Adult-onset Still's Disease Patients Research Articles

Real-Life Data on the Efficacy of Canakinumab in Patients with Adult-Onset Still's Disease.

Background Interleukin-1 inhibition has revealed to be a successful treatment approach for patients with adult-onset Still's disease (AOSD). However, real-life experience is focused on the use of anakinra, while data about canakinumab (CAN) are mainly based on case reports and small case series. Patients and Methods. Patients classified with AOSD according to Yamaguchi criteria and treated with CAN were consecutively enrolled. Their clinical and therapeutic data were retrospectively collected and statistically analysed to assess the role of CAN as a therapeutic opportunity in AOSD patients in terms of clinical and laboratory disease control along with corticosteroid-sparing effect. Results Nine AOSD patients (8 females and 1 male) treated with CAN for 15.00 ± 12.3 months were enrolled. Resolution of clinical manifestations was reported in 8/9 cases at the 3-month assessment; a significant decrease in the number of tender joints (p = 0.009), swollen joints (p = 0.027), and disease activity score on 28 joints-C-reactive protein (DAS28-CRP) (p = 0.044) was observed during the study period. The systemic score of disease activity significantly decreased at the 3-month and 6-month assessments and at the last visit compared to the start of treatment (p = 0.028, p = 0.028, and p = 0.018, respectively). The daily corticosteroid dosage was significantly reduced at the 3-month and at the last follow-up visits (p = 0.017 and p = 0.018, respectively). None of the patients experienced adverse events or severe adverse events during the follow-up. Conclusions CAN has shown prompt and remarkable effectiveness in controlling AOSD activity in a real-life contest, with a significant glucocorticoid-sparing effect and an excellent safety profile.

Clinical features of elderly-onset Adult-onset Still’s disease

Objectives To clarify the characteristics of patients with elderly-onset Adult-onset Still’s disease (AOSD). Methods Patients were classified into elderly-onset (>60 years: 47 patients) and younger-onset (≤60 years: 95 patients) groups according to their age at diagnosis of AOSD. Clinical features, treatments, and prognosis were compared between the elderly-onset and younger-onset groups. Results In the elderly-onset group, compared with the younger-onset group, typical skin rashes were less frequent (21.3% vs 58.9%, respectively; p < .0001), whereas pleuritis (27.7% vs 7.4%, respectively; p = .0011) and disseminated intravascular coagulation (19.1% vs 2.1%, respectively; p = .0004) were more frequent, and serum ferritin levels were higher (median 12,700 ng/ml vs 2526 ng/ml, respectively; p < .0001). Overall survival and AOSD-related survival were reduced (p = .0006 and p = .0023, respectively) and drug-free remission was less frequent (p = .0035) in the elderly-onset group compared with the younger-onset group. Conclusions Our results demonstrated that elderly-onset AOSD patients had several characteristics that differed from younger-onset AOSD patients, including less typical skin lesions, more AOSD-related complications, higher ferritin levels, and poorer prognoses.

Elevated Granulocyte Colony-stimulating Factor Levels in Patients With Active Phase of Adult-onset Still Disease.

Neutrophilia is a hallmark of adult-onset Still disease (AOSD). We aimed to investigate the levels of granulocyte colony-stimulating factor (G-CSF), an essential regulator of neutrophil production and function, in the pathogenesis of AOSD. Sera were collected from 70 patients with AOSD and 20 healthy controls (HCs). The levels of G-CSF were determined by ELISA. Low-density granulocytes (LDGs) were quantified by flow cytometry. Correlations between G-CSF levels and disease activity, laboratory variables, and LDG levels in patients with AOSD were analyzed by Spearman correlation test. Patients with active AOSD presented significantly higher levels of G-CSF compared to inactive AOSD patients (P < 0.001) and HCs (P < 0.0001). The G-CSF levels were significantly decreased after active AOSD patients achieved disease remission (P = 0.0015). The G-CSF levels were significantly correlated with C-reactive protein, erythrocyte sedimentation rate, ferritin, and systemic score in AOSD (P < 0.0001). Significant correlations between the levels of G-CSF and circulating neutrophils (P < 0.0001), neutrophil-to-lymphocyte ratio (P < 0.0001), percentages of LDGs in the peripheral blood mononuclear cells (P = 0.004), as well as absolute numbers of circulating LDGs (P = 0.018) were identified. Patients with fever, evanescent rash, sore throat, arthralgia, myalgia, lymphadenopathy, or hepatomegaly/elevated liver enzymes displayed significantly higher levels of G-CSF compared to patients without these manifestations (P < 0.05). Our findings indicate that G-CSF is implicated in the pathogenesis of AOSD, and targeting G-CSF may have therapeutic potential for AOSD. In addition, introducing circulating G-CSF levels into the clinical assessment system may help to monitor disease activity.

Neutrophil-derived lipocalin-2 in adult-onset Still's disease: a novel biomarker of disease activity and liver damage.

