Refractory Adult-onset Still's Disease Research Articles

P07 The use of JAK inhibitors in difficult-to-treat adult-onset Still’s disease

Abstract Introduction Adult-onset Still’s Disease (AOSD) is a rare systemic auto-inflammatory disorder characterised by fever, arthritis and rash. Some patients with AOSD exhibit resistance or intolerance to conventional treatments, necessitating alternative therapeutic strategies. This case explores the efficacy and safety of janus kinase (JAK) inhibitors in managing difficult-to-treat AOSD. The driving force behind Still’s disease lies in the excessive and inappropriate production of pro-inflammatory cytokines, notably interleukin-6 (IL-6) and interferon (IFN). Given the pivotal role of JAK inhibitors in mitigating these cytokine pathways, this study highlights their potential therapeutic impact in the management of difficult-to-treat AOSD. Case description A 32-year-old male presented in July 2021 with a three-week history of fevers, night sweats, rigors, and weight loss. A CT scan revealed widespread lymphadenopathy above and below the diaphragm. Blood cultures were negative and, despite antibiotics, the patient continued to experience intermittent fevers. Anemia was asymptomatic, and the patient was transfused with two units of blood. Chronic B infection led to the initiation of entecavir. The patient also experienced palpitations and tachycardia, with an echo revealing a small pericardial effusion, hypertrophied and hyperdynamic left ventricle (LV) with an ejection fraction of 70-75%. A lymph node biopsy was inconclusive, prompting a second biopsy. In September 2021, hyponatremia due to SIADH developed. The patient had ongoing symptoms, including weight loss, and a bone marrow biopsy showed reactive features. CT and PET scans revealed generalised lymphadenopathy. Rheumatology consultation in November 2021 indicated intermittent fever, weight loss, joint pain, and elevated inflammatory markers. The patient had dermatographic lymphadenopathy, and a negative lymph node biopsy lowered the probability of HLH. Methotrexate was initiated, later switched to azathioprine and prednisolone due to ongoing symptoms. In June 2022, the patient started tocilizumab, which resolved joint pain but caused ongoing dermatitis. Tocilizumab was discontinued in January 2023 due to inefficacy, and anakinra was initiated. Prednisolone was gradually tapered off. The patient experienced shortness of breath, and echo revealed pulmonary hypertension. Tocilizumab was discontinued due to injection site reactions and increased hepatitis B virus titers. In March 2023, the decision was made to start the JAK inhibitor tofacitinib. By May 2023, ferritin levels were 1196, and the patient was successfully coming off prednisolone with well-controlled symptoms. Discussion This case underscores the efficacy of JAK inhibitors as a successful therapeutic intervention in challenging cases of AOSD. The 32-year-old male presented with severe symptoms including fevers, night sweats, weight loss, and widespread lymphadenopathy. Initial treatments with antibiotics, methotrexate, azathioprine, prednisolone, and tocilizumab were either ineffective or led to adverse reactions. Despite these setbacks, the patient showed a remarkable clinical response to the JAK inhibitor tofacitinib, initiated in March 2023. The swift and sustained improvement in symptoms, along with a favourable safety profile, suggests that JAK inhibitors can be a promising treatment for refractory AOSD. The ability to taper off steroids while maintaining symptom control is particularly noteworthy, as long-term steroid use is associated with significant side effects. The success of JAK inhibitors in this case is likely attributed to their mechanism of action, which strategically blocks pro-inflammatory cytokine pathways, particularly IL-6 and IFN. This targeted approach addresses the underlying pathophysiology of AOSD, leading to better disease management. However, this case also highlights the importance of monitoring for potential side effects, such as increased hepatitis B virus titres observed in this patient. This necessitated adjustments in therapy and careful monitoring of liver function. The encouraging outcomes in this case prompt the need for further prospective studies to validate these findings. Future research should focus on elucidating the optimal dosing and duration of JAK inhibitor therapy in patients with refractory AOSD. Additionally, long-term follow-up studies are essential to fully understand the safety profile of these agents. Key learning points • Refractory AOSD treatment: JAK inhibitors, such as tofacitinib, can be effective for patients with refractory AOSD who do not respond to conventional therapies. • Steroid sparing: JAK inhibitors may allow for the tapering off of steroids, reducing the risk of long-term steroid-related side effects. • Cytokine pathway targeting: The success of JAK inhibitors highlights the importance of targeting specific pro-inflammatory cytokine pathways, particularly IL-6 and IFN, in managing AOSD. • Monitoring side effects: Continuous monitoring for potential side effects, including increased the risk of thromboembolic events is crucial when using JAK inhibitors. • Need for further research: Prospective studies are needed to validate the efficacy and safety of JAK inhibitors in AOSD and to determine optimal dosing and treatment duration.

