Adult-onset Still's Disease Patients Research Articles

Evidence for genetic overlap between adult onset Still's disease and hereditary periodic fever syndromes.

Adult onset Still's disease (AOSD) is a severe, autoimmune disease that can be challenging to treat with conventional therapeutics and biologicals in a considerable number of cases. Therefore, there is a high need to understand its pathogenesis better. As major clinical symptoms overlap between AOSD and hereditary periodic fever syndromes (HPFS), we analysed four known HPFS genes in AOSD. We performed Sanger sequencing and quantitative analysis of all coding regions of MEFV, TNFRSF1A, MVK and NLRP3 in 40 AOSD patients. All rare coding variants (n = 6) were evaluated for several aspects to classify them as benign to pathogenic variants. Statistical analysis was performed to analyse whether variants classified as (likely) pathogenic were associated with AOSD. We identified three rare variants in MEFV, one previously not described. Association to the three likely pathogenic MEFV variants was significant (p c = 2.34E- 03), and two of the three carriers had a severe course of disease. We observed strong evidence for significant association to mutations in TNFRSF1A (p c = 2.40E- 04), as 5% of patients (2/40) carried a (likely) pathogenic variant in this gene. Both of them received a biological for treatment. Our results indicate TNFRSF1A as a relevant gene in AOSD, especially in patients with a more challenging course of disease, while causal variants remain to be identified in the majority of patients.

A Pilot Study on Tocilizumab for Treating Refractory Adult-Onset Still\u2019s Disease

To investigate the efficacy and safety of Tocilizumab (TCZ) in patients with refractory adult-onset Still’s disease (AOSD). We enrolled 8 female patients from October 2013 to July 2014. All patients fulfilled Japan’s Yamaguch AOSD classification and recognized as refractory AOSD. All Patients received TCZ treatment 4–8 mg/kg every 4 weeks. Evaluation of efficacy was conducted after 3 months and 6 months, including clinical manifestations of AOSD patients, improvement of inflammatory markers as well as glucocorticoids dosage adjustments. Treatment-related adverse events were also recorded. Patients treated with Tocilizumab with average age 41.1 years old, the average disease duration 23.6 months. Two patients drop off due to infusion side effects. Others were followed at least 6 months. After 3 months of follow-up, remission rates of fever, arthritis and rashes from 8 patients were 87.5%, 100% and 87.5%. White blood cell counts, erythrocyte sedimentation rate, C-reactive protein and ferritin levels were decreased (P < 0.01) significantly compared to treatment before. Furthermore, the average dose of prednisone was reduced from 51.7 ± 38.4 mg/d to 12.9 ± 7.7 mg/d (P < 0.01). Our findings suggest that tocilizumab could alleviate the clinical manifestations of refractory AOSD rapidly and efficiently.

Red blood cell distribution width is useful in discriminating adult onset Still's disease and sepsis within 24 hours after hospitalization.

Background/AimsRed blood cell distribution width (RDW) is a value representing the heterogeneity in the size of red blood cell, and it is usually used in distinguishing types of anaemia. Recently, it was reported that it could reflect the burden of inflammation in diverse diseases and their prognosis. Hence, in this study, we investigated whether RDW may contribute to discriminating adult onset Still’s disease (AOSD) from sepsis in serious febrile patients within 24 hours after hospitalization. MethodsWe reviewed the medical records and enrolled 21 AOSD patients, 27 sepsis patients and 30 matched healthy controls. We collected at least two laboratory results of variables including RDW within 24 hours after hospitalization, and we calculated their mean values. ResultsSepsis patients showed the significantly increased median white blood cell count, compared to AOSD patients (14,390.0/mm3 vs. 12,390.0/mm3 , p = 0.010). The median RDW in sepsis patients was higher than that in AOSD patients (15.0% vs. 13.3%, p = 0.001), and furthermore, the median RDW in both patient-groups was significantly higher than that in healthy controls. In contrast, the median ferritin level in sepsis patients was lower than that in AOSD patients (544.0 mg/dL vs. 3,756.6 mg/dL, p = 0.001). In multivariate analysis, RDW ≥ 14.8% (odds ratio, 17.549) and ferritin < 2,251.0 mg/dL (odds ratio, 32.414) independently suggested sepsis more than AOSD in patients initially presenting with fever requiring hospitalization. ConclusionsRDW might be a rapid and helpful marker for a differential diagnosis between AOSD from sepsis at an early phase.

