Systematic Review and Metaanalysis of Pharmacological Interventions in Adult-Onset Still Disease and the Role of Biologic Disease-Modifying Antirheumatic Drugs.

OBJECTIVE: To conduct a systematic review of the effectiveness and safety of pharmacological treatments for adult-onset Still disease (AOSD). METHODS: Six databases, 2 trial registries, and conference abstracts were searched from January 2012 to February 2023 for studies of pharmacological interventions in people with AOSD. Outcomes were rates of remission and response, discontinuation of concurrent treatments, complications of AOSD, and treatment-related adverse events. Risk of bias was assessed with the Cochrane risk of bias tool and the Joanna Briggs Institute tool for case series. RESULTS: Forty-four studies evaluated treatments, including nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids (CS), conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and biologic DMARDs (bDMARDs). For bDMARDs, tocilizumab (TCZ), anakinra (ANK), and canakinumab (CNK) had the most available data. Although 3 randomized controlled trials did not show statistically significant benefits of bDMARDs, metaanalyses showed high rates of complete remission and CS discontinuation. Complete remission was 80% (95% CI 59-92%, I 2 36%), 73% (95% CI 58-84%, I 2 66%), and 77% (95% CI 29-97%, I 2 82%) and CS discontinuation was 57% (95% CI 29-81%, I 2 66%), 47% (95% CI 18-78%, I 2 79%), and 34% (95% CI 6-81%, I 2 59%), respectively, for TCZ, ANK, and CNK. Studies with a higher proportion of patients previously treated with bDMARDs showed a trend toward lower rates of CS discontinuation (P = 0.05). The analyses had high clinical heterogeneity, largely because treatments were prescribed as different lines of therapy. CONCLUSION: Evidence supports TCZ, ANK, and CNK therapy for AOSD. However, the magnitude of effect and comparative effectiveness of treatments is uncertain.

Inactivated SARS-CoV-2 vaccine does not increase the risk of relapse in patients with clinically inactive adult-onset Still's disease.

OBJECTIVE: A succession of cases have reported flares of adult-onset Still's disease (AOSD) after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), raising concerns. We aimed to investigate the impact of inactivated SARS-CoV-2 vaccines on disease activity in patients with AOSD. METHODS: We prospectively enrolled clinically inactive AOSD patients visiting the outpatient clinics of our department. The patients received SARS-CoV-2 vaccines (BBIBP-CorV, Sinopharm, Beijing, China) voluntarily. The occurrence of relapse in the participants was recorded during the follow-up period, and a propensity score matching (PSM) method was used to compare the relapse rates between vaccinated and unvaccinated patients. Localized and systemic symptoms were assessed in the vaccinated patients. RESULTS: A total of 122 patients with inactive AOSD were included, of which 49.2% (n = 60) voluntarily received the inactivated SARS-CoV-2 vaccine. The relapse rate did not increase significantly in vaccinated patients in comparison with unvaccinated patients (after PSM: 6.8% vs 6.8%), and no relapse occurred within 1 month after vaccination. No obvious adverse reactions were reported in 75.0% of the participants, and none of the patients reported severe reactions. CONCLUSION: Increased disease activity or relapse following vaccination with inactivated SARS-CoV-2 was rare in patients with inactive AOSD. Local and systemic adverse reactions were found to be mild and self-limiting. These safety profiles of inactivated SARS-CoV-2 vaccines in patients with AOSD may assist in eliminating vaccine hesitancy and increase the vaccination rate against SARS-CoV-2.

A case of recurrence of adult-onset Still's disease in the third trimester: a case report and literature review.

