Real-world safety and effectiveness of canakinumab in patients with tumour necrosis factor receptor-associated periodic syndrome or hyperimmunoglobulinaemia D syndrome: Interim results from post-marketing surveillance in Japan.

To assess the real-world safety and effectiveness of canakinumab in patients in Japan with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate kinase deficiency/hyperimmunoglobulinaemia D with periodic fever syndrome (MKD/HIDS). All patients with TRAPS or MKD/HIDS who received canakinumab following drug approval in Japan were registered in a post-marketing all-patient surveillance with a 2-year observation period. Herein, the interim results are reported. Fifteen patients with TRAPS and seven with MKD/HIDS were included in the safety and effectiveness analysis set. Adverse drug reactions were reported in 26.67% (n = 4) and 42.86% (n = 3) of TRAPS and MKD/HIDS patients, respectively. Most common adverse drug reactions were upper respiratory tract inflammation (13.33%, n = 2) and pyrexia (42.86%, n = 3) in TRAPS and MKD/HIDS patients, respectively. No serious adverse drug reactions were observed in either TRAPS or MKD/HIDS patients. The proportion of responders was 46.67% and 14.29% in the TRAPS and MKD/HIDS groups, respectively; 72.73% and 66.67% achieved clinical remission, while 90.91% and 66.67% achieved serological remission by Week 4 in the TRAPS and MKD/HIDS groups, respectively. These interim results provide the first evidence of the real-world effectiveness of canakinumab in patients with TRAPS or MKD/HIDS in Japan. No new safety concerns were identified.

Hosono K ，Matsumoto K ，Shimbo M ，Tsumiyama I ，Kato C ... -  《-》

Systematic literature review of efficacy/effectiveness and safety of current therapies for the treatment of cryopyrin-associated periodic syndrome, hyperimmunoglobulin D syndrome and tumour necrosis factor receptor-associated periodic syndrome.

Several therapies are used for the treatment of rareautoinflammatory conditions like cryopyrin-associated periodic fever syndromes (CAPS), hyperimmunoglobulin Dsyndrome (HIDS)/mevalonate kinase deficiency (MKD) and tumour necrosis factor receptor-associated periodic syndrome (TRAPS). However, reviews reporting on treatment outcomes of these therapies are lacking. A systematic literature review was conducted using Embase, MEDLINE, MEDLINE-In Process and Cochrane databases to identify the randomised/non-randomised controlled trials (RCTs/non-RCTs) and real-world observational studies of CAPS, HIDS/MKD and TRAPS published as full-texts (January 2000-September 2017) or conference abstracts (January 2014-September 2017). Studies with data for ≥1 biologic were included. Studies with <5 patients were excluded. Of the 3 342 retrieved publications, 72 studies were included (CAPS, n=43; HIDS/MKD, n=9; TRAPS, n=7; studies with ≥2 cohorts, n=13). Most studies were full-text (n=56), published after 2010 (n=56) and real-world observational studies (n=58). Among included studies, four were RCTs (canakinumab, n=2 (CAPS, n=1; HIDS/MKD and TRAPS, n=1); rilonacept, n=1 (in CAPS); simvastatin, n=1 (in HIDS/MKD)). Canakinumab and anakinra were the most commonly used therapies for CAPS and HIDS/MKD, whereas etanercept, canakinumab and anakinra were the most common for TRAPS. The available evidence suggested the efficacy or effectiveness of canakinumab and anakinra in CAPS, HIDS/MKD and TRAPS, and of etanercept in TRAPS; asingle RCT demonstrated the efficacy of rilonacept in CAPS. Canakinumab, anakinra, etanercept and rilonacept were reported to be well tolerated; however, injection-site reactions were observed frequently with anakinra, rilonacept and etanercept. Data on the use of tocilizumab, infliximab and adalimumab in these conditions were limited; thus, further research is warranted.

Kuemmerle-Deschner JB ，Gautam R ，George AT ，Raza S ，Lomax KG ，Hur P ... -  《-》

Long-term safety and effectiveness of canakinumab in patients with monogenic autoinflammatory diseases: results from the interim analysis of the RELIANCE registry.

Interim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens and effectiveness of canakinumab in patients with cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumour-necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate-kinase deficiency (MKD)/hyperimmunoglobulin-D syndrome (HIDS). From September 2017 for patients with CAPS, and June 2018 for patients with FMF, TRAPS or MKD/HIDS, the registry enrolled paediatric (aged ≥2 years) and adult patients (aged ≥18 years) receiving canakinumab as part of their routine medical care. Safety, canakinumab dose, disease activity and quality of life outcome measures were evaluated at baseline and every 6 months until end of study visit. At the analysis cut-off date (December 2020), 168 patients (91 CAPS, 54 FMF, 16 TRAPS and 7 MKD/HIDS) were enrolled. 85 (50.9%) patients were female and 72 (43.1%) were children (<18 years). The median patient age was 20.0 years (range 2.0-79.0 years). In the CAPS cohort, serious infections and serious adverse drug-reactions were more common in patients receiving higher than the recommended starting dose (SD) of canakinumab. A trend to receive >SD of canakinumab was observed in the pooled population. The majority of patients were reported as having either absent or mild/moderate disease activity (physician's global assessment) from baseline to Month 30, with a stable proportion of patients (~70%) in remission under canakinumab treatment. Patient-reported disease activity (Visual Analogue Scale (VAS), Autoinflammatory Disease Activity Index), fatigue (VAS); markers of inflammation (C-reactive protein, serum amyloid A and erythrocyte sedimentation rate) remained well-controlled throughout. Data from this analysis confirm the long-term safety and effectiveness of canakinumab for the treatment of CAPS, FMF, TRAPS and MKD/HIDS.