Validation of the Fautrel classification criteria for adult-onset Still's disease.

To validate the Fautrel classification criteria for adult-onset Still's disease (AOSD) and to compare the discriminative performance to that of the Yamaguchi criteria. We retrospectively reviewed the medical charts of 426 patients who had serum ferritin level and percentage glycosylated ferritin assayed at the biochemistry laboratory of Bichat Hospital. Medical data were extracted by use of a standardized form. All clinical, biological, and imaging features were collected, as well, evidence favoring an alternative diagnosis, specifically symptoms suggestive of other immune-mediated inflammatory diseases (IMID) or active infections. Patients were classified as AOSD patients or controls according to a predefined procedure, including consultation with a multidisciplinary expert group. Algorithms corresponding to the Fautrel and Yamaguchi classification criteria were applied for each patient. In all, 54 AOSD and 278 control patients were included. For the Fautrel criteria, the sensitivity was 87.0%, specificity 97.8%, and positive and negative predictive values 88.7% and 97.5%, respectively. For the standard Yamaguchi set-without strict application of exclusion criteria-the sensitivity was 96.3%, specificity 98.9%, and positive and negative predictive values 94.5% and 99.3%, respectively. If we applied a stricter definition of exclusion criteria, the sensitivity of the Yamaguchi set decreased to 31.5%. As wall, 37 AOSD diagnoses were missed. This study validates the Fautrel classification criteria with a cohort independent of that used for the original publication. This criteria set demonstrates good sensitivity and specificity, overcomes exclusion criteria, and includes glycosylated ferritin level. It also confirms the high discriminative power of the Yamaguchi criteria, albeit substantially affected by how exclusion criteria are interpreted.

Upregulation of circulating microRNA-134 in adult-onset Still\u2019s disease and its use as potential biomarker

Adult-onset Still’s disease (AOSD) is a multi-systemic inflammatory disorder of unknown etiology. To date, no single diagnostic test is available for AOSD. Herein, we investigated the pathogenic role of microRNAs in AOSD. MicroRNA profiles in plasma from AOSD patients and healthy controls were analyzed by microarray analysis, followed by quantitative reverse transcription PCR validation. The biological functions of microRNAs were evaluated using in vitro cell-based assay. Among the differentially expressed microRNAs, microRNA-134 (miR-134) expression was positively correlated with AOSD activity scores and significantly decreased after effective treatment. An increased miR-134 level is significantly associated with the activation of Toll-like receptor 3 (TLR3). The reporter assay identified IL-18 binding protein (IL-18BP) as the target of miR-134. A negative correlation between miR-134 expression and IL-18BP mRNA levels were detected in peripheral blood cells following TLR3 ligand treatment. Lower plasma IL-18BP levels and higher IL-18 levels were also observed in active AOSD patients who had higher miR-134 expression than inactive patients. Upregulation of circulating miR-134 was associated with elevated IL-18 levels by targeting IL-18BP in AOSD patients and was positively correlated with disease activity, suggesting its involvement in AOSD pathogenesis. MiR-134 may be a novel activity indicator or potential prognostic biomarker in AOSD.

Response to Interleukin-1 Inhibitors in 140 Italian Patients with Adult-Onset Still's Disease: A Multicentre Retrospective Observational Study.

