Refractory Adult-onset Still's Disease Research Articles

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.

THU0401 Successful use of canakinumab in adult-onset still’s disease refractory to short acting IL-1 inhibitors

BackgroundAdult onset Still’s Disease (AOSD) is a protean systemic seronegative spondyloarthropathy with, often dramatic, systemic clinical manifestations, including quotidian fever and a cutaneous eruption. Diagnosis requires exclusion of mimicking disorders....

THU0388 Tocilizumab strongly suppresses the serum amyloid a level in refractory adult – onset still’s disease associated amyloidosis

BackgroundA amyloidosis, is a rare but serious complication of chronic inflammatory conditions including Adult-onset Still’s disease (AOSD). Treatment can be frustrating too.ObjectivesWe describe the case of refractory AOSD who developed...

Successful treatment of glucocorticoid and cyclosporine refractory adult-onset Still's disease complicated with hemophagocytic syndrome with plasma exchange therapy and tocilizumab : a case report

A 35-year-old woman was admitted to a hospital because of fever, sore throat, cervical lymph node swelling, and skin rashes. Laboratory data revealed leukocytosis and elevated C-reactive protein (CRP), aspartate aminotransferase, alanine aminotransferase, and ferritin levels. No antinuclear antibody or rheumatoid factor was found. She was diagnosed as having adult-onset Still's disease (AOSD). Although treatment with high-dose glucocorticoid (GC) and cyclosporine (CsA) was started, her condition did not improve because of complication with severe hemophagocytic syndrome (HPS). Therefore, she was transferred to our hospital. Immediately after admission, GC pulse therapy was started again, and treatment with CsA was replaced with tacrolimus (TAC), in addition, plasma exchange therapy was initiated. After treatment, her condition improved. However, 1 week after plasma exchange was discontinued, her condition deteriorated slightly with a slight fever and elevation of CRP level. This indicated that her condition could not be managed with GC and TAC, therefore, tocilizumab (TCZ) was added to her treatment, which improved her symptoms and enabled reduction in GC and TAC doses. Although many reports have indicated that biological agents are effective for refractory AOSD, their safety and efficacy in cases of AOSD complicated with HPS are controversial as these agents may exacerbate HPS. Our present case indicates that TCZ can be used after control of the disease activity by plasma exchange against refractory AOSD complicated with HPS.

Tocilizumab-Induced Acute Liver Injury in Adult Onset Still's Disease.

Background. Tocilizumab, a monoclonal humanized anti-IL-6 receptor antibody, is used in treatment of refractory adult onset Still's disease (AOSD). Mild to moderate liver enzyme elevation is a well-known side effect, but severe liver injury has only been reported in 3 cases in the literature. Case. A young female suffering from corticoid and methotrexate refractory AOSD was treated by tocilizumab. After 19 months of consecutive treatment, she developed acute severe liver injury. Liver biopsy showed extensive hepatocellular necrosis with ballooned hepatocytes, highly suggestive of drug-induced liver injury. No other relevant drug exposure beside tocilizumab was recorded. She recovered totally after treatment discontinuation and an initial 3-day course of intravenous N-acetylcysteine with normalization of liver function tests after 6 weeks. Conclusion. Acute severe hepatitis can be associated with tocilizumab as documented in this case. Careful monitoring of liver function tests is warranted during tocilizumab treatment.

Tocilizumab in the treatment of the adult-onset Still's disease: current clinical evidence

This study aimed to review and analyze the effectiveness and safety of tocilizumab in the treatment of patients with adult-onset Still's disease (AOSD). We report on two patients with AOSD who were successfully treated with tocilizumab. All published information on the use of tocilizumab in this disease was also retrieved through a systematic review of the English-language literature. Including our cases, 35 patients were given tocilizumab for AOSD (8mg/kg/month in 22 patients). The main clinical manifestations were arthritis in all 35 patients and systemic symptoms such as fever or skin rash in 28 (80%). Thirty-three (94%) patients had unsuccessfully tried other immunosuppressive agents such as methotrexate, tumor necrosis factor-α blockers, or anakinra. Most of the patients achieved a response with tocilizumab, such as a prompt articular improvement in 30/35 (86%) patients and a disappearance of systemic symptoms in 27/28 (96%). Twenty-eight (80%) patients tapered their steroid intakes, including seven (20%) who were able to discontinue them. Four (11%) patients relapsed, and two were successfully retreated with tocilizumab. Regarding safety, tocilizumab is a well-tolerated treatment, but severe side effects such as macrophage activation syndrome or cytomegalovirus reactivation are possible and require ongoing vigilance. Our findings suggest that tocilizumab should probably be proposed in refractory AOSD, as it allows for remission to be induced and the dose of steroid intakes to be reduced. It is a well-tolerated treatment that can be administered according to the therapeutic sequence of rheumatoid arthritis. Further prospective studies are required to assess the better use of this treatment (dosage and duration) and its place among other conventional treatments.