Kuemmerle-Deschner JB ，Kallinich T ，Henes J ，Kortus-Götze B ，Oommen PT ，Rech J ，Krickau T ，Weller-Heinemann F ，Horneff G ，Janda A ，Foeldvari I ，Schuetz C ，Dressler F ，Borte M ，Hufnagel M ，Meier F ，Fiene M ，Andreica I ，Weber-Arden J ，Blank N ... -  《-》

Reasons for canakinumab initiation among patients with periodic fever syndromes: a retrospective medical chart review from the United States.

Although canakinumab has demonstrated efficacy in multiple trials in patients with periodic fever syndromes (PFS), the evidence on initiation of canakinumab among PFS patients in real world setting is not well understood. We aimed to characterize the reasons for canakinumab initiation among patients with PFS, specifically, cryopyrin-associated periodic syndrome (CAPS), hyperimmunoglobulin D syndrome/mevalonate kinase deficiency (HIDS/MKD), TNF receptor-associated periodic syndrome (TRAPS) and familial Mediterranean fever (FMF). Physicians retrospectively reviewed the medical charts of PFS patients prescribed canakinumab between 2016 and 2018. Information collected included patient clinical characteristics, reasons for previous treatment discontinuation and canakinumab initiation. The results were summarized for overall patients, and by children (< 18 years) and adults and by subtype of PFS. Fifty-eight physicians in the US (rheumatologists, 44.8 %; allergists/immunologists, 29.3 %; dermatologists, 25.9 %) abstracted information for 147 patients (children, 46.3 %; males, 57.1 %; CAPS, 36.7 %; TRAPS, 26.5 %; FMF, 26.5 %; HIDS/MKD, 6.8 %; Mixed, 3.4 %). Overall, most patients (90.5 %) received treatment directly preceding canakinumab (NSAIDs, 27.8 % [40.0 % in HIDS/MKD]; anakinra, 24.1 % [32.7 % in CAPS]; colchicine, 21.8 % [35.9 % in FMF]), which were discontinued due to lack of efficacy/effectiveness (39.5 %) and availability of a new treatment (36.1 %). The common reasons for canakinumab initiation were physician perceived efficacy/effectiveness (81.0 %; children, 75.0 %; adults, 86.1 %), lack of response to previous treatment (40.8 %; children, 38.2 %; adults, 43.0 %) and favorable safety profile/tolerability (40.1 %; children, 42.6 %; adults, 38.0 %). Within subtypes, efficacy/effectiveness was the most stated reason for canakinumab initiation in HIDS/MKD (90.9 %), lack of response to previous treatment in FMF (52.4 %) and convenience of administration/dosing in CAPS (27.1 %). This study provided insights into how canakinumab is initiated in US clinical practice among PFS patients, with physician perceived efficacy/effectiveness of canakinumab, lack of response to previous treatment and favorable safety profile/tolerability of canakinumab being the dominant reasons for canakinumab initiation in all patients and in children and adults and PFS subtypes. Notably, the favorable safety profile/tolerability of canakinumab was more often the reason for initiation among children versus adults.

Hur P ，Lomax KG ，Ionescu-Ittu R ，Manceur AM ，Xie J ，Cammarota J ，Gautam R ，Sanghera N ，Kim N ，Grom AA ... -  《Pediatric Rheumatology》

International Retrospective Chart Review of Treatment Patterns in Severe Familial Mediterranean Fever, Tumor Necrosis Factor Receptor-Associated Periodic Syndrome, and Mevalonate Kinase Deficiency/Hyperimmunoglobulinemia D Syndrome.

Periodic fever syndrome (PFS) conditions are characterized by recurrent attacks of fever and localized inflammation. This study examined the diagnostic pathway and treatments at tertiary centers for familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), and mevalonate kinase deficiency (MKD)/hyperimmunoglobulinemia D syndrome (HIDS). PFS specialists at medical centers in the US, the European Union, and the eastern Mediterranean participated in a retrospective chart review, providing de-identified data in an electronic case report form. Patients were treated between 2008 and 2012, with at least 1 year of followup; all had clinical and/or genetically proven disease and were on/eligible for biologic treatment. A total of 134 patients were analyzed: FMF (n = 49), TRAPS (n = 47), and MKD/HIDS (n = 38). Fever was commonly reported as severe across all indications. Other frequently reported severe symptoms were serositis for FMF patients and elevated acute-phase reactants and gastrointestinal upset for TRAPS and MKD/HIDS. A long delay from disease onset to diagnosis was seen within TRAPS and MKD/HIDS (5.8 and 7.1 years, respectively) compared to a 1.8-year delay in FMF patients. An equal proportion of TRAPS patients first received anti-interleukin-1 (anti-IL-1) and anti-tumor necrosis factor (anti-TNF) biologic agents, whereas IL-1 blockade was the main choice for FMF patients resistant to colchicine and MKD/HIDS patients. For TRAPS patients, treatment with anakinra versus anti-TNF treatments as first biologic agent resulted in significantly higher clinical and biochemical responses (P = 0.03 and P < 0.01, respectively). No significant differences in responses were observed between biologic agents among other cohorts. Referral patterns and diagnostic delays highlight the need for greater awareness and improved diagnostics for PFS. This real-world treatment assessment supports the need for further refinement of treatment practices.

Ozen S ，Kuemmerle-Deschner JB ，Cimaz R ，Livneh A ，Quartier P ，Kone-Paut I ，Zeft A ，Spalding S ，Gul A ，Hentgen V ，Savic S ，Foeldvari I ，Frenkel J ，Cantarini L ，Patel D ，Weiss J ，Marinsek N ，Degun R ，Lomax KG ，Lachmann HJ ... -  《-》