Background: Interleukin (IL)-1 plays a crucial role in the pathogenesis of Adult onset Still’s disease (AOSD).Objectives: To evaluate the efficacy and safety of anakinra (ANA) and canakinumab (CAN) in a large group of AOSD patients.Methods: Data on clinical, serological features, and concomitant treatments were retrospectively collected at baseline and after 3, 6, and 12 months from AOSD patients (Yamaguchi criteria) referred by 18 Italian centers. Pouchot’s score was used to evaluate disease severity.Results: One hundred forty patients were treated with ANA; 4 were subsequently switched to CAN after ANA failure. The systemic pattern of AOSD was identified in 104 (74.2%) of the ANA-treated and in 3 (75%) of the CAN-treated groups; the chronic-articular type of AOSD was identified in 48 (25.8%) of the ANA-treated and in 1 (25%) of the CAN-treated groups. Methotrexate (MTX) was the most frequent disease modifying anti-rheumatic drug (DMARD) used before beginning ANA or CAN [91/140 (75.8%), 2/4 (50%), respectively]. As a second-line biologic DMARD therapy in 29/140 (20.7%) of the patients, ANA was found effective in improving all clinical and serological manifestations (p < 0.0001), and Pouchot’s score was found to be significantly reduced at all time points (p < 0.0001). No differences in treatment response were identified in the ANA-group when the patients were stratified according to age, sex, disease pattern or mono/combination therapy profile. ANA primary and secondary inefficacy at the 12-month time point was 15/140 (10.7%) and 11/140 (7.8%), respectively. Adverse events (AEs) [mainly represented by in situ (28/47, 59.5%) or diffuse (12/47, 25.5%) skin reactions and infections (7/47, 14.8%)] were the main causes for discontinuation. Pouchot’s score and clinical and serological features were significantly ameliorated at all time points (p < 0.0001) in the CAN-group, and no AEs were registered during CAN therapy. Treatment was suspended for loss of efficacy only in one case (1/4, 25%).Conclusion: This is the largest retrospective observational study evaluating the efficacy and safety of IL-1 inhibitors in AOSD patients. A good response was noted at 3 months after therapy onset in both the ANA- and CAN-groups. Skin reaction may nevertheless represent a non-negligible AE during ANA treatment.

Efficacy and safety analysis of off-label treatment with biologics in autoinflammatory diseases : Experiences from aGerman registry(GRAID2)

To evaluate the safety and efficacy of therapy with biologics in patients with autoinflammatory diseases (AIF) or macrophage activating syndrome (MAS) in areal-life setting in Germany. The German Register of Autoimmune Diseases2 (GRAID2) is aretrospective, non-interventional, multicenter registry collecting data from all patients with inflammatory rheumatic diseases refractory to conventional therapy and treated with initial off-label biologics between August 2006 and December 2013. Patients with MAS could be included without prior treatment with abiologic agent. Data from 26patients with AIF and 5with MAS were collected. Of the AIF patients 13(50%) were diagnosed with adult onset Still's disease (AOSD), 6(23%) with familial Mediterranean fever (FMF), 4(15.4%) with tumor necrosis factor-associated periodic syndrome (TRAPS), 1(3.8%) patient with cryopyrin-associated periodic syndrome (CAPS) and 2(8%) with undifferentiated fever syndromes. The 5MAS patients suffered from rheumatoid arthritis (RA) with chronic myeloid leukemia, systemic lupus erythematosus and in 2cases AOSD. In 1patient achronic neurological disease was documented without further differentiaton. All patients with TRAPS were primarily treated with etanercept and all CAPS patients with canakinumab. The AOSD and FMF patients were treated with anakinra as the first line off-label biologic in 6 out of 13 and 5 out of 6cases, respectively. The MAS patients responded very well or well to therapy in 40% and 60% had amoderate response. There were no non-responders. Within the group of AIF patients the physicians documented avery effective or effective treatment in 38.5%, amoderate response in 30.8% and no response in 30.7%. The tolerance was very good in 5 out of 5of the MAS and in 92% of the AIF patients. The data of this retrospective register provide indications for an effective and safe treatment with off-label biologic medication in patients with AIF and MAS in daily practice.