ObjectiveLiver damage is a common manifestation and can be life-threatening in adult-onset Still’s disease (AOSD), an autoinflammatory disease. The hallmark of AOSD is activation of neutrophils, whose infiltration in liver is suspected to promote tissue injury. Here we aimed to identify a candidate biomarker and to validate its association with liver damage in AOSD.MethodsTranscriptome analysis of neutrophils from treatment-naïve active AOSD patients and healthy donors was performed. Lipocalin-2 (LCN2) expression was assessed in neutrophils, plasma and liver biopsies of AOSD. The correlations of LCN2 with different variables and its ability to identify liver damage from AOSD patients were analysed.ResultsLCN2, a novel biomarker in hepatic inflammation, was found to be upregulated in AOSD neutrophils by RNA sequencing and confirmed at the mRNA and protein levels. Plasma levels of LCN2 were significantly higher in AOSD patients than healthy controls, RA and SLE patients. Plasma LCN2 levels were closely correlated with inflammatory markers, systemic score, HScore and cytokines. Moreover, LCN2 levels were increased in active AOSD with liver involvement and independently associated with liver dysfunction. Enhanced expression of LCN2 was detected in liver biopsies from three patients with ongoing liver injury. Furthermore, the area under the curve value of LCN2 for identifying AOSD with liver injury from other liver diseases was 0.9694.ConclusionOur results reveal that neutrophils-derived LCN2 is higher in plasma and liver tissue in AOSD patients than in healthy controls, and it could serve as a potent biomarker for identifying AOSD with systemic inflammation, especially liver damage caused by hyperinflammation.

Elevated circulating pro-inflammatory low-density granulocytes in adult-onset Still's disease.

Neutrophilia is a hallmark of adult-onset Still's disease (AOSD). This study aimed to investigate the role of a distinct subset of granulocytes, the low-density granulocytes (LDGs) in the pathogenesis of AOSD. A total of 56 patients with AOSD were included in the study. LDGs were quantified by flow cytometry. Correlations between LDGs with disease activity and laboratory parameters were determined by Spearman's nonparametric test. The cellular sources of the pro-inflammatory cytokines in AOSD were determined by intracellular staining. Active AOSD patients displayed significantly higher levels of LDGs compared with inactive AOSD patients and healthy controls (HCs) (P<0.001). Circulating LDGs were significantly correlated with CRP, ESR and the modified Pouchot score in patients with AOSD (P<0.01). The levels of LDGs were significantly decreased after the active AOSD patients achieved disease remission (P=0.0391). CD14+ monocytes constituted over 90% IL-1β+ peripheral blood mononuclear cells (PBMCs) and over 80% TNF-α+ PBMCs in both active AOSD patients and HCs, respectively. In active AOSD, CD14+ monocytes accounted for 24.6% to 75.0% of IL-6+ PBMCs, while LDGs comprised 22.8% to 72.2% of IL-6+ PBMCs. In contrast, over 90% IL-6+ PBMCs were CD14+ monocytes in HCs. A significant correlation was identified between the levels of LDGs and serum IL-6 levels in AOSD (P<0.0001). Active AOSD is associated with elevated levels of a pro-inflammatory subset of neutrophils, the LDGs that produce IL-6. Our data highlight an unappreciated role of LDGs in the aberrant innate immune responses in AOSD.

SAT0557 RESIDUAL DISEASE ACTIVITY IN ADULT-ONSET STILL’S DISEASE: QUALITATIVE AND QUANTITATIVE ANALYSIS OF A SERIES OF 18F FDG-PET/MR

Background:Adult-onset Still’s disease (AOSD) is a systemic autoinflammatory disorder characterized by episodes of spiking fever, the presence of an evanescent pink-salmon rash, arthritis/arthralgias, sore throat and increased inflammatory serum markers. The diagnosis is clinical and needs the exclusion of potential mimickers such as infections and lymphoproliferative disorders. Currently, a specific diagnostic test to assess the disease activity is not available.Objectives:To define the residual disease activity in AOSD and establish a possible response to therapy through18F-FDG PET/MR imaging technique.Methods:23 patients affected by AOSD and 24 controls underwent18F-FDG PET/MR between 2014 and 2018. A total of 5418F-FDG PET/MR were analysed. AOSD patients were diagnosed according to the Yamaguchi’s criteria and were in follow-up at the Rheumatology Unit of Padova University Hospital. The controls were chosen among non-AOSD patients with a previous diagnosis of solid tumors (lymphomas excluded). Aqualitative analysisof PET/RM carried out by a Nuclear Medicine Specialist and asemiquantitative analysiscarried out by measuring SUVs-to-liver (Standardized Uptake Value) for spleen, bone marrow (BM), lymph nodes and pharynx were performed. A SUVmax BM/SUVmean liver higher than 2.09 was set up as significant area of uptake for each organ considered. This threshold was calculated by adding the standard deviation multiplied by 2 at the mean ratio between SUVmax BM and SUVmean liver of the control group. The Pouchot score for disease activity was calculated for each subject. The distribution of the variables was investigated by Shapiro-Wilk test. The analysis of the association between the variables was carried out using the Mann-Whitney U test.Results:AOSD patients present areas of focal18F-FDG uptake mainly in BM, lymph nodes, pharynx, spleen and salivary glands. Sites of uptake in spleen were found in 3.3% of PET/MR, in BM in 23.3%, in lymph nodes in 23.3% and in pharynx in 36.6% of PET/RM respectively. Eleven/thirty (47.8%) patients were defined as “positive” since the uptake was higher than liver, and twelve/thirty (52.2%) were defined as “negative” since the uptake was lower than liver, regardless of SUVs and clinical manifestations. A semi-quantitative analysis assessed whether the values of the SUVmax BM/liver were higher than the cut-off of 2.09 in “positive” PET/MR and lower in the “negative” ones and if the clinical manifestations were present or absent in agreement with the evaluation of SUVs for each patient. BM was found to be active (SUVmax ratio &gt; of 2.09) in 7 out of 11 patients when the PET/MR was defined “positive”, while only in 1 case out of 12 BM SUVmax was &gt;2.09 when the exam was “negative”. Clinical manifestations were present in 10 out of 11 AOSD with a “positive” scan and in 7 out of 11 with both a “positive” scan and a SUV max BM/liver &gt;2.09. Clinical manifestations were present in 1 out of 12 patients with a “negative” scan, while in 10 out of 12 cases with both a negative scan and a SUV max BM/liver &lt;2.09 were absent. Six patients repeated PET/MR during follow-up. The values of the SUVmax BM/liver significantly decreased after anti IL-1β treatment with anakinra. In two cases in which anakinra was deferred, the BM SUVmax values exceeded the cut-off of 2.09 despite the patients did not complain any symptom or inflammation markers increase.Conclusion:18F FGD-PET/MR could be able to evaluate the disease activity in AOSD when clinical manifestations and serum markers are not sufficient to establish it. The uptake on BM seems quite sensitive in pointing out the disease severity and in assessing the response to anti IL-1β therapy.18F PET/MR is an accurate and repeatable method, however further studies are required to validate its applicability in routinary clinical practice.Disclosure of Interests:None declared