BACKGROUND: Adult-onset Still's disease (AOSD) is a self-inflammatory disease showing macrophage and neutrophil activation by inflammatory cytokines such as TNF-α, IL-6, and IL-18. Although some cases with the flare of AOSD during pregnancy have been reported, most had flares in the first or second trimester and few had flares in the third trimester. In this report, we present the case of a patient with recurrent flare of AOSD in the third trimester and discuss the management of AOSD in the third trimester with the review of previous literatures. CASE PRESENTATION: A 38-year-old woman in complete AOSD remission without medication presented with impaired liver function, low platelet count, mild fever, abdominal pain, splenomegaly, and elevated ferritin and IL-18 levels at 30 gestational weeks. Although the laboratory data and physical examination finding suggested HELLP syndrome or acute fatty liver of pregnancy and we considered the termination of her pregnancy, her fetus was in a reactive status. Considering her fetal status, some specific findings of AOSD, and her AOSD history, we and rheumatologists diagnosed her with AOSD recurrence and started systemic steroid therapy. In her clinical course, three flares of AOSD occurred, twice in the third trimester and once in postpartum; twice systemic steroid pulse therapies were then needed. Ultimately, a healthy infant was delivered transvaginally at 36 gestational weeks spontaneously. CONCLUSIONS: Specific findings of the flare of AOSD such as fever, splenomegaly, elevated ferritin and IL-18 levels, and fetal status could be useful findings for differentiation from HELLP syndrome and AFLP in the third trimester. With the careful management supported by rheumatologists, patients complicated with the flare of AOSD may continue their pregnancy longer than we expected.

[Successful treatment of adult Still's disease with tofacitinib in a HIV-2 positive female patient]. / Erfolgreiche Behandlung eines adulten Morbus Still mit Tofacitinib bei einer HIV-2-positiven Patientin.

A 46-year-old female patient with a known HIV-2-infection suffered from adult onset Still's disease, which was initially complicated by a macrophage activation syndrome (MAS). The required glucocorticoid treatment induced a psychosis and the patient developed an aversion to glucocorticoids. After failure of treatment with anakinra, an alternative option with the JAK-inhibitor tofacitinib was introduced because of the short half-life and to reduce glucocorticoid exposure. A switch to tofacitinib was only successful after an overlapping treatment with anakinra and tofacitinib for 3 weeks. The patient is currently being treated with monotherapy with tofacitinib as well as NSAID on demand, is in stable remission and can continue working as normal.

Intravitreal dexamethasone implants for the treatment of refractory scleritis combined with uveitis in adult-onset Still's disease: a case report.

BACKGROUND: Adult-onset Still's disease is a systemic inflammatory disease which presents with uveitis and scleritis in the eye. Intravitreal dexamethasone implants are used for the treatment of refractory uveitis. CASE PRESENTATION: A 19-year-old woman diagnosed to have adult-onset Still's disease for fevers, joint pain, and a salmon-colored bumpy rash presented with scleritis and uveitis in the left eye. Topical and systemic steroids with oral methotrexate failed to control the inflammation. We performed intravitreal injections of dexamethasone implants for side effects of steroid and refractory ocular inflammation. The therapy resulted in improvements in the patient's uveitis with reductions in scleral vessel engorgement and redness. There was no recurrence of uveitis or scleritis during 4 months following treatment. CONCLUSIONS: Intravitreal injections of dexamethasone implants may result in clinical improvements of refractory scleritis combined with uveitis.

A case report of successful treatment of 90° knee flexion contracture in a patient with adult-onset Still's disease.

BACKGROUND: Severe knee flexion contractures greater than 80° are rare and challenging to manage. Previous studies have demonstrated unsatisfactory clinical results after correcting these deformities because residual flexion contractures were not corrected within a short period of time. We herein report the case of a patient with adult-onset Still's disease with 90° of bilateral knee flexion contracture, which was successfully corrected by total knee arthroplasty and serial casting over a period of five weeks. CASE PRESENTATION: A 47-year-old male was admitted to our orthopedic department for bilateral knee pain and a preoperative fixed flexion contracture of 90°. A diagnosis of adult-onset Still's disease was made based on the patient's medical history of a high spiking fever, salmon-colored rash and bilateral knee and wrist pain. Bilateral total knee arthroplasty was carried out to address these deformities, but residual flexion contracture was present. Subsequently, serial casting was used to achieve full extension at four weeks after surgery. Excellent function and patient satisfaction were observed at two years of follow-up. CONCLUSION: The new protocol of total knee arthroplasty with subsequent serial casting seems to be an efficient solution for knee flexion contractures greater than 80°. This report adds to the very small number of reported cases of adult-onset Still's disease with severe knee flexion contractures and describes a patient who was successfully treated with a new protocol.

Successful treatment of refractory adult onset Still's disease with rituximab.