Successful treatment of adult-onset Still’s disease with tocilizumab monotherapy: two case reports and literature review

Adult-onset Still's disease (AOSD) is a systemic inflammatory disease of unknown etiology. Recently, it has been reported that quite a few cases of refractory AOSD were successfully treated with tocilizumab (TCZ) and corticosteroids were withdrawn in some of these patients. We report two AOSD patients who were treated successfully with TCZ monotherapy; thus, avoiding corticosteroid treatment. Because both of the patients refused to take corticosteroids, we planned to treat them with 8mg/kg of TCZ monotherapy at weeks 0, 2, 6 and subsequently every 4weeks. The efficacy of TCZ was assessed by patients' clinical symptoms such as fever, arthralgia, skin eruptions, and laboratory markers such as serum levels of CRP, ferritin, and IL-6. We also reviewed 14 previous case reports including 30 cases who had been treated with TCZ for AOSD. Our patients responded rapidly and have been maintained in clinical remission without corticosteroid treatment. In the literature review, concomitant corticosteroid treatment described in 13 cases was successfully tapered in 7 and discontinued in 6 cases. TCZ monotherapy can be a candidate for the first-line therapy for some AOSD patients.

Two Cases of Refractory Adult-Onset Still's Disease Responding to Anakinra

Adult-onset Still`s disease (AOSD) is a systemic inflammatory disorder with variable clinical features. The interleukin (IL)-1 receptor antagonist anakinra has been proposed as an alternative effective treatment in refractory AOSD. We report, for the first time in Korea, two cases of refractory AOSD in which anakinra treatment produced a clinical response. The first patient had frequent clinical flare-ups with fever, sore throat, myalgia, and pleuritic chest pain despite treatment with methotrexate and etanercept. In the second patient, treatments with various immunosuppressive agents failed to control the disease activity. Treatment with anakinra 100 mg/day was initiated in both cases. A complete clinical remission and improvement in the laboratory parameters were observed. The steroid dose was tapered without further clinical flare-ups. Anakinra appears to be an effective alternative treatment modality in patients with AOSD refractory to conventional disease-modifying anti-rheumatic drugs and corticosteroid therapy. (Korean J Med 2012;82:520-524)

Refractory Adult-Onset Still Disease Successfully Treated With Abatacept

Adult-onset Still disease (AOSD) is an inflammatory condition of unknown etiology that responds to glucocorticosteroids and disease-modifying antirheumatic drugs, particularly methotrexate. However, disease refractory to conventional treatment has led to the reported use of biologic therapy including tumor necrosis factor α inhibitors (infliximab, etanercept, and adalimumab), anakinra, rituximab, and tocilizumab. We report the successful use of abatacept in the treatment of a patient with AOSD manifested by polyarthritis, rash, fevers, elevated liver function tests, and ferritin levels refractory to treatment with methotrexate and hydroxychloroquine. Remission has been maintained for 35 months with the addition of abatacept administered once monthly. There is evidence that T-cell activity plays an important role in the autoimmune activity of AOSD, and modulation of CD28 costimulation of T cells by abatacept has specific immunosuppressive actions that make it an appealing alternative therapeutic option for refractory AOSD.

Successful tocilizumab treatment in a patient with adult-onset Still’s disease complicated by chronic active hepatitis B and amyloid A amyloidosis

We report successful tocilizumab (TCZ) use in a patient with adult-onset Still's disease (AOSD) complicated by chronic hepatitis B (CHB) and AA amyloidosis (AAA). Treatments with corticosteroid and various types of immunosuppressants were unsuccessful. Aggravation of CHB ensued, and entecavir was started. Normalisation of liver function and hepatitis B virus (HBV) DNA were confirmed. TCZ was then started. His arthritis and AAA improved dramatically. TCZ is an excellent treatment for refractory AOSD and is feasible in an HBV-infected patient.