FRI0506 EFFICACY AND SAFETY OF CANAKINUMAB IN ADULT-ONSET STILL’S DISEASE: A SINGLE-CENTER REAL-LIFE EXPERIENCE

Background:The pro-inflammatory cytokine interleukin (IL)-1 has a central role in the pathogenesis of adult-onset Still’s disease (AOSD), a rare auto-inflammatory condition. Anakinra, has been for years the cornerstone of IL-1-blocking therapy in AOSD. More recently, the monoclonal antibody canakinumab, a new agent blocking IL-1, has become availableObjectives:To describe our real-life experience with CNK in a cohort of AOSD patients from a single Italian CenterMethods:AOSD patients diagnosed according to Yamaguchi’s criteria followed-up at our Autoinflammatory Unit and treated with CNK for at least 3 months were included. Demographic features, disease characteristics, reasons for CNK introduction, concomitant therapies, variation in systemic steroids dose, adverse events, and response to treatment were retrospectively evaluated. Non-parametric tests were used for statistical comparisonResults:13 patients (5 women; median age 49 years, range 21-74), treated with subcutaneous CNK 4 mg/kg 4-weekly, were identified. Median disease duration before CNK introduction was 12 (6-240) months. After CNK introduction, 2 patients were followed-up for 18 months, 3 for 12 months, 6 for 6 months, 2 for 3 months. CNK was introduced as first-line biologic DMARD in 6 patients. The other 7 patients had been already treated with at least one other bDMARD, for a total of 15 treatment courses (7, anakinra, ANK; 4, tocilizumab; 4, TNF-inhibitors), with a median bDMARD therapy duration of 8 (4-178) months. Previous bDMARDs had been interrupted because of inefficacy (8 cases) or adverse events (AE, 7 cases); of the 7 ANK-treated patients, therapy interruption was due to inefficacy in 3 cases. At CNK introduction, 11 patients were on systemic steroid therapy, prednisone (PDN) equivalent dose 15 (5-80) mg, and 10 were concomitantly receiving a conventional DMARD (7, methotrexate; 2, colchicine; 1, cyclosporine-A).Graphic 1summarizes main clinical features at CNK introduction. After CNK start, a striking and rapid clinical response was observed, as demonstrated by a substantial decrease of modified Pouchot score and a normalization of acute phase reactants after only 3 months (see Table 1 for details). CNK showed also a significant steroid-sparing effect: median PDN dose was reduced to 7.5 (2.5-12.5) mg at month 3 and 5 (0-7.5) mg at month 6; PDN was stopped in 3 patients (1 at month 3, 1 at month 6, 1 at month 12) due to optimal disease control. CNK was temporarily held-off in 3 patients (zoster reactivation, 1; prostatitis, 1; mild leukopenia, 1). We observed no case of primary inefficacyTable 1.Disease activity and blood tests at canakinumab introduction and during follow-upDaily prednisone dosemgBaseline(n=13)3 months(n=13)6 months(n=11)12 months(n=5)18 months(n=2)Pouchot score15 (5-80)7.5 (2.5-12.5)5 (0-7.5)5 (0-7.5)2.5VAS pain3 (2-5)1 (0-2)0 (0-1)00Erythrocyte sedimentation ratemm/h7 (2-10)3 (1-8)2 (1-4)1 (1-2)1C-reactive proteinmg/L42 (8-120)21 (2-69)13 (2-55)14 (2-41)11Ferritinng/mL20.8 (3-180)3.1 (0.5-22.5)1.6 (0.5-8.4)1 (0.3-6.3)0.5Hemoglobing/dL379.5 (161-914)282 (82-552)215 (34-464)177 (77-401)19913.1 (9.4-15.7)13.2 (10.7-15.3)13.8 (11.5-15.5)13.9 (11.3-14.3)13.5Figure 1.Graphic 1 Main clinical features at canakinumab introductionConclusion:Our real-life data confirm that CNK is highly effective and safe in AOSD treatment and has significant steroid-sparing effects. CNK showed its efficacy both as first-line therapy and after other bDMARDs failure, also in patients who have previously failed IL-1 inhibition through ANK