Adult-onset Still's disease (AOSD) is an uncommon inflammatory condition of unknown origin. In chronic disease, joint involvement is often predominant and erosions are noted in one third of patients. Therapeutic strategies derive from observational data. Corticosteroids are usually the first-line treatment. With inadequate response to corticosteroids, methotrexate appears the best choice to control disease activity and allow for tapering of steroid use. For refractory disease, biological therapy seems the most promising. We report here the case of a 38-year-old female patient with AOSD refractory to cytotoxic agents, treated by rituximab infusion therapy with favorable outcome.

Efficacy of Low-Dose Tocilizumab on Relapsing Adult-Onset Still's Disease.

Still's disease is an inflammatory disorder of unknown etiology. First-line therapy is based on corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) but the frequency of relapses and corticosteroid-induced adverse events are limiting factors. The efficacy of intravenous tocilizumab (TCZ) has been shown at a dose of 8 mg/kg but the corticosteroid-sparing effect of intravenous low-dose TCZ followed by subcutaneous (SC) injection in the course of the disease has been poorly investigated. We report the case of a 28-year old Caucasian woman presenting a relapse of Still's disease eleven months after diagnosis under treatment with 6 mg of methylprednisolone. TCZ at a dose of 4 mg/kg every 2 weeks was combined with 32 mg of methylprednisolone, followed by 162 mg SC every 3 weeks. Evolution was rapidly favourable with a decrease in corticosteroid doses. We reviewed previously published cases.

Successful tocilizumab therapy in seven patients with refractory adult-onset Still's disease.

To evaluate the effects of tocilizumab (TCZ) on adult-onset Still's disease (AOSD), we reviewed medical records of seven patients with refractory AOSD treated with TCZ at our institution. TCZ therapy might allow rapid corticosteroid tapering and help maintain remission status, that is, resolution of clinical symptoms and normalization of biomarkers such as CRP and ferritin. Patients, however, should be monitored for the development of macrophage activation syndrome when TCZ is administered for active AOSD.

[Kikuchi-Fujimoto's disease and adult-onset Still's disease. A rare co-occurence]. / Kikuchi-Fujimoto-Syndrom und adulter Morbus Still. Eine seltene Koinzidenz.

Kikuchi-Fujimoto's disease and adult-onset Still's disease are rare inflammatory conditions with overlapping clinical features. Adult-onset Still's disease causes high fevers, a typical salmon-colored rash, and joint pain. The principal symptom of Kikuchi's disease is cervical lymphadenopathy with typical histopathological features including extensive necrosis of the involved lymph nodes. Here, we report on a rare case of concurrent adult-onset Still's disease and Kikuchi-Fujimoto syndrome in a young Caucasian patient.

[Adult onset Still's disease with small vessel vasculitis]. / Adulter Morbus Still mit Kleingefäßvaskulitis.

This article presents a particularly severe case of adult onset Still's disease aggravated by small vessel vasculitis. A satisfactory therapy was concluded 1.5 years after onset of the disease. The small vessel vasculitis was difficult to treat: methotrexate (MTX), cyclophosphamide and rituximab were not sufficiently effective. Tocilizumab in combination with intravenous immunoglobulin (IVIG) induced remission and maintenance therapy was carried out with tocilizumab.

Biologic treatments for adult-onset Still's disease.

Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder that is a diagnosis of exclusion. It is characterized by high spiking fevers, arthritis or arthralgia, and an evanescent salmon-coloured rash. Many other systemic manifestations and laboratory test abnormalities may occur. Biologic drugs, TNF-α inhibitors, and IL-1 and IL-6 blockers have been used for the treatment of patients with AOSD refractory to conventional treatment or those with life-threatening manifestations aiming for better disease control. Data on biologic treatments in AOSD are limited and consist mainly of case reports, small case series and retrospective studies. Using biologic agents (anti-TNF-α, anti-IL-1 and anti-IL-6) with traditional immunosuppressive drugs resulted in significant improvement of disease outcomes. IL-1 and IL-6 inhibitors seem to be more efficient than TNF-α inhibitors.

Optimal time of starting tocilizumab in acute phase of adult-onset Still's disease and comparison of its efficacy with that of methotrexate: a case series and a review of the literature.

