Canakinumab Research Articles

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Canakinumab for the treatment of hyperimmunoglobulin D syndrome

ABSTRACTIntroduction: Mevalonate Kinase Deficiency (MKD) is a rare monogenic autoinflammatory disorder (AID) with autosomal recessive inheritance caused by mutations in the MVK gene. It includes hyperimmunoglobulinemia D syndrome (HIDS) and mevalonic aciduria (a severe form). Patients have recurrent inflammatory attacks with high fever, gastrointestinal symptoms, lymphadenopathy, splenomegaly, arthralgia, rash, pharyngitis, aphtosis and constitutional complaints. Heightened understanding of molecular mechanisms in monogenic autoinflammatory disorders has provided tools for targeted treatment. HIDS is an extrinsic inflammasomopathy and is responsive to anti-IL-1 therapies, such as the recombinant IL-1-receptor antagonist anakinra, the monoclonal antibody against IL-1b canakinumab (CAN), and the recombinant IL-1R fusion protein rilonacept.Areas covered: CAN is a human monoclonal anti-IL-1β antibody that binds with high affinity and neutralizes the activity of IL-1 β. Both observational registries and some case reports have seemed promising in the efficacy of CAN in the HIDS treatment. Two clinical trials have corroborated CAN as an effective and safe drug.Expert commentary: CAN is effective and safe for the treatment of HIDS patients. Some data suggest these patients may need higher dosage or shorter dosing interval than other AIDs, to achieve and maintain complete clinical and laboratory response. Reported adverse events were mild, most often non-complicated infections.

Drug Retention Rate and Predictive Factors of Drug Survival for Interleukin-1 Inhibitors in Systemic Juvenile Idiopathic Arthritis.

Background and Objectives: Few studies have reported the drug retention rate (DRR) of biologic drugs in juvenile idiopathic arthritis (JIA), and none of them has specifically investigated the DRR of interleukin (IL)-1 inhibitors on systemic JIA (sJIA). This study aims to describe IL-1 inhibitors DRR and evaluate predictive factors of drug survival based on data from a real-world setting concerning sJIA.Methods: Medical records from sJIA patients treated with anakinra (ANA) and canakinumab (CAN) were retrospectively analyzed from 15 Italian tertiary referral centers.Results: Seventy seven patients were enrolled for a total of 86 treatment courses. The cumulative retention rate of the IL-1 inhibitors at 12-, 24-, 48-, and 60-months of follow-up was 79.9, 59.5, 53.5, and 53.5%, respectively, without any statistically significant differences between ANA and CAN (p = 0.056), and between patients treated in monotherapy compared to the subgroup co-administered with conventional immunosuppressors (p = 0.058). On the contrary, significant differences were found between biologic-naive patients and those previously treated with biologic drugs (p = 0.038) and when distinguishing according to adverse events (AEs) occurrence (p = 0.04). In regression analysis, patients pre-treated with other biologics (HR = 3.357 [CI: 1.341–8.406], p = 0.01) and those experiencing AEs (HR = 2.970 [CI: 1.186–7.435], p = 0.020) were associated with a higher hazard ratio of IL-1 inhibitors withdrawal. The mean treatment delay was significantly higher among patients discontinuing IL-1 inhibitors (p = 0.0002).Conclusions: Our findings suggest an excellent overall DRR for both ANA and CAN that might be further augmented by paying attention to AEs and employing these agents as first-line biologics in an early disease phase.

Low-Dose Methotrexate Doesn't Prevent Atherosclerotic Events …

Atherosclerosis has long been hypothesized to be an inflammatory disease; recent data from the CANTOS trial demonstrating that canakinumab, an antibody

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Safety profile of the interleukin-1 inhibitors anakinra and canakinumab in real-life clinical practice: a nationwide multicenter retrospective observational study.