AB1041 BIOLOGICS IN ADULT’S ONSET STILL’S DISEASE: TREATMENT STRATEGIES AND SAFETY IN SINGLE CENTER COHORT WITH LONG-TERM FOLLOW-UP

Background:Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disorder. In recent years biological disease modifying antirheumatic drugs (bDMARDs) are becoming increasingly important for its treatment.Objectives:To evaluate disease outcomes, treatment strategies and their long-term safety in a cohort of AOSD patients treated with bDMARDs.Methods:A single-center retrospective study of patients diagnosed with AOSD until 2019 was conducted. Patients were included if they: a) were 16 years old or older, b) met the Yamaguchi criteria and c) had received a bDMARDDemographics, clinical and laboratory parameters were collected at the time of diagnosis.Data regarding treatment lines included: the previous and concomitant conventional disease modifying antirheumatic drugs (cDMARDs), the type of initial bDMARD, switches, survival and corticosteroids discontinuation. Adverse events related to treatment and disease outcomes including death and amyloidosis were also recorded.Results:Sixteen patients with AOSD (Table 1) refractory to cDMARDs were administered biologics. The median duration of follow-up was 14 years (range 1-24). Consistent with recent literature1, two distinct disease patterns were recognized: the systemic form (SF) and the chronic articular form (CAF). In the SF the leading clinical symptoms were fever, pericarditis and pleuritis. In CAF the leading clinical symptom was persistent RA-like arthritis.Table 1.Some clinical and laboratory features of patients with FMF or MEFV mutations accompanied by demyelination diseaseCasesAge/SexDiseasesMEFV mutationsThe onset age/diagnostic age for FMFThe onset age for DD/MS/Presenting manifestations/MRI findingsTreatment for FMF /DD/MSCase 1(F1)17/FFMF+DDM694V homozygous3/515OB (-)Fusiform plaques in the cingulate gyrus; plaques in T4-6ColchicineIL-1 RAGlatiramer acetateCase 2(F1)46/FFMF+MSM694V homozygous8/928Optic nerve involvementOB(+)Plaques (+)ColchicineGlatiramer acetateCase 3(F1)17/FFMF+MSM694V heterozygous3/515Loss of the right eye, vertigoOB(+)PlaquesColchicinePulse steroidBeta-interferonTeriflunomideCase 4(F2)36/FMS+MEFV mutationM694V/R202Q-27Headache, blurred vision, optic nerve atrophyOB(+)Plaques (+)Glatiramer acetateCase 5(F2)16/FMS?+FMF+Cutaneous vasculitisM694V/R202Q16/1611Headache, blurred visionNo LP (denied by pt)Plaques-F: Female, F1: Family 1, F2: Family 2; DD: Demyelination disease;MS: Multiple sclerosis;MRI: Magnetic resonance imaging; OB:Oligoclonal band; LP: Lumbar punctionTable 1.Summary of patient characteristics at the time of diagnosisCharacteristicsResultsAge at the time of diagnosis median, (range) years32.5 (18-64)Sex (N)11 female, 5 maleFever14 (87.5%)Rash8 (50%)Lymphadenopathy2 (12.5%)Arthritis15 (93.75%)Pleuritis7 (43.7%)Pericarditis9 (56.25%)Hepatosplenomegaly2 (12.5%)Elevated liver enzymes2 (12.5%)Hyperferritinaemia4 (25%)Patients with the SF were treated with anakinra (n=4), tocilizumab (TCZ; n=3), canakinumab (n=1) and anti-TNFa (1 adalimumab, 1 etanercept) (n=2). Patients with the CAF received anti-TNFa (3 infliximab, 1 etanercept) (n=4) and TCZ (n=2). The median time from biologic initiation to corticosteroids discontinuation was 6.5 months, (range 2-32), (Table 2). 9 patients (56.25%) remained on treatment with the initial bDMARD, 4 patients (25%) received treatment with two and 3 patients (18.75%) with ≥ 3 bDMARDs. All patients with the CAF were on bDMARD at the end of follow-up, while 4/10 patients (40%) with the SF discontinued it. During follow-up only one serious adverse event was attributed to bDMARD (allergic reaction to infliximab infusion). There were no cases of amyloidosis or deathsConclusion:Dichotomous phenotype in AOSD can determine treatment strategy for initial biologic treatment. Inhibition of IL-1 and IL-6 was the preferred therapeutic option for systemic form while inhibition of TNF and IL-6 was the preferred option for the chronic articular form. All of the above bDMARDs have favorable long-term safety profile in patients with AOSD.

Anxiety and depression in adult-onset Still's disease patients and associations with health-related quality of life.