Etanercept-refractory adult-onset Still’s disease with thrombotic thrombocytopenic purpura successfully treated with tocilizumab

We report the case of a 69-year-old Japanese woman who presented with thrombotic thrombocytopenic purpura (TTP) which had manifested soon after the onset of adult-onset Still's disease (AOSD). Her disease was multi-drug resistant. She had undergone treatment with high-dose glucocorticoids, two courses of steroid pulse therapy, and cyclosporine A. The patient initially had a favorable response to the administration of etanercept (an anti-tumor necrosis factor agent) and glucocorticoids. However, her disease became refractory to etanercept after 6 months. Therefore, we administered tocilizumab (a humanized monoclonal anti-IL-6 receptor antibody) which dramatically improved the patient's refractory AOSD with TTP. This is the first report of an effective treatment for AOSD with TTP using the biological agents. Our report strongly suggests that biological agents, especially a humanized monoclonal anti-IL-6 receptor antibody, may be a new option for a safe and effective treatment of multi-drug-resistant AOSD and TTP associated with AOSD.

Successful treatment of refractory adult still’s disease and membranous glomerulonephritis with infliximab

Adult onset Still's Disease (ASD) is a systemic inflammatory disorder of unknown etiology characterized by chronic and fluctuant fever with accompanying rash, polyarthritis and involvement of multiple organs, especially lymphoid tissues. Although kidney involvement may appear in some cases of adult Still's disease, membranous glomerulonephyritis has not been described before. We herein report a 38-year-old man diagnosed with Still's disease with longstanding polyarthritis unresponsive to high-dose steroids and various immunosuppressive drugs for 5 years. He was referred to our clinic with bilateral pretibial edema on his legs. Urine examination revealed 10.5 g/day proteinuria with membranous glomerulonephritis and his renal biopsy came up with it. Infliximab was initiated, and his complaints were totally resolved also with a normal urine test in the following 3 months. To the best of our knowledge, this is the first report that clearly shows the efficacy of infliximab in a patient with refractory ASD with membranous glomerulonephyritis.

Tocilizumab for multirefractory adult-onset Still’s disease

Adult-onset Still’s disease (AOSD) is a multisystemic inflammatory disease of unknown cause, characterised by daily spiking fever, rash, leucocytosis and arthritis. Cytokines such as interleukin (IL)1, 6 and 18, interferon...

A case report of a patient with refractory adult-onset Still’s disease who was successfully treated with tocilizumab over 6 years

Interleukin-6 overproduction is pathologically involved in adult onset Still's disease (AOSD). We successfully treated a man with refractory AOSD utilizing tocilizumab. Tocilizumab was discontinued after 15 doses due to intestinal bleeding, but the efficacy was sustained over 21 months. Tocilizumab was readministered safely upon recurrence and showed similar efficacy over 6 years. Corticosteroid and NSAIDs could be discontinued and intestinal bleeding was no more observed. Tocilizumab can be a therapeutic option for AOSD.

Heart biomarkers as prognostic tools for chronic thromboembolic pulmonary hypertension: a step forward by the fatty acid-binding protein

