 loci in 98 patients with AOSD and 151 healthy controls. Genotyping was performed using sequence-specific PCR. Patients with AOSD were subdivided into groups according to disease course: monocyclic systemic, polycyclic systemic, or chronic articular type. Allelic, genotypic, and haplotypic associations were analyzed by chi-square test. RESULTS: No significant skewing in any of the 3 FcgammaR polymorphisms was found between Korean AOSD patients and controls. FcgammaRIIA R/R131 and R/H131 genotype in patients with chronic articular-type disease was more frequent than in controls (p = 0.006 and p(corr) = 0.018). No differences of genotypic and allelic frequencies were found between other disease course types and controls. Haplotype IIA R131-IIIA F176-IIIB NA2 was more frequent in AOSD patients than in controls (p = 0.021). CONCLUSION: Although FcgammaR polymorphisms are not associated with development of AOSD in Koreans, the haplotype IIA R131-IIIA F176-IIIB NA2 may be associated with AOSD. Also, the FcgammaRIIA polymorphism may be associated with chronic articular-type AOSD. We need to identify whether these polymorphisms are associated with a response to anti-tumor necrosis factor agents in patients with AOSD.

Different articular outcomes of Still's disease in Chinese children and adults.

The clinical manifestations, treatment and course, and articular outcomes of 24 children with juvenile-onset Still's disease (JOSD) and 21 adults with adult-onset Still's disease (AOSD) were compared retrospectively. There was no significant difference in the initial clinical and laboratory manifestations except that more adults presented with a sore throat (81% vs. 46%, p = 0.03). Although serum ferritin was almost always elevated in both diseases, adults had significantly higher serum ferritin concentrations compared with those of children. Steroid treatment was required in 71% of children and 52% of adults, while disease-modifying antirheumatic drugs were used in 42% of children and 24% of adults during the course. Chronic arthritis (>6 months) occurred in comparable proportions of patients with JOSD and AOSD (46% vs 38%, p = 0.82), irrespective of the disease pattern (monocyclic or polycyclic). However, severe deforming arthritis with marked functional limitation occurred only in JOSD, particularly with polyarthritis at disease onset (more than five affected joints). In contrast, AOSD patients with chronic arthritis had a favourable functional outcome at the end of the follow-up. Our study suggested different articular outcomes of Still's disease in Chinese children and adults.

Autoantibodies to DEK oncoprotein in human inflammatory disease.

OBJECTIVE: To evaluate the specificity of anti-DEK antibodies for juvenile rheumatoid arthritis (JRA). METHODS: Anti-DEK autoantibodies were measured by enzyme-linked immunosorbent assay (ELISA) using affinity-purified his6-DEK fusion protein. Sera from 639 subjects (417 patients with systemic autoimmune disease, 13 with sarcoidosis, 44 with pulmonary tuberculosis, 125 with uveitis, and 6 with scleritis, and 34 healthy control subjects) were screened. Reactivity was verified by immunoblotting and immunoprecipitation studies using baculovirus-expressed human DEK. RESULTS: Anti-DEK activity was found at the following frequencies: JRA 39.4% (n = 71), systemic lupus erythematosus (SLE) 25.1% (n = 216), sarcoidosis 46.2% (n = 13), rheumatoid arthritis 15.5% (n = 71), systemic sclerosis 36.0% (n = 22), polymyositis 6.2% (n = 16), and adult Still's disease 0% (n = 21). Autoantibodies also were detected in 9.1% of tuberculosis sera (n = 44), but were undetectable in sera from the 34 healthy controls. Western blot and immunoprecipitation assay results correlated well with the ELISA findings. In general, levels of anti-DEK autoantibodies were higher in SLE than in other patient subsets, including JRA. CONCLUSION: Anti-DEK autoantibodies are less specific for JRA than previously believed. They are produced in association with a variety of inflammatory conditions, many of which are associated with granuloma formation and/or predominant Thl cytokine production. Anti-DEK antibodies may be a marker for a subset of autoimmunity associated with interferon-gamma production rather than a particular disease subset.

Adult-onset Still's disease in an oriental population: manifestations, course and outcome in 16 patients.

This retrospective descriptive study aims to characterise and compare the clinical manifestations, course and outcome of 16 Oriental patients with adult-onset Still's disease diagnosed in the last 4 years with published data based on Western populations and another Oriental (Japanese) series. Like the Japanese, we found a female preponderance, an older age at onset, and fewer patients with abdominal pain, myalgia, sore throat and serositis compared to the Western series. A longer delay in diagnosis occurred in patients lacking either arthritis or rash at presentation. Most patients had mild hyponatraemia and 2 patients had overt syndrome of inappropriate anti-diuretic hormone secretion. All patients showed a dissociation of elevated aldolase with normal to low creatine kinase levels. Over 50% relapsed within a year from diagnosis and needed slow-acting anti-rheumatic drugs as steroid-sparing agents. Two were given intravenous pulse cyclophosphamide therapy for progressive pneumonitis. Outcome was generally good with minimal functional impairment and no mortality.