P05 The role of JAK inhibitors in difficult-to-treat adult-onset Still’s disease: a case series

Abstract Introduction Adult-onset Still’s Disease (AOSD) is a rare systemic auto-inflammatory disorder characterised by fever, arthritis and rash. Some patients with AOSD exhibit resistance or intolerance to conventional treatments, necessitating alternative therapeutic strategies. This case series aims to explore the efficacy and safety of JAK inhibitors in managing difficult-to-treat AOSD. The driving force behind Still’s disease lies in the excessive and inappropriate production of pro-inflammatory cytokines, notably IL-6 and interferon. Given the pivotal role of JAK inhibitors in mitigating these cytokine pathways, this study highlights their potential therapeutic impact in the management of difficult to treat AOSD. Case description In this retrospective case series, three adult patients with difficult-to-treat AOSD were evaluated for their response to JAK inhibitors, specifically tofacitinib and baricitinib. Case 1: A 32-year-old male presented with a three-week history of fevers, night sweats, weight loss, and lymphadenopathy. Diagnosed with AOSD 18 months later, his treatment began with prednisolone and methotrexate, which was subsequently switched to azathioprine. Tocilizumab was then introduced, alleviating joint pain but causing dermatitis. He was switched to anakinra, allowing a reduction in prednisolone but failing to induce remission and resulting in abnormal liver functions and increased hepatitis B virus titers. Finally, he commenced tofacitinib, achieving symptom resolution, reduced serum ferritin levels, and cessation of steroids. Case 2: A 32-year-old woman presented with a six-month history of joint pain, swelling, stiffness, night sweats, weight loss, and a recurrent rash. Laboratory tests showed anemia, lymphopenia, elevated inflammatory markers, and high ferritin levels. Initial treatment with 60 mg oral prednisolone showed some response, but polyarthritis necessitated further intervention. Anakinra initially managed systemic symptoms, though joint swelling persisted. Tocilizumab was tried but proved ineffective. Subsequently, transitioning to baricitinib at 4 mg daily resulted in good symptomatic control. Case 3: An 18-year-old female presented with recurrent fevers, an intermittent macular rash, joint pains, diarrhoea and splenomegaly. Despite initial antibiotic treatment, persistent symptoms led to an AOSD diagnosis, prompting steroid therapy. Methotrexate failed to control symptoms and caused significant nausea, leading to a switch to tocilizumab. While anakinra initially resolved skin and joint symptoms, recurrent flares necessitated further changes. Azathioprine was trialed but discontinued due to side effects. Colchicine was tried next. Finally, tofacitinib was introduced, and one year later, she achieved significant progress, reducing prednisolone dosage to 5 mg. Discussion The findings from this case series underscore the potential of JAK inhibitors, particularly tofacitinib and baricitinib, as effective treatments for refractory AOSD. In all three cases, patients showed substantial clinical improvement and were able to reduce or discontinue steroids. This suggests a promising role for JAK inhibitors in managing AOSD, especially given the disease’s association with excessive pro-inflammatory cytokine production, including IL-6 and IFN pathways. The transition to JAK inhibitors was often necessitated by inadequate responses or adverse effects from conventional therapies like methotrexate, azathioprine, and biologics such as tocilizumab and anakinra. The successful outcomes with JAK inhibitors highlight their ability to achieve disease control where other treatments failed, demonstrating their efficacy in reducing systemic inflammation and disease activity. Further research is warranted to establish optimal dosing, duration of therapy, and long-term safety profiles of JAK inhibitors in this patient population. These preliminary results are encouraging and suggest a new avenue for treating AOSD. Key learning points • Efficacy of JAK inhibitors: JAK inhibitors, particularly tofacitinib and baricitinib, demonstrated substantial clinical improvement in patients with refractory AOSD. • Steroid reduction: All three patients were able to reduce or discontinue steroid use, highlighting the potential of JAK inhibitors to minimise long-term steroid dependency. • Management of refractory AOSD: JAK inhibitors provided effective disease control where conventional therapies such as methotrexate, azathioprine, and biologics like tocilizumab and anakinra were inadequate or resulted in adverse effects. • Mechanism of action: The efficacy of JAK inhibitors may be attributed to their ability to block pro-inflammatory cytokine pathways, particularly IL-6 and IFN, which are crucial in AOSD pathogenesis. • Safety profile: The treatment was well-tolerated, with significant symptomatic relief and no severe adverse events reported during the study period. • Need for further research: There is a need for further prospective studies to determine the optimal dosing, duration of therapy, and long-term safety profiles of JAK inhibitors in AOSD patients. • Personalised treatment approach: The study supports a personalised treatment approach, considering JAK inhibitors for patients with difficult-to-treat AOSD who do not respond adequately to conventional therapies.