Adult-onset still's disease is a rare condition that is generally treated by glucocorticoids. Importantly, due to the limited established treatments, glucocorticoid-refractory cases are particularly difficult to treat. Between December 2009 and August 2022, nine patients with adult-onset Still's disease were treated with tocilizumab (tocilizumab group). The therapeutic efficacy and safety of tocilizumab initiation in the acute phase were evaluated in cases of initial onset and recurrence. We also compared the efficacy of tocilizumab with that of methotrexate (methotrexate group, n = 13), which has been the drug of choice for adjunctive therapy. Tocilizumab demonstrated the expected efficacy in all four patients who received it at relapse and in three of the five patients who received it at the initial onset. However, two patients developed macrophage activation syndrome following treatment. A comparison of treatment effects between the methotrexate and tocilizumab groups revealed that the ferritin and C-reactive protein levels, severity score, and glucocorticoid doses decreased over time in both groups; nonetheless, the tocilizumab group experienced a more stable effect. Tocilizumab is undoubtedly a valuable treatment option for adult-onset Still's disease, especially when administered at relapse. This suggests that it shows both high safety and good efficacy. Nevertheless, a larger sample size is required to validate the efficacy and safety of tocilizumab compared with those of the existing alternatives. Key Points • We examined the significance of TCZ in terms of therapeutic efficacy, reduction in glucocorticoid usage, and safety in patients with AOSD. • We compared the therapeutic efficacy of TCZ with that of MTX, which is often used to treat glucocorticoid-resistant AOSD. • TCZ is undoubtedly a valuable treatment option for AOSD, especially when administered at relapse, suggesting both high safety and good efficacy.

A case of uveitis in adult-onset Still's disease with ophthalmologic symptoms.

Adult-onset Still's disease (AOSD) is a rare and systemic inflammatory disorder of unknown etiology and pathogenesis. AOSD is characterized by high fever accompanied by a range of systemic symptoms. However, there are rare cases of AOSD with ophthalmologic symptoms as well as with an obvious causation of corticosteroid withdrawal. In this case, a 43-year-old male patient diagnosed with AOSD showed ocular inflammation after withdrawing from corticosteroid treatment. This patient was treated with prednisolone for AOSD and discharged after achieving complete remission of breathlessness, backache, thoracalgia, joint pain, and spiking fever. The patient unauthorizedly stopped taking prednisolone after he was discharged from the hospital and returned to the Department of Ophthalmology with the complaint of decreased visual acuity in both eyes for half a month and sudden vision loss in the left eye for 3 days. After regular ophthalmologic examinations and fluorescence angiography examination, he was diagnosed with acute panuveitis as the manifestation of AOSD. Uveitis was effectively treated with corticosteroid drugs. This case reported a rare manifestation of AOSD in an ophthalmological system that was associated with the withdrawal of corticosteroid treatment. This report highlighted the therapeutic effect of local and systemic corticosteroid use for AOSD manifested with uveitis. This case is interesting for both rheumatologists and ophthalmologists.

Systematic review on the use of biologics in adult-onset still's disease.

This systematic review (SR) describes the efficacy and safety of biologic disease modifying anti-rheumatic drugs (bDMARDs) for patients with adult-onset Still's disease (AOSD). Three randomised controlled trials (RCTs), one retrospective case series of multiple interventions, and 17 case series of single interventions met the inclusion criteria for this SR. Comparisons of biologic therapy in AOSD were only available against conventional DMARDs in one RCT and against placebo in two RCTs. There was a lack of common assessment criteria, meaning treatment efficacy across studies could not be compared. Uncontrolled retrospective case series suggested that bDMARDs have an effect for patients with AOSD, but these studies did not provide comparative data to show whether bDMARDs were more effective than other interventions or, whether any bDMARD was more effective than another bDMARD. However, there was evidence that bDMARDs could reduce steroid dose. Safety data from all included studies showed that bDMARDs appear to be a safe alternative to conventional DMARDs. This SR has highlighted the need for larger comparative studies in AOSD and has shown the need to standardize the definition of therapeutic response in AOSD. This would allow comparisons between studies in order to gain clarity on which bDMARDs may be more effective treatments for AOSD.