Adult-onset Still's disease (AOSD) is an autoinflammatory disorder leading to multiorgan involvements. We sought to investigate mood status and the health-related quality of life (HRQoL) in these patients. In this study, 82 AOSD patients and 82 age- and sex-matched healthy controls were included. Demographic and clinical data of recruited patients were collected. The Hospital Anxiety and Depression Scale (HADS) and Medical Outcomes Survey Short Form-36 (SF-36) were used to evaluate the mood status and quality of life, respectively. Spearman correlation and multivariable linear regression analyses were used to assess the disease-related risk factors associated with anxiety and depression. Forty-four active and thirty-eight relieved patients were enrolled. We found that scores of both HADS anxiety (HADS-A) and depression (HADS-D) subscales in active AOSD were significantly higher than inactive patients, which were significantly higher than controls. Moreover, the HADS-A was positively correlated to the patient's global assessment (PGA), pain, and dosage of prednisone, and the HADS-D was positively correlated to systemic score, PGA, and pain. Female, high dosage of corticosteroids, and PGA more than 50 had a significant association with HADS-A score, while the sore throat and PGA more than 50 had a significant association with HADS-D score. Furthermore, AOSD patients' anxiety and depression had a negative impact on HRQoL. Active AOSD patients tended to be anxious and depressed, suffering from poorer HRQoL compared to patients in remission. Therefore, the evaluation of mental health and HRQoL should be included in AOSD patients' long-term management. Key Points • Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder leading to multiorgan involvement. This study was so far the first published research focuses on AOSD patients' mental involvement and health-related quality of life (HRQoL). • Active AOSD patients were more tended to be anxious and depressive and suffered from poorer HRQoL compared to inactive patients. • Patients' anxiety and depression were associated with impaired HRQoL.

Combination value of biomarkers in discriminating adult onset Still's disease and sepsis.

Lymphocyte and plateletcrit (PCT) as proportions of routine complete blood count tests, have been studied as simple biomarkers for inflammatory diseases. The aim of our study was to investigate whether blood routine parameters, especially platelet parameters could be auseful tool to distinguish Adult onset Still's disease (AOSD) from sepsis. We retrospectively reviewed 58patients with AOSD and 55sepsis patients diagnosed at the First Affiliated Hospital of Nanjing Medical University between January, 2015 to December 2018. Laboratory data including ferritin, blood routine parameters and C‑reactive protein (CRP) level were collected, and the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte (PLR) were calculated. The results showed that AOSD patients showed higher ferritin, lymphocyte and PCT (all P < 0.01) and these factors are independent risk factors for predicting AOSD. In receiver operating characteristic (ROC) curve analysis of LY, PCT and ferritin for distinguish of AOSD, the area under the curve (AUC) was 0.676 (0.576-0.777); 0.706 (95% CI = 0.596-0.816); 0.715 (0.617-0.814). Meanwhile, the AUC of the combination of lymphocyte, PCT and ferritin was 0.836 (0.737-0.909) with sensitivity 67.3, specificity 92.3, and the difference was significant. Thus we suggest that lymphocyte, PCT may be auseful tool to make adistinction between AOSD and sepsis, as supplementary biomarkers to ferritin.

Elevated Expression of C-Type Lectin Domain Family 5-Member A (CLEC5A) and Its Relation to Inflammatory Parameters and Disease Course in Adult-Onset Still's Disease.

C-type lectin domain family 5-member A (CLEC5A) associates with adaptor DAP12 (DNAX activation protein 12) to form receptor complexes involved in inflammatory responses. We postulated a potential role of CLEC5A in the pathogenesis of adult-onset Still's disease (AOSD) and aimed to investigate CLEC5A expression and its association with activity parameters and disease course. In 34 AOSD patients and 12 healthy controls (HC), circulating levels of CLEC5A-expressing monocytes or granulocytes were determined by flow cytometry analysis, the mRNA expression of CLEC5A and DAP12 on PBMCs by quantitative PCR, and plasma levels of proinflammatory cytokines by ELISA. AOSD patients had significantly higher percentages and mean fluorescence intensity (MFI) of CLEC5A-expressing monocytes (median 62.1% and 3.20, respectively) or granulocytes (72.6% and 3.22, respectively) compared with HC (in monocytes: 17.0% and 0.65, both p < 0.001; in granulocytes: 67.3%, p < 0.05 and 0.90, p < 0.001; respectively). Patients also had significantly higher levels of CLEC5A mRNA expression on PBMCs compared with HC (median 1.77 vs. 0.68, p < 0.05). The levels of CLEC5A-expressing monocytes or granulocytes were positively associated with activity scores and levels of IL-1β and IL-18 in AOSD patients. The patients with a systemic pattern had significantly higher levels of CLEC5A-expressing granulocytes and IL-18 compared to those with a chronic articular pattern of disease course. After 6 months of therapy, levels of CLEC5A-expressing monocytes and granulocytes significantly declined, paralleling the decrease of AOSD activity. Elevated CLEC5A levels and their positive association with activity parameters suggest that CLEC5A is involved in the pathogenesis and may serve as an activity indicator of AOSD.

Serum sTREM-1 in adult-onset Still's disease: a novel biomarker of disease activity and a potential predictor of the chronic course.