Fulminant myocarditis with adult-onset Still's disease: case-based review.

Myocarditis has been reported as a life-threatening complication of adult-onset Still's disease (AOSD), but fulminant myocarditis with AOSD is very rare. We hereby report a case of a 43-year-old female with fulminant myocarditis with AOSD. She had a refractory AOSD and cardiogenic shock with markedly elevated ferritin level up to 67,370 ng/mL. She was successfully treated with canakinumab and mechanical circulatory support (MCS) such as venoarterial extracorporeal membrane oxygenation and Impella CP. We also reviewed the previous cases of fulminant myocarditis with AOSD published from 1976 to December 2022, and only 8 cases of fulminant myocarditis with AOSD have been reported. The characteristics of these cases showed that the average age at presentation was 37.6 years (range 24-47 years). The time to myocarditis from the onset of AOSD ranged from 2 weeks to 2 years; however, most cases developed myocarditis within 1 year. Initial presenting symptoms included fever, dyspnea, chest pain, myalgia, rash, and sore throat. The median peak ferritin was 13,000 ng/mL. Left ventricular ejection fractions were not greater than 35%. Our case was the first reported case successfully treated with canakinumab and MCS. This review suggests that myocarditis may be an early phase of the complication in patients with AOSD, and the severity of AOSD may correlate with the severity of myocarditis. Canakinumab for AOSD and MCS for fulminant myocarditis may be one of the choices for overcoming the comorbidities.

Efficacy of Baricitinib in Patients with Refractory Adult-Onset Still's Disease.

Adult-onset Still's disease (AOSD) is an idiopathic systemic inflammatory disease of unknown aetiology. Some patients exhibit resistance to conventional treatment during long-term therapy. Janus kinase inhibitors (JAKinibs) may contribute to the improvement in AOSD symptoms via the JAK-signal transducer and activator of transcription (STAT) pathway. We aimed to explore the efficacy and safety of baricitinib in patients with refractory AOSD. Patients were enrolled if they fulfilled the Yamaguchi AOSD classification criteria in China between 2020 and 2022. All patients were recognized as having refractory AOSD and were treated with oral baricitinib at a dosage of 4mg once daily. A systemic score and prednisone dosage were used to evaluate the efficacy of baricitinib at months 1, 3, and 6 and at the last follow-up visit. The safety profiles were recorded and analysed at every assessment. Seven female patients with refractory AOSD received baricitinib. The median age was 31 (IQR 10) years. Treatment was terminated in one patient due to progressive macrophage activation syndrome (MAS). Others continued baricitinib treatment until the last assessment. The systemic score decreased significantly at 3 months (p=0.0216), 6 months (p=0.0007), and the last follow-up visit (p=0.0007) compared with baseline. One month after the initiation of baricitinib, the rates of improvement in fever, rash, sore throat, and myalgia symptoms were 71.4% (5/7), 40% (2/5), 80% (4/5), and 66.7% (2/3), respectively. Five patients remained symptom-free at the last follow-up visit. In most patients, their laboratory values had returned to normal by the last follow-up visit. A significant reduction in the levels of C-reactive protein (CRP) (p=0.0165) and ferritin (p=0.0047) was observed at the last visit compared with baseline. The daily prednisolone dosage significantly decreased from 35.7± 15.1mg/day at baseline to 8.8± 4.4mg/day by month 6 (p=0.0256), and it was 5.8± 4.7mg/day at the last assessment (p=0.0030). Leukopenia due to MAS was noted in one patient. Except for mild abnormalities in lipid parameters, no other severe adverse events occurred during follow-up. Our findings suggest that baricitinib therapy could provide rapid and durable clinical and laboratory improvement in patients with refractory AOSD. Treatment seemed to be well tolerated by these patients. The long-term efficacy and safety of baricitinib therapy for AOSD should be assessed further in prospective controlled clinical trials in the future. Trial registration number (TRN): ChiCTR2200061599. Date of registration: 29 June 2022 (retrospectively registered).

