Canakinumab for Treatment of Adult-Onset Still’s Disease to Achieve Reduction of Arthritic Manifestation (CONSIDER): phase II, randomised, double-blind, placebo-controlled, multicentre, investigator-initiated trial

BackgroundInhibition of interleukin (IL)-1 represents a promising treatment option in adult-onset Still's disease (AOSD).ObjectiveTo investigate the efficacy and safety of canakinumab in patients with AOSD and active joint involvement by means of a multicentre, double-blind, randomised, placebo-controlled trial.MethodsPatients with AOSD and active joint involvement (tender and swollen joint counts of ≥4 each) were treated with canakinumab (4 mg/kg, maximum 300 mg subcutaneous every 4 weeks) or placebo. The primary endpoint was the proportion of patients with a clinically relevant reduction in disease activity at week 12 as determined by the change in disease activity score (ΔDAS28>1.2).ResultsAt enrolment, patients had high active disease with a mean DAS28(ESR) of 5.4 in the canakinumab and 5.3 in the placebo group, respectively. In the intention-to-treat analysis, 12 patients (67%) in the canakinumab group and 7 patients (41%) in the placebo group fulfilled the primary outcome criterion (p=0.18). In the per-protocol analysis, significantly higher American College of Rheumatology (ACR) 30% (61% vs 20%, p=0.033), ACR 50% (50% vs 6.7%, p=0.009) and ACR 70% (28% vs 0%, p=0.049) response rates were observed in the canakinumab group compared with the placebo group. Two patients in the canakinumab group experienced a serious adverse event.ConclusionAlthough the study was terminated prematurely and the primary endpoint was not achieved, treatment with canakinumab led to an improvement of several outcome measures in AOSD. The overall safety findings were consistent with the known profile of canakinumab. Thus, our data support indication for IL-1 inhibition with canakinumab in AOSD.

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Tocilizumab in patients with adult-onset still’s disease refractory to glucocorticoid treatment: a randomised, double-blind, placebo-controlled phase III trial

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-213920 ◽

2018 ◽

Vol 77 (12) ◽

pp. 1720-1729 ◽

Cited By ~ 41

Author(s):

Yuko Kaneko ◽

Hideto Kameda ◽

Kei Ikeda ◽

Tomonoti Ishii ◽

Kosaku Murakami ◽

...

Keyword(s):

Placebo Group ◽

Phase Iii ◽

Adult Onset Still’S Disease ◽

Adult Onset ◽

Still’S Disease ◽

Double Blind ◽

Phase Iii Trial ◽

Systemic Feature ◽

Still's Disease ◽

Adult Onset Still's Disease

ObjectiveTo evaluate the efficacy and safety of tocilizumab, an interleukin-6 receptor antibody, in patients with adult-onset Still’s disease.MethodsIn this double-blind, randomised, placebo-controlled phase III trial, 27 patients with adult-onset Still’s disease refractory to glucocorticoids were randomised to tocilizumab at a dose of 8 mg/kg or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients received open-label tocilizumab for 40 weeks subsequently. The primary outcome was American College of Rheumatology (ACR) 50 response at week 4. The secondary outcomes included ACR 20/50/70, systemic feature score, glucocorticoid dose and adverse events at each point.ResultsIn the full analysis set, ACR50 response at week 4 was achieved in 61.5% (95% CI 31.6 to 86.1) in the tocilizumab group and 30.8% (95% CI 9.1 to 61.4) in the placebo group (p=0.24). The least squares means for change in systemic feature score at week 12 were –4.1 in the tocilizumab group and –2.3 in the placebo group (p=0.003). The dose of glucocorticoids at week 12 decreased by 46.2% in the tocilizumab group and 21.0% in the placebo group (p=0.017). At week 52, the rates of ACR20, ACR50 and ACR70 were 84.6%, 84.6% and 61.5%, respectively, in both groups. Serious adverse events in all participants who received one dose of tocilizumab were infections, aseptic necrosis in the hips, exacerbation of adult-onset Still’s disease, drug eruption and anaphylactic shock.ConclusionThe study suggests that tocilizumab is effective in adult-onset Still’s disease, although the primary endpoint was not met and solid conclusion was not drawn.