Recurring Lower Abdominal Pain and Fever as Initial Presentation of Adult Onset Still's Disease in the Absence of Arthralgia and Other System Involvement.

A 34 year-old Afro-Caribbean female presented with recurring episodes of fever and lower abdominal pain over a period of two months not improving despite courses of antibiotics for possible recurrent urinary tract infections. On admission to hospital, patient was treated for a possible pyelonephritis or pelvic inflammatory disease (PID). Extensive investigations into possible source of infection were carried out. However, all of the repeated microbiological cultures were normal. Patient was investigated further for other possible causes including connective tissue disease, haematological disorders, or neoplasm, all of which were normal. Diagnosis of adult onset Still’s disease (AOSD) was confirmed by a rheumatologist based on Yamaguchi’s diagnostic criteria for AOSD alongside significantly raised serum ferritin. Patient was treated with steroids to which she showed remarkable clinical improvement alongside marked reduction in her serum ferritin levels.LEARNING POINTSThe four giant causes of fever of unknown origin are: infections, connective tissue diseases, haematological disorders, and malignancies.AOSD is a diagnosis of exclusion using Yamaguchi criteria alongside raised ferritin levels (the most sensitive biomarker).Most AOSD patients will respond to steroid treatment. However, approximately one third of the patients require further immunosuppression to achieve disease remission.

Elevated circulating levels of the interferon-\u03b3\u2013induced chemokines are associated with disease activity and cutaneous manifestations in adult-onset Still\u2019s disease

C-X-C motif chemokine 9 (CXCL9), CXCL10, and CXCL11 are produced in response to interferon-γ (IFN-γ) and trigger inflammation with the accumulation of activated lymphocytes. It appears that these chemokines could play a role in the pathogenesis of adult-onset Still’s disease (AOSD). Therefore, we investigated the associations between the levels of these chemokine and clinical manifestations in patients with active AOSD. Serum levels of IFN-γ, CXCL9, CXCL10 and CXCL11 were determined using enzyme-linked immunosorbent assays. IFN-γ levels were higher in AOSD patients than in rheumatoid arthritis (RA) patients (p = 0.001) or healthy controls (HCs) (p = 0.032). AOSD patients also exhibited higher levels of CXCL9, CXCL10, and CXCL11 compared with RA patients (p < 0.001) and HCs (p < 0.001). In follow-up AOSD patients after treatment with corticosteroid, the levels of CXCL9, CXCL10 and CXCL11 fell significantly, whereas IFN-γ levels were not significantly different. On immunohistochemistry, the percentage of CXCL10-positive inflammatory cells was higher in skin biopsy samples from AOSD patients than in those from normal control (p = 0.012), eczema (p = 0.019), and psoriasis (p = 0.009) groups. Levels of the IFN-γ–induced chemokines, CXCL9, CXCL10 and CXCL11, were elevated and correlated with several disease activity markers. These interferon-γ–induced chemokines may contribute to inflammatory responses and skin manifestations in AOSD.

Highly Expression of CD11b and CD32 on Peripheral Blood Mononuclear Cells from Patients with Adult-Onset Still's Disease.