Baseline clinical features predicting macrophage activation syndrome in patients with systemic adult-onset Still's disease receiving interleukin-6 inhibitor treatment.

Macrophage activation syndrome (MAS), a severe complication of systemic adult-onset Still's disease (AOSD), has been reported to occur during interleukin-6 (IL-6) inhibitor treatment. However, predictors for MAS development are unknown. Therefore, this study investigated predictive features for MAS development after starting IL-6 inhibitor treatment in systemic AOSD patients. In a single-center retrospective study involving systemic AOSD patients who were refractory to high-dose glucocorticoids with immunosuppressants and started IL-6 inhibitor treatment between April 2008 and March 2020, we compared the baseline clinical features between patients who developed AOSD flare with MAS features (MAS group) and those who did not (non-MAS group) during IL-6 inhibitor treatment. Only tocilizumab was used as an IL-6 inhibitor. Six of 14 refractory systemic AOSD patients developed AOSD flares with MAS features during tocilizumab treatment, including 4 who developed them shortly after initiation. The MAS group had significantly lower neutrophil counts, fibrinogen, and higher IL-18/C-reactive protein (CRP) ratio at starting tocilizumab (baseline) than the non-MAS group. Before starting tocilizumab, neutrophil counts were trending downward and upward in the MAS and non-MAS groups, respectively, with significant differences in changes. Receiver operating characteristic analysis showed that baseline neutrophil counts and fibrinogen and their changes before tocilizumab treatment and baseline IL-18/CRP ratio had significant discriminatory abilities for subsequent MAS development. We identified baseline laboratory features associated with MAS development after initiating an IL-6 inhibitor in refractory systemic AOSD patients. These features may reflect the suppression of IL-6 signaling, and further suppression of IL-6 signaling might trigger early-onset MAS.

Short-term, low-dose etoposide in refractory adult-onset Still’s disease-associated macrophage activation syndrome

In this study, we modified the classical regimen of the hemophagocytic lymphohistiocytosis-04 protocol and evaluated the efficacy and safety of short-term, low-dose etoposide in patients with refractory macrophage activation syndrome (MAS) associated with adult-onset Still's disease (AOSD). A total of 17 patients with refractory AOSD-associated MAS were enrolled and received short-term, low-dose etoposide (100mg twice a week for four times). Another 11 patients, who were not treated with etoposide, were included as historical controls. Patient information, such as clinical manifestations, laboratory results, treatments, and short-term prognosis, were recorded and analyzed. In this case series, 88.24% of the patients with MAS who were treated with short-term, low-dose etoposide had a favorable response in 3weeks, which was significantly higher (p = 0.017) than that in the patients with MAS who were treated without etoposide (45.45%). The 90-day survival rate after the onset of MAS was significantly higher (p = 0.0029) among the patients in the short-term etoposide group (16/17, 94.12%) than in the control group (5/11, 45.45%). The regimen of short-term (2weeks), low-dose etoposide was highly effective in the treatment for patients with refractory AOSD-associated MAS with an acceptable safety profile. Key Points • There is no high level evidence to guide the management of refractory MAS-associated AOSD patients. • This study was the first to propose and confirm the efficacy and safety of short-term, low-dose etoposide in the treatment of refractory MAS-associated AOSD patients.