ObjectivesTriggering receptor expressed on myeloid cells-1 (TREM-1) is an amplifier of inflammatory signals. Recently, a soluble form of TREM-1 (sTREM-1) was described. This study aimed to investigate the role of serum sTREM-1 in patients with adult-onset Still’s disease (AOSD).MethodsSerum sTREM-1 levels were detected in 108 AOSD patients, 88 RA patients and 112 healthy controls (HC). The correlations of sTREM-1 with disease activity, clinical characteristics and laboratory parameters in AOSD patients were analysed by the Spearman correlation test. Risk factors for the chronic course of AOSD were evaluated by multivariate logistic regression analysis.ResultsAOSD patients had significantly higher serum sTREM-1 levels than RA patients and HC, and serum sTREM-1 levels were correlated with the systemic score, ferritin, leucocyte count, CRP, IL-1β and IL-6. The elevation in the initial sTREM-1 level by itself could discriminate patients developing the chronic course from patients developing the nonchronic course. Moreover, an elevated sTREM-1 level (> 526.4475 pg/ml) was an independent risk factor for the chronic course in active AOSD patients. Furthermore, interfering with TREM-1 engagement led to reductions in the secretion of pro-inflammatory cytokines, such as IL-1β, IL-6 and TNF-α, in neutrophils and monocytes from active AOSD patients.ConclusionSerum sTREM-1 levels are correlated with disease activity, and an elevation in the initial serum sTREM-1 level is a potential predictor of the chronic course in AOSD patients, which currently provides the best predictive model for identifying patients prone to developing the chronic course of AOSD.

FDG PET/CT used in identifying adult-onset Still’s disease in connective tissue diseases

To explore the 18F-fluoro-dexoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging characteristics of adult-onset Still's disease (AOSD) and its significance in differential diagnosis from other connective tissue diseases (CTDs). FDG PET/CT images of 54 patients with AOSD and 66 with other CTD from patients suffering from fever of unknown origin (FUO) were retrospectively studied and compared with 40 healthy controls. Clinical and PET/CT characteristics of AOSD and other CTDs were compared, and SUVmax (maximum standardized uptake value) was used to analyze the differences of FDG uptake in the blood pool, liver, spleen, bone marrow, and hyperplastic lymph nodes between the AOSD and other CTDs. The SUVmax ratios of the spleen, bone marrow, and lymph nodes to the liver were used to establish the diagnostic criteria for differential diagnosis of AOSD, and its diagnostic efficiency was evaluated. Positive findings are presented in 53/54 (98.1%) AOSD patients and 61/66 (92.4%) other CTD patients in PET/CT imaging. AOSD manifested as diffusely increased FDG uptake in the spleen and bone marrow, and multiple reactive hyperplasia lymph nodes are symmetrically distributed mainly in the neck and axilla, while other organs were seldom involved. Although these abnormalities could be seen in other CTDs, its incidence and uptake value were both higher in AOSD. If two or more of the following three standard were met, the sensitivity, specificity, and accuracy of diagnosing AOSD could reach 90.7%, 92.4%, and 91.7%, respectively: ① spleen SUVmax/liver SUVmax ≥ 1.2 and/or bone marrow SUVmax/liver SUVmax ≥ 1.4; ②symmetrically distributed reactive hyperplastic lymph nodes mainly in the neck and axilla with a lymph node SUVmax/liver SUVmax ≥ 1.8; and ③ no other abnormal uptake found in other organs. Characteristic manifestations in AOSD were found on FDG PET/CT. These findings could help to identify AOSD from the other CTDs, especially in cases of fever of unknown origin, where it can assist in identifying the cause. Key Points • Image characteristics of FDG PET/CT in adult-onset Still's disease were described. • FDG PET/CT helps in identifying adult-onset Still's disease from the other connective tissue diseases. • FDG PET/CT imaging standard for diagnosing adult-onset Still's disease were established.

Macrophage activation syndrome associated with adult-onset Still's disease: a multicenter retrospective analysis.

To explore the clinical features, treatments, and prognostic factors of adult-onset Still's disease (AOSD)-associated macrophage activation syndrome (MAS), we conducted a multicenter retrospective clinical study of AOSD-associated MAS patients. AOSD patients were collected from six tertiary hospitals in China. Medical charts were reviewed and clinical information was recorded and analyzed. There were 447 AOSD patients enrolled into this retrospective clinical study. Among them, 55 were diagnosed with MAS. Liver dysfunction was the most reliable predictive factor for the screening of MAS in AOSD patients (OR = 75.744, 95%CI = 23.015-249.284, p < 0.0001). In multivariate analysis, clinical features including platelets < 100 × 109/L (OR = 9.546, p = 0.005), aspartate transaminase (AST) > 120U/L (OR = 25.853, p < 0.0001), triglycerides > 3mmol/L (OR = 12.9833, p = 0.011)), ferritin > 1500ng/mL (OR = 5.513, p = 0.050), as well as hemophagocytosis in bone puncture (OR = 18.132, p = 0.001) were highly associated with the occurrence of MAS. The mortality rate of total AOSD patients was 4.47%, MAS was the main cause of death in AOSD patients (OR = 11.705, 95%CI = 4.783-28.647, p < 0.0001). PLT ≤ 100 × 109/L (p = 0.0001), fibrinogen < 1.5g/L (p = 0.0286), splenomegaly (p = 0.0002), and liver dysfunction (p = 0.0008) highly suggested poor prognosis. MAS occurrence is the major cause of death in AOSD patients. Notable liver dysfunction, as well as splenomegaly, low number of platelets or neutrophils, high levels of serum ferritin, and reduced level of fibrinogen are risk factors for poor outcome. Key Points • This is a multicenter retrospective study of AOSD-associated MAS with large number of cases.