Background: We investigated the potential role of several pattern-recognition receptors (PRRs; CD11b, CD11c, CD32, CD206, CD209, and dectin-1) in adult-onset Still’s disease (AOSD). Methods: The study included 13 untreated AOSD patients, 19 rheumatoid arthritis (RA) patients (as a disease control), and 19 healthy controls (HCs). The PRRs were quantified in peripheral blood using flow cytometry. The serum levels of interleukin-17 (IL-17), IL-18, and IL-23 were measured by enzyme-linked immunosorbent assay. Results: Significantly higher mean frequencies of cells presenting CD11b and CD32 from whole blood were observed in patients with AOSD than in patients with RA or HC. The levels of IL-17, IL-18, and IL-23 were elevated in AOSD patients compared to HCs. CD11b frequencies from whole cells correlated with systemic scores, lactate dehydrogenase (LDH) levels, aspartate transaminase levels, interleukin-23 (IL-23) levels, and IL-18. Frequencies of CD209 from granulocytes were significantly correlated with systemic scores, and the erythrocyte sedimentation rate and levels of C-reactive protein, ferritin, LDH, IL-23, and interleukin-18 (IL-18). Conclusions: Elevated frequencies of circulating CD11b-positive cells and positive correlations with disease activity markers suggest that circulating CD11b-positive cells contribute to the pathogenesis of AOSD.

The role of 18F-fluorodeoxyglucose positron emission tomography in the assessment of disease activity of adult-onset Still's disease.

Background/Aims18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) has been suggested as a reliable imaging technique for monitoring of disease activity in patients with adult-onset Still’s disease (AOSD). Therefore, we investigated the clinical significance of 18F-FDG PET/CT in Korean AOSD patients.MethodsThirteen AOSD patients were included in the study. The PET/CT images were evaluated with visual and semiquantitative method using standardized uptake values (SUVs).ResultsThe presence of increased 18F-FDG uptake was noted in 90% of clinically active AOSD patients. 18F-FDG uptake was located in the lymph node, spleen, and bone marrow. Visual grade and SUV intensity of lymph node was significantly correlated with the systemic score of AOSD. Visual grade of spleen was significantly correlated with the systemic score, erythrocyte sedimentation rate (ESR), and ferritin. Additionally, visual grade and SUV intensity of bone marrow was significantly correlated with the systemic score, ESR, leukocyte, and neutrophil.ConclusionsVisual grade and SUV intensity of lymph node, spleen, and bone marrow on 18F-FDG PET/CT scan showed significant correlations with known disease activity markers. The data suggest that 18F-FDG PET/CT scan may be a useful imaging technique for evaluation of disease activity in AOSD patients.

Elevated serum levels of free interleukin-18 in adult-onset Still's disease.

IL-18 is a pro-inflammatory cytokine of the IL-1 family that is naturally inhibited by IL-18 binding protein (IL-18BP). High levels of IL-18 have been described in the serum of adult-onset Still's disease (AOSD) patients, but only total IL-18 levels (including inactive IL-18 bound to IL-18BP) have been measured. With a specific immunoassay, we aimed to measure free IL-18 serum levels in AOSD patients and other rheumatic diseases. An ELISA was developed to measure free IL-18. Its sensitivity and specificity were tested by spiking recombinant IL-18 or IL-18BP in serum and PBS supplemented with 5% BSA. The binding affinity of IL-18 to IL-18BP was calculated by titration experiments using the ELISA and by Biacore analysis. Sera of 37 AOSD patients and 138 controls (40 healthy controls, 30 RA, 29 SLE, 21 AS and 18 PsA) were assayed for free IL-18, IL-18BP, total IL-18 and other cytokines. Correlations were performed between free IL-18 and markers of disease activity in AOSD patients. Free IL-18 serum levels were significantly higher in AOSD patients (median 8.89 pg/ml) than in healthy and disease controls (1.37 pg/ml; P < 0.01). Free IL-18 serum levels correlated with AOSD activity. The affinity of IL-18 to IL-18BP was found to be much higher than previously described, with a dissociation constant ranging from 30 to 50 pM. Free IL-18 levels are specifically elevated in AOSD compared with other inflammatory diseases, suggesting that IL-18 represents a potential target for the treatment of AOSD.

TLR4 Endogenous Ligand S100A8/A9 Levels in Adult-Onset Still's Disease and Their Association with Disease Activity and Clinical Manifestations.