A Case of Macrophage Activation Syndrome During the Treatment of Adult-onset Still's Disease With Tocilizumab.

Macrophage activation syndrome (MAS) is a fatal complication of adult-onset Still's disease (AOSD). Although anti-cytokine agents have been recommended for refractory AOSD or complicated with MAS, MAS cases have been rarely reported during anti-cytokine treatment. Herein, we describe the first AOSD case complicated with MAS during the treatment with tocilizumab in Korea. Two years after tocilizumab maintenance therapy, high fever and hypertransaminasemia recurred. MAS was diagnosed based on hyperferritinemia, elevated soluble IL-2 receptor levels, and the presence of hemophagocytic histiocytes in the bone marrow. However, she had normal white blood cell counts and acute phase reactant levels. High-dose glucocorticoid and anakinra therapies were not effective, but her disease improved with etoposide. This case shows that tocilizumab may not prevent MAS development and can modify clinical features making it challenging to diagnose. Cytotoxic therapy such as etoposide may be required in MAS cases that develop during anti-cytokine therapy.

Adult-Onset Still’s Disease: Novel Biomarkers of Specific Subsets, Disease Activity, and Relapsing Forms

Adult-onset Still’s disease (AOSD) is a systemic inflammatory disease of unknown etiology. Recent studies have demonstrated that the hallmark of AOSD is a cytokine storm, which is characterized by the excessive production of interleukin (IL)-1, IL-6, IL-18, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), suggesting how pro-inflammatory cytokines play an important role in the pathogenesis of this disease. Actually, a certain proportion of patients (around 17–32%) with severe clinical symptoms achieves only partial remission or is resistant to both first-line corticosteroids and second-line DMARDs. These patients are defined as refractory AOSD patients, requiring higher dosage glucocorticoids, longer treatment duration, or the simultaneous introduction of immunosuppressive drugs, further leading to AOSD relapses. In this narrative review, we will analyze the latest literature data to unravel potential pathogenetic factors associated with specific patterns of AOSD disease or relapses in order to identify biomarkers that may guide clinical decisions, eventually leading to new therapeutic options.

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.

A Cohort Study of Liver Involvement in Patients With Adult-Onset Still's Disease: Prevalence, Characteristics and Impact on Prognosis.

Objective: Adult-onset Still's disease (AOSD) is a systemic disorder commonly accompanied by liver involvement. This study aims to illustrate the detailed information of liver abnormalities in patients with AOSD and evaluate the impact on the prognosis.Methods: A total number of 128 hospitalized patients, who met the Yamaguchi criteria of AOSD in the Department of Rheumatology and Immunology, Ruijin Hospital from July 2016 to August 2019 were consecutively enrolled and followed up. The demographic characteristics, clinical features, laboratory tests, treatments and prognosis were recorded. Correlations of liver function tests (LFTs) with disease activity and laboratory parameters were analyzed by the Spearman test. Risk factors of the refractory AOSD were evaluated by multivariate logistic regression analysis.Results: Liver involvement was presented in 104 (81.3%) patients with AOSD. We observed that 34 (32.7%) patients were with mild elevation, 32 (30.8%) patients were with moderate elevation, and 38 (36.5%) patients were with severe elevation. The majority of elevated ALT, AST and ALP decreased to normal within the range of 2 months, except for GGT. Furthermore, the LFTs were found significantly correlated with disease activity. Besides, we found patients with higher levels of LFTs tended to require more intensive treatments and suffered from poorer prognosis. Multivariate logistic regression analysis showed ALP ≥ 141 IU/L and GGT ≥ 132 IU/L are independent risk factors of refractory AOSD.Conclusion: Liver involvement is common in patients with AOSD, the levels of LFTs are associated with disease activity and related to the treatment strategies and prognosis.

Refractory adult-onset Still disease treated by tocilizumab combined with methotrexate: A STROBE-compliant article.