Comparison of Early vs. Delayed Anakinra Treatment in Patients With Adult Onset Still's Disease and Effect on Clinical and Laboratory Outcomes

Background: Aim of this study was to search for any difference in the outcome of patients with adult onset Still's disease (AOSD) treated with anakinra (ANK) in relation with the interval between disease onset and the start of anti-interleukin(IL)-1 treatment and according with the different lines of ANK treatment.Patients and Methods: One hundred and forty-one AOSD patients treated with ANK have been retrospectively assessed. Statistically significant differences (p < 0.05) were analyzed in the frequency of ANK effectiveness, primary or secondary inefficacy to ANK and rate of resolution of clinical and laboratory AOSD manifestations after 3, 6, and 12 months since ANK treatment according with different lines of treatment and different times between AOSD onset and start of ANK.Results: No significant differences were identified in the ANK effectiveness and frequency of primary or secondary inefficacy for patients starting ANK within 6 months (p = 0.19, p = 0.14, and p = 0.81, respectively) or 12 months (p = 0.37, p = 0.23, and p = 0.81, respectively) since AOSD onset compared with patients starting ANK thereafter; no significant differences were identified in ANK effectiveness and primary or secondary inefficacy according with different lines of ANK treatment (p = 0.06, p = 0.19, and p = 0.13, respectively). Patients starting ANK within 6 and 12 months since AOSD onset showed a significantly quicker decrease of erythrocyte sedimentation rate and C-reactive protein than observed among patients undergoing ANK treatment after 6 and 12 months. The number of swollen joints at the 3 month follow-up visit was significantly lower among patients undergoing ANK within 6 months since AOSD onset (p = 0.01), while no significance was identified at the 6 and 12 month assessments (p = 0.23 and p = 0.45, respectively). At the 3 and 6 month visits, the number of swollen joints was significantly higher among patients previously treated with conventional and biological disease modifying anti-rheumatic drugs (DMARDs) compared with those formerly treated only with conventional DMARDs (p < 0.017).Conclusions: Clinical and therapeutic outcomes are substantially independent of how early ANK treatment is started in AOSD patients. However, a faster ANK effectiveness in controlling systemic inflammation and resolving articular manifestations may be observed in patients benefiting from IL-1 inhibition as soon as after disease onset.

Genetic Association and Expression Correlation between Colony-Stimulating Factor 1 Gene Encoding M-CSF and Adult-Onset Still's Disease.

Adult-onset Still's disease (AOSD) is a rare and inflammatory disorder characterized by spiking fever, rash, arthritis, and multisystemic involvement. HLA has been shown to be associated with AOSD; however, it could not explain the innate immunity and autoinflammatory characteristics of AOSD. To assess the genetic susceptibility of AOSD, we conducted a genome-wide association study (GWAS) on a cohort of 70 AOSD cases and 688 controls following a replication study of 36 cases and 200 controls and meta-analysis. The plasma concentrations of associated gene product were determined. The GWAS, replication, and combined sample analysis confirmed that SNP rs11102024 on 5′-upstream of CSF1 encoding macrophage colony-stimulating factor (M-CSF) was associated with AOSD (P = 1.20 × 10−8, OR (95% CI): 3.28 (2.25~4.79)). Plasma levels of M-CSF increased in AOSD patients (n = 82, median: 9.31 pg/mL), particularly in the cases with activity score ≥ 6 (n = 42, 10.94 pg/mL), compared to the healthy donors (n = 68, 5.31 pg/mL) (P < 0.0001). Patients carrying rs11102024TT genotype had higher M-CSF levels (median: 20.28 pg/mL) than those with AA genotype (6.82 pg/mL) (P < 0.0001) or AT genotype (11.61 pg/mL) (P = 0.027). Patients with systemic pattern outcome were associated with elevated M-CSF and frequently observed in TT carriers. Our data suggest that genetic variants near CSF1 are associated with AOSD and the rs11102024 T allele links to higher M-CSF levels and systemic outcome. These results provide a promising initiative for the early intervention and therapeutic target of AOSD. Further investigation is needed to have better understandings and the clinical implementation of genetic variants nearby CSF1 in AOSD.

Dyskeratotic cells in persistent pruritic skin lesions as a prognostic factor in adult-onset Still disease.

Adult-onset Still disease (AOSD), a systemic inflammatory disorder, is characterized by high fever, evanescent rash, arthritis, and hyperferritinaemia. AOSD is also reported to be associated with other skin lesions, including persistent pruritic papules and plaques. This study aimed to assess the significance of dyskeratotic skin lesions in Japanese AOSD patients.We retrospectively assessed the histology of persistent pruritic skin lesions and evanescent rashes and the relationship between dyskeratotic cells, serum markers, and outcomes in 20 Japanese AOSD patients, comparing AOSD histology with that of dermatomyositis (DM), drug eruptions, and graft-versus-host disease (GVHD).As the results, Persistent pruritic lesions were characterized by scattered single keratinocytes with an apoptotic appearance confined to the upper layer of the epidermis and horny layer without inflammatory infiltrate. In contrast to AOSD, the histology of DM, drug eruption, and GVHD demonstrated dyskeratotic cells in all layers of the epidermis with inflammatory infiltrate. AOSD with evanescent rash showed no dyskeratotic cells. The dyskeratotic cells in pruritic AOSD lesions stained positive for ssDNA and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling, indicating apoptosis. Serum IL-18 was significantly higher in AOSD patients with dyskeratotic cells than those without, and generally required higher doses of glucocorticoids, immunosuppressants, and biologic agents. Two of ten AOSD patients with dyskeratotic cells died from hemophagocytic lymphohistiocytosis.In conclusion, Persistent pruritic AOSD skin lesions are characterized by dyskeratotic cells with apoptotic features, involving the upper layers of the epidermis. There may be a link to elevated IL-18. This dyskeratosis may be a negative prognostic indicator.