S100A8/A9 has been suggested as a marker of disease activity in patients with adult-onset Still’s disease (AOSD). We evaluated the clinical significance of S100A8/A9 as a biomarker and its pathogenic role in AOSD. Blood samples were collected prospectively from 20 AOSD patients and 20 healthy controls (HCs). Furthermore, skin and lymph node biopsy specimens of AOSD patients were investigated for S100A8/A9 expression levels via immunohistochemistry. Peripheral blood mononuclear cells (PBMCs) of active AOSD patients and HCs were investigated for S100A8/A9 cell signals. S100A8/A9, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) levels in active AOSD patients were higher than those of HCs. S100A8/A9 levels correlated positively with IL-1β, TNF-α and C-reactive protein. The inflammatory cells expressing S100A8/A9 were graded from one to three in skin and lymph node biopsies of AOSD patients. The grading for S100A8/A9 was more intense in the skin lesions with karyorrhexis, mucin deposition, and neutrophil infiltration. Like lipopolysaccharide (LPS), S100A8/A9 induced phosphorylation of p38 and c-Jun amino-terminal kinase (JNK) in PBMCs, suggesting that S100A8/A9 activates Toll-like receptor 4 signaling pathways. These findings suggest that S100A8/A9 may be involved in the inflammatory response with induction of proinflammatory cytokines and may serve as a clinicopathological marker for disease activity in AOSD.

Epidemiological study of adult-onset Still's disease using a Japanese administrative database.

Adult-onset Still's disease (AOSD) is a rare disease, and large epidemiological studies of this disease are limited. Furthermore, it has been difficult to show the incidence and characteristics of severe AOSD complications due to the rarity of this disease. The aim of our study was to describe the demographics of AOSD and the incidence and characteristics of severe complications. Using a large Japanese administrative database, we identified hospitalized patients with AOSD and described the demographics. We also calculated the incidence of severe complications (i.e., macrophage activation syndrome [MAS] and disseminated intravascular coagulation [DIC]) and in-hospital mortality in AOSD patients, and then analyzed the age-controlled difference between men and women. We identified 513 patients with AOSD (mean age: 53.1years; women 64.1%). According to the age distribution, there was no distinct peak age. The thirties and the sixties were relatively large age groups. There were 76 patients of AOSD with MAS or DIC observed in this study. The incidence of severe complications was 14.8%, 95% CI [11.9, 18.2]. Women were more likely to have severe complications than men after controlling for age (odds ratio: 2.07; [1.14, 3.73]; p=0.014). AOSD does not predominantly affect young adults in our study population. Elderly AOSD patients can be observed more than before due to global population aging. Severe complications are more likely to occur in women than in men.

Clinical features of adult-onset Still's disease patients with pulmonary complications

Objective To review the clinical characteristics of adult-onset Still's disease (AOSD) patients with special pulmonary complications. Methods Medical records of 506 AOSD inpatients, who were admitted in Peking Union Medical Hospital from October 1997 through March 2015, were retrospectively reviewed. The clinical features, biochemical parameters, radiology, pulmonary function tests, ultrasound, treatments and prognosis of AOSD patients with special pulmonary complications were analyzed. Results The incidence of special pulmonary complications in AOSD inpatients was 2.2% (11/506), including 3 cases of interstitial lung disease and 8 cases of pulmonary artery hypertension. All 11 patients had common manifestations of AOSD, including fever (11/11), arthralgia/arthritis (11/11), rash (9/11), lymphadenopathy and/or splenomegaly (8/11), serositis (10/11), abnormal liver function (9/11), neutrophilia (11/11), and hyperferritinemia (11/11). The patients with interstitial lung disease had no or mild symptom, and were diagnosed by HRCT and pulmonary function test. The patients with pulmonary artery hypertension had various symptoms including dyspnea of exertion (8/8), cough (4/8), chest suppression (2/8), and chest pain (2/8). Four patients died from severe infection, including 3 cases of pulmonary artery hypertension and 1 case of interstitial lung disease. Conclusions Interstitial lung disease and pulmonary artery hypertension are life-threatening complications of AOSD patients. Earlier recognition and prompt treatment should be made to improve patient outcomes. Key words: Still's disease, adult-onset; Lung disease; Signs and symptoms

Elevated high-mobility group B1 levels in active adult-onset Still's disease associated with systemic score and skin rash.