Some patients have poor response to adult-onset Still disease (AOSD) traditional treatment, which easily recurs during the reduction of prednisone. We observed the efficacy and safety of tocilizumab combined with methotrexate (MTX) in the treatment of refractory AOSD, and to explore the possibility of reducing the dosage of tocilizumab after disease control.A total of 28 refractory AOSD cases who had an inadequate response to corticosteroids combined with at least 1 traditional immunosuppressive agent, and even large-dose prednisone could not relieve their conditions after recurrence, were selected in this study. They were treated with tocilizumab (intravenous 8 mg/kg) combined with MTX (oral 12.5 mg once a week). In detail, tocilizumab was firstly given every 4 weeks and after 6-month remission, it was then given every 8 weeks. Some items including body temperature, skin rash, joint swelling and pain, hepatosplenomegaly, blood routine, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum ferritin, and dosage of prednisone were observed before treatment as well as 2, 4, 8, 12, 24, 36, and 48 weeks after treatment. The adverse reactions occurring during the treatment were recorded.The body temperature was normal, the skin rash as well as joint swelling and pain disappeared, and laboratory indexes including CRP, ESR, white blood cell, neutrophilic granulocyte, platelet, hemoglobin, and ferritin were significantly improved after 8-week treatment (all P < .05). The clinical symptoms and laboratory indexes above mentioned were continuously improved 12, 24, 36, and 48 weeks after treatment. The mean dosage of prednisone was reduced from 71.4 ± 20.7 mg/day to 55.0 ± 11.1 mg/day after 2-week treatment, and to 3.3 ± 2.1 mg/day after 48-week treatment (all P < .05). Prednisone was discontinued in 5 cases after 36-week treatment and in 7 cases after 48-week treatment. No serious adverse reactions occurred during the treatment.Tocilizumab can rapidly and markedly improve the clinical symptoms and laboratory indexes and contribute to reduction and discontinuation of prednisone in refractory AOSD. The patients’ conditions are stable after reduction or discontinuation of prednisone and the tocilizumab possesses good safety.

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

ABSTRACTIntroduction: Adult-onset Still´s disease (AOSD) is a systemic inflammatory condition that affects mainly young people. The clinical course consists of two distinctive patterns: one with a predominance of systemic symptoms and another manifested by progressive chronic polyarthritis. Glucocorticoids remain the mainstay in the treatment of AOSD. However, biologic therapies are often required to achieve clinical remission and allow glucocorticoid discontinuation.Areas covered: The review summarizes the main retrospective and prospective studies, and case series on the use of the anti-interleukin (IL)-6 receptor tocilizumab in AOSD.Expert opinion: Since IL-6 serum levels are highly increased in both active systemic and polyarticular phenotypes, IL-6 blockade was considered to be a plausible therapeutic option for the management of AOSD. Tocilizumab, the only anti-IL-6-receptor antagonist currently available for AOSD, has proved to be effective for the management of refractory AOSD patients, including those with life-threatening complications. Nevertheless, there are some reports describing patients who are refractory to any therapy. Future research should focus on the identification of prognostic biomarkers that help us to tailor an individualized treatment for each type of patient and in the search of new disease activity indices that help us to monitor the response to the therapy more closely.

Biological therapy of traditional therapy-resistant adult-onset Still's disease: an evidence-based review.

BackgroundBiotherapy is becoming increasingly important in the treatment of adult-onset Still’s disease (AOSD). The aim of our study was to evaluate the efficacy and safety of biological therapy for AOSD resistant to traditional therapy.Patients and methodsDatabase of Library of Congress, the PubMed, and Web of Science Core Collection were used to retrieve relevant articles published in English language until March 2017. Only studies published in English language were included, and the additional references quoted in these articles were also checked. Articles concerning the efficacy and safety of all the biotherapies in refractory AOSD were evaluated.ResultsThere were 112 articles available in total; 422 AOSD patients were given at least one biologic. We found that 293 patients (69.43%) had received TNF-α blocking agents (infiliximab, etanercept, and adalimumab), 194 patients (45.97%) were treated with IL-1 receptor antagonists (anakinra, rilonacept, and canakinumab), 163 patients (38.63%) were given IL-6 inhibitor (tocilizumab), and 24 patients (5.69%) received rituximab and abatacept. The efficacy of biological therapy and overall tolerance of biological therapy for refractory AOSD were good. Thirty two of 271 patients given anti-TNF-α therapies (11.81%), 116 patients receiving IL-1 inhibitors (65.54%), 124 patients receiving tocilizumab (76.07%), and 13 patients given other biological therapies (36.11%) achieved remission. Side effects of biologic therapy were infections such as urinary tract infections and soft tissue abscess.ConclusionOur findings suggest that anakinra and tocilizumab may be good choices for the treatment of refractory AOSD considering the effectiveness and safety.