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

Rheumatology ◽

10.1093/rheumatology/keaa135 ◽

2020 ◽

Vol 59 (11) ◽

pp. 3293-3302 ◽

Cited By ~ 2

Author(s):

Zhihong Wang ◽

Huihui Chi ◽

Yue Sun ◽

Jialin Teng ◽

Tienan Feng ◽

...

Keyword(s):

Disease Activity ◽

Multivariate Logistic Regression Analysis ◽

Soluble Form ◽

Adult Onset Still’S Disease ◽

Adult Onset ◽

Still’S Disease ◽

Potential Predictor ◽

Still's Disease ◽

Chronic Course ◽

Adult Onset Still's Disease

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

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Response to: ‘Changing the outcome measures, changing the results? The urgent need of a specific Disease Activity Score to adult-onset Still’s disease’ by Ruscitti et al

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-218143 ◽

2020 ◽

pp. annrheumdis-2020-218143

Author(s):

Claudia Kedor ◽

Joachim Listing ◽

Jan Zernicke ◽

Eugen Feist

Keyword(s):

Disease Activity ◽

Outcome Measures ◽

Disease Activity Score ◽

Activity Score ◽

Adult Onset Still’S Disease ◽

Adult Onset ◽

Still’S Disease ◽

Specific Disease ◽

Still's Disease ◽

Adult Onset Still's Disease

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Elevated Levels of G-CSF in Patients with Active Phase of Adult-onset Still’s Disease

The Journal of Rheumatology ◽

10.3899/jrheum.200617 ◽

2020 ◽

pp. jrheum.200617

Author(s):

Yudong Liu ◽

Shulan Zhang ◽

Changshe Xia ◽

Jiali Chen ◽

Chunhong Fan

Keyword(s):

Disease Activity ◽

Therapeutic Potential ◽

Assessment System ◽

Adult Onset Still’S Disease ◽

Adult Onset ◽

Still’S Disease ◽

Still's Disease ◽

Elevated Liver Enzymes ◽

Csf Levels ◽

Adult Onset Still's Disease

Objective Neutrophilia is a hallmark of adult-onset Still’s disease (AoSD). We aimed to investigate the levels of granulocyte colony-stimulating factor (G-CSF), an essential regulator of neutrophil production and function, in the pathogenesis of AoSD. Methods Sera were collected from 70 patients with AoSD and 20 healthy controls (HCs). The levels of G-CSF were determined by ELISA. Low-density granulocytes (LDGs) were quantified by flow cytometry. Correlations between G-CSF levels and disease activity, laboratory parameters, or LDGs levels in patients with AoSD were analyzed by Spearman’s correlation test. Results Active AoSD patients presented significantly higher levels of G-CSF compared to inactive AoSD patients (p<0.001) and HCs (p<0.0001). The levels of G-CSF were significantly decreased after active AoSD patients achieved disease remission (p=0.0015). The levels of G-CSF were significantly correlated with CRP, ESR, ferritin and systemic score in AoSD (p<0.0001). Significant correlations between the levels of G-CSF and circulating neutrophils (p<0.0001), neutrophil-to-lymphocyte ratio (p<0.0001), percentages of LDGs in the PBMCs (p=0.0042) as well as absolute numbers of circulating LDGs (p=0.0180) were identified. Patients with fever, evanescent rash, sore throat, arthralgia, myalgia, lymphadenopathy or hepatomegaly/elevated liver enzymes displayed significantly higher levels of G-CSF compared to patients without these manifestations (p<0.05). Conclusion Our findings indicate that G-CSF is implicated in the pathogenesis of AoSD, and targeting G-CSF may have therapeutic potential for AoSD. In addition, introducing circulating G-CSF levels into the clinical assessment system may help to monitor disease activity.

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