High-mobility group box-1 (HMGB1) is a nuclear protein, and such prototypical damage-associated molecular patterns mediate the immune response in the noninfectious inflammatory response. Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder involved in the dysregulation of innate immunity. We investigated the serum HMGB1 level in patients with AOSD and evaluated its clinical significance. Blood samples were collected from 40 patients with active AOSD and 40 healthy controls (HC). Of the patients with AOSD, follow-up samples were collected from 16 patients after a resolution of AOSD disease activity. Serum HMGB1 levels in patients with AOSD were higher than those of the HC (10.0 ± 5.85 vs. 5.15 ± 1.79ng/mL, p < 0.001). Serum HMGB1 levels were found to be correlated with C-reactive protein (CRP) and the systemic score. The AOSD patient who had a sore throat showed a higher serum HMGB1 level than those patients who did not, and the patient with a skin rash had higher levels than the patients without. In addition, the serum HMGB1 levels were decreased after the resolution of disease activity in the AOSD patients who were followed up. The serum HMGB1 levels were elevated in AOSD patients compared to the HC and were correlated with both CRP and the systemic score. The HMGB1 levels were associated with skin rash and a sore throat in AOSD patients. After the resolution of disease activity, serum HMGB1 levels were found to have decreased.

Adult-onset Still's disease: an Italian multicentre retrospective observational study of manifestations and treatments in 245 patients.

Adult-onset Still's disease (AOSD) is a systemic inflammatory condition of unknown aetiology characterized by typical episodes of spiking fever, evanescent rash, arthralgia, leukocytosis and hyperferritinemia. Given the lack of data in Italian series, we promote a multicentric data collection to characterize the clinical phenotype of Italian patients with AOSD. Data from 245 subjects diagnosed with AOSD were collected by 15 centres between March and May 2013. The diagnosis was made following Yamaguchi's criteria. Data regarding clinical manifestations, laboratory features, disease course and treatments were reported and compared with those presented in other published series of different ethnicity. The most frequent features were the following: arthritis (93%), pyrexia (92.6%), leukocytosis (89%), negative ANA (90.4%) and neutrophilia (82%). As compared to other North American, North European, Middle Eastern and Far Eastern cohorts, Italian data show differences in clinical and laboratory findings. Regarding the treatments, in 21.9% of cases, corticosteroids and traditional DMARDs have not been able to control the disease while biologics have been shown to be effective in 48 to 58 patients. This retrospective work summarizes the largest Italian multicentre series of AOSD patients and presents clinical and laboratory features that appear to be influenced by the ethnicity of the affected subjects.

Clinical characteristics and follow-up analysis of adult-onset Still's disease complicated by hemophagocytic lymphohistiocytosis.