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.

Adult onset Still's disease-The evidence that anti-interleukin-1 treatment is effective and well-tolerated (a comprehensive literature review).

The literature contains many reports of the use of commercially available anti-IL-1 agents (anakinra/Kineret®, canakinumab/Ilaris®, or rilonacept/Arcalyst®) in treatment-resistant adult-onset Still's disease (AOSD). These have been widely summarized in many review articles, but a full account of all reports with each of the agents used is not available. This literature review includes all reports of treatment outcomes in patients treated for AOSD with any commercially available anti-IL-1 agent (excluding cases of unconfirmed or atypical AOSD or treatments only for rare AOSD complications). The summary makes use of tabular formats, to identify the available reports and to provide data for compiling and comparison to classical therapies. For each anti-IL-1 agent used, a table shows the frequency of remission during treatment and the frequency of stopping or reducing steroid use, which were reported in almost all articles. A brief textual summary is used to describe other relevant but less often described efficacy aspects and any safety information. The compiled data show that treatment with all anti-IL-1 agents is effective in AOSD, indicating that IL-1 has a central role in the pathogenesis of AOSD. Rates of full or partial remission with each agent were similar to each other (91-100%) and superior to the outcomes published for classical therapies. Primary treatment failures were rare, but efficacy was lost over time in some cases. Of note, the newer anti-IL-1 agents with longer half-lives may show prolonged efficacy. An articular involvement seems to be less responsive than systemic features of disease. However, long-term follow-up shows that efficacy may persist for many years. There is substantial evidence that anti-IL-1 agents have a strong steroid-sparing effect and considerable evidence that the use of disease-modifying anti-rheumatic drugs can also be reduced or stopped. Thus, the use of anti-IL-1 agents may reduce the side-effects of co-treatment. The high response rate to anti-IL-1 agents, especially in refractory AOSD cases, suggests that their appropriate use in a timely manner can slow disease progression and reduce treatment side-effects.

Efficacy and safety of biological agents in adult-onset Still’s disease

Objectives: To describe the efficacy and safety of different biological agents in a large cohort of 20 patients with adult-onset Still’s disease (AOSD).Method: We retrospectively evaluated 20 patients with severe or refractory AOSD treated with at least one biological agent (anakinra, etanercept, tocilizumab, and adalimumab), followed up for at least 12 months at our Institution. We collected and analysed data on the disease course, treatment outcome, and adverse effects, and compared our data with other published series.Results: The median duration of follow-up was 5 years. In 12 patients a single biological drug induced a clinical response. In eight patients the biological agent that was first administered proved ineffective, and a switch to a different biologic was necessary. In three patients a third biologic was necessary to achieve disease control. The biologics eventually determined a clinical response in all patients. Patients with systemic disease showed better responses than patients with chronic articular disease (p < 0.05). Biological agents allowed either the withdrawal or the tapering of corticosteroid therapy (p < 0.0001) and of disease-modifying anti-rheumatic agents (DMARDs; p < 0.05). Three patients experienced herpes zoster reactivation.Conclusions: This is the longest follow-up of a cohort of AOSD patients treated with biological agents. Our data show that biologics are safe and generally effective in the long-term management of AOSD, particularly in cases with systemic disease, and suggest that a clinical response can be obtained in almost all AOSD patients, although a switch to drugs with a different mechanism of action may be necessary.

Two cases of adult-onset Still's disease treated with tocilizumab that achieved tocilizumab-free remission.

There have been many previously reported cases of adult-onset Still's disease (AOSD) which were successfully treated with tocilizumab (TCZ). However, the efficacy and safety of TCZ therapy for AOSD-associated macrophage activation syndrome (MAS), and the optimal duration of TCZ therapy, remain unclear. We herein report two cases of refractory AOSD, one of which was associated with MAS. These two patients were treated with TCZ, and the withdrawal of TCZ was planned according to the serum interleukin-6 level, which resulted in TCZ-free remission.