Clinical characteristics and comorbidities in adult-onset Still's disease using a large US administrative claims database.

We aimed to describe clinical characteristics, treatment patterns and major comorbidities of a US-based adult-onset Still's disease (AOSD) cohort. Administrative claims data from Truven MarketScan were collected from 2009 to 2015. An AOSD case was defined as ≥1 M06.1 International Classification of Diseases 10th revision (ICD-10) medical claim code. We extracted data for the AOSD cohort (n = 106) and 1:5 matched controls (n = 530) without AOSD. Outcomes of interest and a novel claims-based set of Yamaguchi criteria were identified by relevant ICD 9th revision (ICD-9) and ICD-10 codes. Bivariate descriptive analyses were conducted on all variables. Comorbidity rates and rate ratios were calculated in AOSD cases and matched controls. Statistical significance of cohort differences was determined to compare AOSD cases and matched controls. The AOSD cohort, with a mean age of 43.08 (standard deviation, s.d. 13.9) years and with female predominance (68.9%) was observed over a mean of 750.12 (637.6) days. A total of 35.9% of AOSD patients fulfilled claims-based Yamaguchi criteria compared with 0.4% matched controls (P< 0.05). We identified severe AOSD-related complications, including macrophage activation syndrome (4.7%) and acute respiratory distress syndrome (12.3%). Treatment commonly involved systemic glucocorticoids (62.2%), MTX (51%) and anakinra (24.5%). Compared with matched controls, serious infections were significantly increased (rate ratio 2.58, 95% CI: 1.53, 4.37, P = 0.0004), while hyperlipidaemia (0.54, 95% CI: 0.35, 0.85; P = 0.008) and obesity (0.30, 95% CI: 0.15, 0.62; P = 0.001) were significantly decreased in AOSD patients. We characterized a first US-based AOSD cohort using a large national administrative claims database, and identified key complications, treatments and comorbidities.

Elevated plasma galectin-3 levels and their correlation with disease activity in adult-onset Still's disease.

With galectin-3 playing an important role in inflammatory responses, elevated galectin-3 levels have been shown in patients with autoimmune diseases. However, there are limited data regarding galectin-3 expression in patients with autoinflammatory diseases such as adult-onset Still's disease (AOSD). This study aimed to investigate the extracellular galectin-3 expression and examine its association with activity parameters and disease outcome in AOSD patients. Plasma levels of galectin-3 and inflammasome downstream cytokines including interleukin (IL)-1β and IL-18 were determined by ELISA in 42 active AOSD patients and 20 healthy controls (HC). The protein levels of galectin-3 and cytokines were determined using immunoblotting. Plasma levels of galectin-3 and inflammasome downstream cytokines including IL-1β and IL-18 were significantly higher in AOSD patients (median 5.02ng/ml, interquartile range [IQR] 3.12-7.88ng/ml; 3.42pg/ml, IQR 1.48-6.70pg/ml; and 5758pg/ml, IQR 859-11,895pg/ml, respectively) compared with HC (1.86ng/ml, IQR 1.09-2.89ng/ml; 0.99pg/ml, IQR 0.62-1.35pg/ml; and 129pg/ml, IQR 71-155pg/ml, respectively, all p < 0.001). Plasma galectin-3 levels were positively correlated with clinical activity scores, inflammatory parameters values, and the levels of IL-1β and IL-18 in AOSD patients. AOSD patients with systemic pattern had significantly higher galectin-3 levels (median 6.08ng/ml, IQR 4.01-9.54ng/ml) compared with those with chronic articular pattern (3.56ng/ml, IQR 3.04-4.98ng/ml, p < 0.05). After 6-month therapy, galectin-3 levels significantly declined, paralleling the decreases in clinical activity scores and plasma levels of IL-1β and IL-18. Elevated galectin-3 levels and their positive correlation with disease activity scores, inflammatory parameter, and inflammasome downstream cytokines suggest the involvement of galectin-3 in AOSD pathogenesis.Key Points• We revealed for the first time the association of plasma galectin-3 levels with AOSD activity parameters.• We explored the link between galectin-3 levels and NLRP3-inflammasome downstream cytokines in AOSD disease.

Canakinumab for the treatment of adult-onset Still’s disease

ABSTRACTIntroduction: Adult-onset Still’s disease (AOSD) is a rare multisystem autoinflammatory disorder of unknown etiology, with clinical and biological similarities with the juvenile form (sJIA).The pivotal role of interleukin (IL)-1 gives rise to the use of IL-1 inhibitors in treating resistant cases.Areas covered: This review focuses on canakinumab, a fully human anti-IL-1β antibody, as treatment for AOSD. The data obtained from case reports and case series on AOSD and two double-blind, randomized, placebo-controlled Phase III trial on sJIA are analyzed. Efficacy and safety profiles of canakinumab are discussed.Expert opinion: There is no unanimous consensus on how to treat with IL-1 inhibitors. Many reviews have focused primarily on anakinra, but the accumulating data for canakinumab have emerged. The choice of treatment is a relevant issue for patients and the national health services. The available data for canakinumab indicate that this drug in AOSD patients is effective and well tolerated.