We evaluated clinical characteristics and prognosis for adult-onset Still's disease (AOSD) complicated by hemophagocytic lymphohistiocytosis (HLH). We retrospectively identified cases of AOSD with (n = 10) and without (n = 305) HLH complications. We reviewed their medical records, completed follow-up through outpatient clinic and telephone interviews, and analyzed their clinical symptoms, signs, laboratory test results, treatments, and prognosis. More AOSD patients with HLH developed hepatomegaly, bleeding, serositis, and neurologic symptoms than those without HLH, and they more commonly presented with leukopenia, thrombocytopenia, severe anemia, severe liver function abnormalities, decreased fibrinogen, elevated immunoglobulin, and bone marrow hemophagocytosis. The ten patients with AOSD complicated by HLH were treated with high-dose steroids or pulse steroid therapy, and eight of them also received cytotoxic drugs, while biological agents showed poor response. Follow-up results indicated that AOSD patients overall had good prognosis, while those with HLH showed worse prognosis, including higher relapse and readmission rates and increased mortality. In patients with AOSD, unexplained decreased blood cells, severe liver dysfunction, and/or hemophagocytosis in the bone marrow should be considered as signs of HLH complication. Patients with AOSD complicated by HLH have worse prognosis and higher relapse rates compared to AOSD patients without HLH complications. Thus, these patients should undergo frequent and careful follow-up.

A retrospective study of patients with adult-onset Still's disease: is pericarditis a possible predictor for biological disease-modifying anti-rheumatic drugs need?

The aims of this study were to look for clinical or serological markers able to predict the use of biological disease-modifying anti-rheumatic drugs (bDMARDs) in patients with adult-onset Still's disease (AOSD) and to evaluate the efficacy and safety of bDMARDs in AOSD. In a single-center retrospective study, 39 patients with AOSD were divided into two groups according to whether they were ever treated with bDMARDs or not. Literature was searched for articles dealing with possible predictors of the use of bDMARDs in AOSD. Among the 18 AOSD patients who received at least one bDMARD, the prevalence of pericarditis was higher than that in the other patients [p = 0.014, odds ratio (OR) = 13.4, 95% confidence interval (CI) = 1.45 to 122]. Literature search retrieved another paper dealing with predictors of bDMARDs need in AOSD: the analysis pooling data from our series and this previous report confirmed pericarditis at disease onset as a predictor of bDMARDs need (p = 0.028, OR = 3.62, 95% CI = 1.22 to 10.7). A complete remission was observed in 17 out of 18 patients treated with bDMARDs, allowing withdrawal or tapering of corticosteroid therapy (p < 0.001), but because of inefficacy or adverse events, some patients received more than one bDMARD during the course of the disease and 31 different trials of bDMARDs were needed. Pericarditis at disease onset may be a predictor of bDMARDs need in AOSD. These drugs have a good efficacy and safety profile and should be considered for patients not responding to conventional therapy.

The CD68(+)/H-ferritin(+) cells colonize the lymph nodes of the patients with adult onset Still's disease and are associated with increased extracellular level of H-ferritin in the same tissue: correlation with disease severity and implication for pathogenesis.

In this work, we aimed to evaluate the levels of ferritin enriched in H subunits (H-ferritin) and ferritin enriched in L subunits (L-ferritin) and the cells expressing these two molecules in the lymph node (LN) biopsies obtained from adult-onset Still's disease (AOSD) patients, and the possible correlation among these data and the severity of the disease. Ten patients with AOSD underwent LN biopsy. All the samples were stained by immunofluorescence. A statistical analysis was performed to estimate the possible correlation among both H-ferritin and L-ferritin tissue expression and the clinical picture of the disease. Furthermore, the same analysis was performed to evaluate the possible correlation among the number of CD68(+)/H-ferritin(+) or CD68(+)/L-ferritin(+) cells and the clinical picture. Immunofluorescence analysis demonstrated an increased tissue H-ferritin expression in the LNs of AOSD patients. This increased expression correlated with the severity of the disease. An increased number of CD68 macrophages expressing H-ferritin was observed in the LN samples of our patients. Furthermore, we observed that the number of CD68(+)/H-ferritin(+) cells correlated significantly with the severity of the clinical picture. Our data showed an imbalance between the levels of H- and L-ferritin in LNs of AOSD patients and the evidence of an increased number of CD68(+)/H-ferritin(+) cells in the same organs. Furthermore, a correlation among both the tissue H-ferritin levels and the CD68(+)/H-ferritin(+) cells and the clinical picture was observed.