Usefulness of tacrolimus for refractory adult-onset still's disease: Report of six cases

Six patients with refractory adult-onset Still's disease (AOSD) were treated with tacrolimus (TAC). Patient 1 was pregnant, for whom high-dose corticosteroid (CS) monotherapy did not achieve clinical remission, whereas TAC concomitant with CS was successful, and her baby had no apparent abnormalities. Patient 2 had hemophagocytic syndrome (HPS), for whom high-dose CS monotherapy did not achieve clinical remission, whereas TAC improved HPS, and a complete clinical remission was achieved with concomitant administration of TAC and methotrexate (MTX) with CS. Cases 3–5 could not have reduced CS doses due to repeated recurrences and other disease-modifying antirheumatic drugs, including MTX, Cyclosporine A, and tumor necrosis factor alpha inhibitors, did not control disease activity. TAC administration allowed for reduced CS doses. Case 6 experienced adverse effects, and TAC was discontinued due to elevated serum creatinine and potassium levels. TAC was useful for five of six patients, which suggests it as an option for refractory AOSD.

Successful treatment with tacrolimus of refractory adult-onset Still's disease

Adult-onset Still`s disease (AOSD) is a systemic inflammatory disorder characterized by high fever, arthralgia, transient rash, hepatosplenomegaly, lymphadenopathy, liver dysfunction and leukocytosis. The diagnosis of AOSD is conferred based on clinical findings after elimination of other causes. The mainstay of treatment is glucocorticoids and/or nonsteroidal anti-inf lammatory drugs, although most cases are refractory to these conventional therapies. To treat steroid- resistant AOSD, previous reports have suggested the use of immunosuppressants such as methotrexate (MTX), cyclosporine A (Cy-A), tumor necrosis factor-alpha (TNF-α) blockers, an interleukin (IL)-1 blocker and an IL-6 receptor blocker. Recent studies suggested that higher levels of IL- 18 are detected in patients with active AOSD, which correlate with disease activity and inf lammatory features. In addition, AOSD with high levels of IL-18 is refractory to treatment and is often steroid-resistant. A successful outcome was reported recently in one case of refractory AOSD treated with tacrolimus (Tac), a calcineurin inhibitor similar to Cy-A [1]. Here, we report a case of AOSD with high IL-18 levels that was treated unsuccessfully with steroid in combination with Cy-A, but was subsequently treated successfully using steroid in combination with Tac.

Tocilizumab for the treatment of adult-onset Still’s disease: results from a case series

Adult-onset Still's disease (AOSD) is a chronic inflammatory disease of unknown etiology which commonly affects young adults. Treatment of AOSD patients includes nonsteroidal anti-inflammatory drugs, corticosteroids, and DMARDs. Interleukin (IL)-6 blockade is an attractive therapeutic option for AOSD because this cytokine contributes to the pathogenesis of major AOSD symptoms. Tocilizumab (TCZ) is a humanized anti-IL-6 receptor antibody that blocks the effects of IL-6. Preliminary results of TCZ in AOSD have been promising. Here, we reported our experience evaluating both the safety and the efficacy of 12months therapy with TCZ in 11 patients with AOSD refractory to corticosteroids and MTX therapy, followed for 18months, including the first 12months of active treatment and the last 6months to evaluate the activity of the disease when the treatment was discontinued. The main outcome measures were the European League Against Rheumatism (EULAR) improvement criteria and improvement of systemic symptoms at the 3, 6, 12, and 18-months follow-up periods. Our patients rapidly responded and experienced a sustained clinical remission over time during active treatment. Disease Activity Score 28 decreased from 5.62 (3.75-8.28) [median (range)] at baseline to 1.61(0.49-3.5) at month 12. EULAR remission was achieved in 81.82% at 12months. Tender joint and swollen joint counts displayed a progressive reduction during active therapy study period. During treatment, we observed a resolution of fever in our AOSD patient. In conclusion, TCZ might represent a suitable option for the therapy of refractory AOSD patients.