Treatment Of Adult-onset Still's Disease Research Articles

Identification of discriminatory factors and construction of nomograms for differentiating AOSD and sepsis.

This study aimed to develop nomogram prediction models to differentiate between adult-onset Still's disease (AOSD) and sepsis. We retrospectively collected laboratory test data from 107 hospitalized patients with AOSD and sepsis at the Affiliated Hospital of Xuzhou Medical University. Multivariate binary logistic regression was used to develop nomogram models using arthralgia, WBC, APTT, creatinine, PLT, and ferritin as independent factors. The performance of the model was evaluated by the bootstrap consistency index and calibration curve. Model 1 had an AUC of 0.98 (95% CI, 0.96-1.00), specificity of 0.98, and sensitivity of 0.94. Model 2 had an AUC of 0.96 (95% CI, 0.93-1.00), specificity of 0.92, and sensitivity of 0.94. The fivefold cross-validation yielded an accuracy (ACC) of 0.92 and a kappa coefficient of 0.83 for Model 1, while for Model 2, the ACC was 0.87 and the kappa coefficient was 0.74. The nomogram models developed in this study are useful tools for differentiating between AOSD and sepsis. Key Points • The differential diagnosis between AOSD and sepsis has always been a challenge • Delayed treatment of AOSD may lead to serious complications • We developed two nomogram models to distinguish AOSD from sepsis, which were not previously reported • Our models can be used to guide clinical practice with good discrimination.

Clinical presentation and treatment of adult-onset Still disease – a single-centre experience

Clinical presentation and treatment of adult-onset Still disease – a single-centre experience

Management of adult-onset Still's disease: evidence- and consensus-based recommendations by experts.

Adult-onset Still's disease (AOSD) is a rare condition characterized by fevers, rash, and arthralgia/arthritis; most doctors treating AOSD in the Netherlands treat <5 patients per year. Currently, there is no internationally accepted treatment guideline for AOSD. The objectives of this study were to conduct a Delphi panel aimed at reaching consensus about diagnostic and treatment strategies for patients with AOSD and to use the outcomes as a basis for a treatment algorithm. The Delphi panel brought together 18 AOSD experts: rheumatologists, internists and paediatricians. The Delphi process consisted of three rounds. In the first two rounds, online lists of questions and statements were completed. In the third round, final statements were discussed during a virtual meeting and a final vote took place. Consensus threshold was set at 80%. Two targeted literature searches were performed identifying the level of evidence of the consensus-based statements. Consensus was reached on 29 statements, including statements related to diagnosis and diagnostic tests, definition of response and remission, the therapy, the use of methotrexate and tapering of treatment. The panel consented on reduction of the use of glucocorticoids to avoid side effects, and preferred the use of biologics over conventional treatment. The role of IL-1 and IL-6 blocking agents was considered important in the treatment of AOSD. In this Delphi panel, a high level of consensus was achieved on recommendations for diagnosis and therapy of AOSD that can serve as a basis for a treatment guideline.

Adult-Onset Still's Disease in Pregnancy: Lessons Learned and an Approach to Subsequent Pregnancies.

Adult-onset Still's disease (AOSD) is a rare autoinflammatory disorder with potential for life-threatening complications in pregnancy. Recently, biologic therapeutics have been increasingly used for treatment of AOSD, but there is little available data on the treatment of AOSD in pregnancy. Here we report a 23-year-old primigravid patient with a history of AOSD who presented at 20 weeks of gestation with fever, arthralgias, rash, fatigue, and highly elevated ferritin, concerning for AOSD flare. She was treated with tocilizumab, an interleukin-6 receptor antagonist, with rapid clinical and laboratory improvement; however, she underwent iatrogenic preterm delivery at 34 weeks of gestation for fetal distress, which was attributed to placental injury. In a subsequent pregnancy, she was treated with tocilizumab throughout and had an uncomplicated term delivery with normal labs and no AOSD flare. This case highlights that the use of tocilizumab may be effective to reduce the risk of AOSD flare during pregnancy.

Tocilizumab-induced mucosal injury in the terminal ileum mimicking intestinal Behçet's disease: A case report.

Tocilizumab, a humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody, is used for the treatment of adult-onset Still disease (AOSD). Despite its efficacy in many clinical situations, concerns have been raised regarding intestinal mucosal injury in patients receiving tocilizumab. A 64-year-old woman with a history of AOSD was admitted to our hospital with hematochezia. She had AOSD for 15 years and underwent treatment with biweekly tocilizumab 9 months prior to admission. Colonoscopy revealed a large punched-out ulcer in the terminal ileum. On pathological evaluation, nonspecific enteritis with lymphocytes and eosinophils were seen. Based on the location and shape of the lesion, we suspected intestinal Behçet's disease. However, the ulcer reduced in size over time by discontinuation of tocilizumab without additional drug treatment, indicating that it was a drug-induced ulcer. The patient was diagnosed with tocilizumab-induced small intestinal ulcer. The patient treated with the discontinuation of tocilizumab. The discontinuation of tocilizumab resulted in ulcer scarring. There was no recurrence of hematochezia. Tocilizumab can cause deep ulcerative lesions in the terminal ileum, which may resemble intestinal Behçet's disease. It is important to continuously monitor abdominal symptoms during tocilizumab therapy and aggressively perform colonoscopy when hematochezia or abdominal pain is observed.