<h3>Background</h3> Inappropriate activation of pro-inflammatory cytokines such as interleukin (IL)-1, IL-6 or IL-18, is a pathogenic cornerstone in adult onset Still’s disease (AOSD). Beyond therapies targeting IL-1 and IL-6, Janus kinases (JAK) inhibitors have been suggested to be efficient in refractory AOSD patients [1]. <h3>Objectives</h3> To assess the efficacy and safety of JAK inhibitors in the treatment of AOSD patient refractory to, or with initial treatment. <h3>Methods</h3> This retrospective study was based on our single center of the department of rheumatology and immunology. The data was collected from the patients’ medical records using a standardized questionnaire and analyzed at different time points. The response to JAK inhibitors was categorized as complete remission (CR), partial remission (PR) or failure (F) [2]. <h3>Results</h3> 7 patients were recruited (Table 1), including 4 refractory patients and 3 initial patients. Mean age at JAK inhibitor treatment start was 27.5 years for refractory patients and 35 years for initial patients; and mean disease duration was 66.5 months and 1 month respectively. All patients had fever and polyarthritis, 5 patents had rash. In addition, pulmonary hypertension, abnormal liver function tests, abdominal pain, and heart failure were also observed in our patients. Response to corticosteroids, conventional synthetic or biological Disease Modifying Anti-Rheumatic Drugs (DMARDs) had been considered inadequate in 4 refractory patients. Tofacitinib was added in the initial treatment for 3 patients for high disease activity. In total, baricitinib was used in 2 patients and tofacitinib in 5 patients. Steroids were concurrently used in 6 patients, MTX in three, SASP and NSAIDs in one. At a mean follow up of 3.8 months, complete remission was observed in one patient (with tofacitinib), partial remission was in 5 patients (4 patients with tofacitinib and one with baricitinib), and failure in one (patients with baricitinib). At the last visit, steroids could be decreased but not stopped in those 6 patients. Tolerance of JAK inhibitors was excellent, none infectious disease or other severe side effect were observed. <h3>Conclusion</h3> JAK inhibitors treatment may be helpful for some patients with refractory AOSD, or patients with severe disease activity at initial treatment. Different treatment responses were observed in these short series of cases, which might be due to the phenotype of patients. However, the scale of patients in our study was too low to draw a conclusion. Further study and additional information are needed to evaluate more precisely the risk-benefit ratio of this treatment, and a possible difference in efficacy among the different groups of patients or JAK inhibitors. <h3>References</h3> [1]Aosd T, Table E. <i>Ann Rheum Dis</i> 2020;<b>79</b>:842–4. [2]Vercruysse F, Barnetche T, Lazaro E, <i>et al. Arthritis Res Ther</i> 2019;<b>21</b>:1–11. doi:10.1186/s13075-019-1838-6. <h3>Acknowledgements</h3> None <h3>Disclosure of Interests</h3> None declared

Rapid responses to anakinra in patients with refractory adult‐onset Still's disease

To assess the efficacy of anakinra treatment in patients with adult-onset Still's disease (AOSD) that is refractory to corticosteroids, methotrexate (MTX), and etanercept. Four patients with AOSD were treated with prednisone and MTX and 2 patients were also treated with etanercept for worsening symptoms and indicators of systemic inflammation. White blood cells (WBCs), C-reactive protein (CRP) levels and/or erythrocyte sedimentation rate, and ferritin levels were measured and, in 1 patient, serum creatinine levels were determined. Treatment with anakinra at 100 mg/day was initiated. The index patient's disease was refractory to treatment with prednisone (30 mg/day) and MTX, with spiking fevers, rash, synovitis, a serum ferritin level of 8,400 ng/ml (normal </=200), and a CRP level of 86 mg/liter (normal <8). Levels of interleukin-1beta (IL-1beta), IL-1alpha, IL-6, IL-1 receptor antagonist, and IL-18 were elevated. Just prior to anakinra treatment, the WBC count was 14,600/mm(3), the CRP level was 86 mg/liter, and the ferritin level was 573 ng/ml, with daily spiking fevers to 104 degrees F, rash, and swollen joints. Within hours of the first injection, the patient was afebrile and asymptomatic; within days, the WBC count, ferritin level, and CRP level decreased into the normal range. On 2 occasions, anakinra was withheld. Within a few days, the WBC count rose to >20,000/mm(3) with prominent neutrophilia, the CRP level rose to >200 mg/liter, and the ferritin level rose to >3,000 ng/ml. Upon restarting anakinra, the patient became afebrile, the WBC count fell to 8,000/mm(3), the CRP level fell to <3 mg/liter, and the ferritin level fell to <300 ng/ml. Three additional patients with refractory AOSD who experienced rapid reductions in fever, symptoms, and markers of inflammation when treated with anakinra are reported. Refractory AOSD appears to be IL-1-mediated since anakinra decreases hematologic, biochemical, and cytokine markers and also produces rapid reductions in systemic and local inflammation. Reported efficacy of tumor necrosis factor-blocking therapies in AOSD may be due to a reduction in IL-1.