Hepatic Superscan in Methotrexate-Associated Lymphoproliferative Disorder.

A 60-year-old man on methotrexate for treatment of adult-onset Still disease presented with acute onset of fever, pancytopenia, and deranged liver function. Besides FDG-avid lesions in spleen and skeleton, his 18F-FDG PET/CT study showed diffuse and intense uptake in the liver with significantly suppressed heart and brain activity (reminiscent of a hepatic superscan). Subsequent biopsy confirmed the diagnosis of methotrexate-associated lymphoproliferative disorder.

Canakinumab for Adult-Onset Still Disease

&#x0D; This review identified limited evidence from 2 systematic reviews about the clinical effectiveness and safety of canakinumab for patients with adult-onset Still disease (AOSD). Most studies in the systematic reviews on AOSD did not have a control group; therefore, the findings related to the effectiveness and safety of canakinumab in this population are uncertain.&#x0D; For adults with AOSD, treatment with canakinumab may be associated with a complete or partial response to treatment, corticosteroid-sparing effect, and a decrease or normalization of key laboratory parameters, such as leukocyte count, erythrocyte sedimentation rate, and serum levels of ferritin and C-reactive protein, compared with baseline.&#x0D; In adults with AOSD, limited evidence suggested there was no statistically significant difference between canakinumab and placebo in articular manifestations.&#x0D; Adverse events associated with canakinumab treatment included infections, leukopenia, musculoskeletal and connective tissue disorders, skin disorders, thoracic and mediastinal disorders, gastrointestinal disorders, and site injection reactions. Severe adverse events included macrophage activation syndrome, hepatocytotoxicity, and serious infections that led to discontinuation of treatment.&#x0D; No studies were found comparing canakinumab and alternative pharmacologic treatments for AOSD.&#x0D; No studies were found on the cost-effectiveness of canakinumab for the treatment of AOSD.&#x0D; No evidence-based guidelines were found on the use of canakinumab for the treatment of ASOD.&#x0D;

Ferritin-induced NETs lead to cytokine storm in AOSD.

New research reveals that ferritin has an essential role in neutrophil extracellular trap (NET)-mediated inflammation, and suggests that NETs or the ferritin receptor MSR1 could be targeted for the treatment of adult-onset Still disease.

Adult-onset Still's Disease during Pregnancy Treated with Tocilizumab

A 28-year-old woman exhibited a spiking fever, arthritis, and liver disfunction when she was 22 weeks pregnant. She was diagnosed with adult-onset Still's disease (AOSD). As her condition was resistant to corticosteroid therapy, tocilizumab (TCZ) was selected. The TCZ treatment was effective, and she delivered a healthy child while receiving TCZ treatment. Cases in which AOSD first arises during pregnancy are rare, and there have been no reports of TCZ treatment for AOSD being initiated during pregnancy. Although the safety of TCZ treatment during pregnancy has not been established, it may be effective against severe AOSD that develops during pregnancy.

Recommendations of diagnosis and treatment of adult-onset Still's disease in China

Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disorder. In China, standardized diagnosis and treatment for AOSD is insufficient. Based on the evidence from China and other countries, Chinese Rheumatology Association developed standardization of diagnosis and treatment of AOSD in China. The purpose is to standardize the methods for diagnosis of AOSD, treatment strategies, and reduce misdiagnosis, missed diagnosis and irreversible damage.

The effectiveness of tocilizumab in treating refractory adult-onset Still’s disease with dichotomous phenotypes: IL-18 is a potential predictor of therapeutic response

Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder with clinical heterogeneity. Although tocilizumab (TCZ), an interleukin (IL)-6 receptor inhibitor, is an effective treatment for AOSD, the evidence regarding its efficacy on systemic or articular subtypes is conflicting. Furthermore, the predictors of therapeutic response are still elusive and worthy of exploration. This two-center retrospective study analyzed the effectiveness and safety profile of TCZ treatment in 28 patients with refractory AOSD. The 28-joint disease activity score (DAS28) and systemic activity score were assessed before and during TCZ treatment period at weeks 12, 24, 36, and 48. Plasma levels of proinflammatory cytokines at baseline were determined using ELISA method. Among the systemic subtype patients, 10 (58.8%), 13 (76.5%), 14 (82.4%), and 15 (88.2%) patients achieved complete remission at week 12, 24, 36, and 48, respectively, in comparison to 2 (22.2%), 5 (55.6%), 6 (66.7%), and 7 (77.8%) who achieved disease remission (DAS28 < 2.6) at weeks 12, 24, 36, and 48, respectively, among articular subtype patients. The systemic activity scores and inflammatory parameters were significantly decreased after 12-week TCZ therapy, and TCZ could significantly reduce corticosteroid dose in AOSD patients. Multivariate analysis reveals that baseline IL-18 level is a significant predictor of poor therapeutic response at week 24 (odds ratio 7.86, p < 0.05). AOSD patients refractory to high-dose corticosteroids and methotrexate may respond well to TCZ treatment with a steroid-sparing effect and an acceptable safety. A high baseline IL-18 level may be a predictor of poor therapeutic response. Key Points • Tocilizumab may be effective and well-tolerated in refractory AOSD patients regardless of disease subtypes. • High plasma levels of IL-18 may predict poor response to tocilizumab in AOSD patients.

Brain Abscess Due To Asian Nocardia in a 63 Years-Old Patient with Adult Still´S Disease: A Rare Case Report and Literature Review

Cerebral nocardiosis is a rare and opportunistic pathology caused by a gram-positive, aerobic bacterium of the order of Actinomycetes called Nocardia spp. It appears in patients with immunodeficiencies affecting cellular immunity. Nocardia can affect an organ (lungs in 75% of cases) or manifest itself as a disseminated infection (central nervous system in 25% of cases). Here we present a rare case of 63-years-old patient immunocompromised by monoclonal biologic treatment for Adult-Onset Still disease (AOSD), who subsequently presents fever, signs of motor focality and resonance imaging findings which show supra and infratentorial lesions. The patient is managed in intensive therapy for sensory impairment, receiving standardized antibiotic scheme, getting through to complicated evolution. Cerebral nocardiosis is a rare infectious disease that requires an early diagnostic study and its respective treatment.

Efficacy of tight control strategy in the treatment of adult-onset Still disease.

Adult-onset Still's disease (AOSD) characterized by a high spiking fever, skin rash, arthritis, and leukocytosis. The aim of the present study was considering the long-term outcomes of patients with AOSD who were treated with tight control strategy with disease modifying anti-rheumatic drugs (DMARDs). Fifty-six patients with AOSD treated with tight control strategy were included. Four levels of remission were defined. Remission on-treatment was defined as the clinical remission, patient global assessment (PGA) ≤ 1, and prednisolone dose ≤ 5mg/day for at least 6months. Remission off-treatment was defined as the clinical remission and PGA ≤ 1 for at least 6months as well as discontinuation of prednisolone, DMARDs, and biologics. Sustained remission on-treatment was defined as the clinical remission, PGA ≤ 1, and prednisolone dose ≤ 5mg/day for ≥ 5years. Sustained remission off-treatment was defined as the clinical remission and PGA ≤ 1 for ≥ 5years as well as discontinuation of prednisolone, DMARDs, and biologics. Throughout a median follow-up of 47months, remission on-treatment and off-treatment were obtained in 94.6% and 44.6% of patients, respectively. Sustained remission on-treatment and off-treatment were obtained in 79.2 and 8.3% of patients, respectively. Glucocorticoids (GCs) and DMARDs were discontinued in 66.1% and 48.2% of the patients, respectively. Apart from the older age of the patients in the on-GCs group, no significant differences were observed between the groups. Our study showed that using DMARDs with tight control strategy at the presentation of AOSD may control disease activity successfully. Key Points • Using DMARDs with tight control strategy at the presentation of adult-onset Still's disease may control disease activity successfully.

成人Still病的诊疗进展

Adult-onset Still disease(AOSD) is a autoimmune rheumatism.Clinical features of AOSD are fever,arthralgia,skin rash and WBC elevation.Laboratory examinations display a nonspecific inflammation reaction.Combining therapy by non-steroidal anti-inflammatory drugs(NSAID)and hormone to treat AOSD has achieved good results.This article aims to introduce diagnosis and treatment of AOSD.

Pathogenesis, disease course, and prognosis of adult-onset Still's disease: an update and review.

Objective:Adult-onset Still's disease (AOSD) is a rare but clinically well-known polygenic systemic autoinflammatory disease. In this review, we aim to present frontiers in the pathogenesis, clinical features, diagnosis, biomarkers, disease course, prognosis, and treatment in AOSD.Data sources:We retrieved information from the PubMed database up to July 2019, using various search terms and relevant words, including AOSD and Still's disease.Study selection:We included data from peer-reviewed journals. Both basic and clinical studies were selected.Results:Pathogenesis of AOSD involves genetic background, infectious triggers, and immunopathogenesis, mainly the activation of macrophages and neutrophils followed by a cytokine storm. Diagnosis and prognosis evaluation of AOSD is still challenging; therefore, there is an urgent need to identify better biomarkers. Biologic agents, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α antagonists in the treatment of AOSD, have good prospect.Conclusion:This review highlights the advances in pathogenesis, potential biomarkers, disease course, and treatment in AOSD.

Adult-Onset Still's Disease: Molecular Pathophysiology and Therapeutic Advances.

Adult-onset Still's disease (AOSD) is a rare inflammatory disorder of unknown etiology generally characterized by persistent high spiking fever, evanescent rash, and polyarthritis. The pathogenesis of AOSD is only partially known. The pivotal role of macrophage cell activation, which leads to T-helper 1 (Th1) cell cytokine activation, is now well-established in AOSD. Moreover, pro-inflammatory cytokines such as interleukin (IL)-1, -6, and -18 seem to play a key role in this disorder, giving rise to the development of new targeted therapies. For years, treatment of AOSD has been largely empirical, using nonsteroidal anti-inflammatory drugs, corticosteroids, and disease-modifying antirheumatic drugs. Patients with steroid- and methotrexate-refractory AOSD can now benefit from efficient and well-tolerated biologic agents such as IL-1, IL-6, and tumor necrosis factor-α antagonists.

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.

THU0393 The Effectiveness of TOCILIZUMAB on Preventing Relapses of Adult-Onset Still's Disease; A Retrospective, Single Center Study

BackgroundPatients with adult-onset Still's disease (AOSD) experience frequent relapses. Several case series and cohort studies showed the relatively short-term effectiveness of tocilizumab (TCZ), an anti-interleukin-6 receptor monoclonal antibody, on the...

A novel therapeutic approach in pulmonary arterial hypertension as a complication of adult‐onset Still's disease: targeting IL‐6

Adult-onset Still's Disease (AOSD), often though as the adult variant of systemic juvenile idiopathic arthritis (JIA), has an incidence of 1-3 cases per 1 million. Cardinal manifestations include fever, arthritis, skin rash, sore throat, hepatosplenomegaly and lymphadenopathy. Prolongation in diagnosing this disease results from its similarity to infectious, malignant and rheumatic diseases and lack of biomarkers. Pulmonary arterial hypertension (PAH) is a rare pulmonary complication of AOSD, and we are aware of only six cases reported in literature to date. Here we present a patient with AOSD who has developed pulmonary hypertension as a complication. We report a case of AOSD complicated by PAH treated successfully with tocilizumab, a humanized monoclonal antibody to human interleukin (IL)-6 receptor. A Pubmed and Medline search for evidence of pulmonary hypertension in AOSD and use of IL-6 inhibition in management was performed. Data for this study was collected from the patient's chart records. No infectious or neoplastic cause of her disease was identified and after extensive diagnostic workup, the patient was diagnosed with AOSD fulfilling Yamaguchi criteria. After initiation of IL-6 therapy the patient was followed over time to monitor the hemodynamic changes in pulmonary vasculature. Following treatment with Tocilizumab, the patient showed dramatic improvement in her clinical symptoms and remains in remission, through combination of tocilizumab (8 mg/kg), methotrexate and prednisone. Improvement of systemic symptoms, right heart catheterization (RHC) findings and the VECTRA-DA score served as a measure of treatment response. Tocilizumab has been effective in demonstrating marked improvement in both the clinical and laboratory parameters. Tocilizumab is an effective novel treatment for AOSD with PAH. This is the first documented report of successful use of tocilizumab in AOSD patients presenting with PAH. Prospective comparative studies could help validate its efficacy and safety.

Subacute Liver Failure Following Anakinra Treatment for Adult-onset Still Disease

To the Editor: Anakinra is approved for the treatment of rheumatoid arthritis and it is used off-label for various other rheumatic diseases1. Although beneficial effects of anakinra on liver inflammation and regeneration have been shown2, we describe a case of subacute liver failure in a patient with adult-onset Still disease (AOSD) who had been treated with anakinra monotherapy. Three months before admission to our hospital, the 20-year-old man had been diagnosed with AOSD. Initial treatment consisted of anakinra 100 mg and prednisolone 100 mg daily. The latter had been tapered to 10 mg after achieving remission 1 week before the first symptoms of liver failure appeared. The patient developed fever and jaundice. C-reactive protein was increased to 42 mg/dl, immunoglobulin E (IgE) was elevated to 709 kU/l, and transaminases were substantially increased, with alanine transaminase levels of 1128 U/l (Figure 1a). With an INR of 2.7, coagulation was massively disturbed. Figure 1. Development of the clinical course and hematoxylin and eosin stainings of the liver biopsy. (a) Development of alanine transaminase (ALT, U/l), bilirubin … Address correspondence to Dr. Benten; E-mail: d.benten{at}uke.de