A few studies have reported the safety profile of interleukin (IL)-1 blockers from real life. The aim of this study is to describe anakinra (ANA) and canakinumab (CAN) safety profile in children and adults, based on data from a real-life setting. Demographic, clinical, and therapeutic data from patients treated with ANA and CAN were retrospectively collected and analyzed. Four hundred and seventy five patients were enrolled; ANA and CAN were prescribed in 421 and 105 treatment courses, respectively. During a mean follow-up of 24.39 ± 27.04months, 89 adverse events (AE) were recorded; 13 (14.61%) were classified as serious AE (sAE). The overall estimated rate of AE and sAE was 8.4 per 100 patients/year. Safety concerns were more frequent among patients aged ≥ 65years compared with patients < 16years (p = 0.002). No differences were detected in the frequency of safety concerns between monotherapy and combination therapy with immunosuppressants (p = 0.055), but a significant difference was observed when injection site reactions were excluded from AE (p = 0.01). No differences were identified in relation to gender (p = 0.462), different lines of biologic therapy (p = 0.775), and different dosages (p = 0.70 ANA; p = 0.39 CAN). The overall drug retention rate was significantly different according to the occurrence of safety concerns (p value < 0.0001); distinguishing between ANA and CAN, significance was maintained only for ANA (p < 0.0001 ANA; p >0.05 CAN). Treatment duration was the only variable associated with onset of AE (OR = 0.399 [C.I. 0.250-0.638], p = 0.0001). ANA and CAN have shown an excellent safety profile; the risk for AE and sAE tends to decrease over time from the start of IL-1 inhibition.

Can Anti-Inflammatory Therapy with Canakinumab Prevent Diabetes?

Inflammation has long been hypothesized to play a causal role in the pathogenesis of atherosclerosis and may also play a role in insulin resistance and

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C-Reactive Protein Response to a Single Canakinumab Dose Predicts Long-Term Benefit

Inflammation has long been hypothesized to play a causal role in the pathogenesis of atherosclerosis, and results from the industry-funded, randomized,

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Response to Interleukin-1 Inhibitors in 140 Italian Patients with Adult-Onset Still's Disease: A Multicentre Retrospective Observational Study.

Background: Interleukin (IL)-1 plays a crucial role in the pathogenesis of Adult onset Still’s disease (AOSD).Objectives: To evaluate the efficacy and safety of anakinra (ANA) and canakinumab (CAN) in a large group of AOSD patients.Methods: Data on clinical, serological features, and concomitant treatments were retrospectively collected at baseline and after 3, 6, and 12 months from AOSD patients (Yamaguchi criteria) referred by 18 Italian centers. Pouchot’s score was used to evaluate disease severity.Results: One hundred forty patients were treated with ANA; 4 were subsequently switched to CAN after ANA failure. The systemic pattern of AOSD was identified in 104 (74.2%) of the ANA-treated and in 3 (75%) of the CAN-treated groups; the chronic-articular type of AOSD was identified in 48 (25.8%) of the ANA-treated and in 1 (25%) of the CAN-treated groups. Methotrexate (MTX) was the most frequent disease modifying anti-rheumatic drug (DMARD) used before beginning ANA or CAN [91/140 (75.8%), 2/4 (50%), respectively]. As a second-line biologic DMARD therapy in 29/140 (20.7%) of the patients, ANA was found effective in improving all clinical and serological manifestations (p < 0.0001), and Pouchot’s score was found to be significantly reduced at all time points (p < 0.0001). No differences in treatment response were identified in the ANA-group when the patients were stratified according to age, sex, disease pattern or mono/combination therapy profile. ANA primary and secondary inefficacy at the 12-month time point was 15/140 (10.7%) and 11/140 (7.8%), respectively. Adverse events (AEs) [mainly represented by in situ (28/47, 59.5%) or diffuse (12/47, 25.5%) skin reactions and infections (7/47, 14.8%)] were the main causes for discontinuation. Pouchot’s score and clinical and serological features were significantly ameliorated at all time points (p < 0.0001) in the CAN-group, and no AEs were registered during CAN therapy. Treatment was suspended for loss of efficacy only in one case (1/4, 25%).Conclusion: This is the largest retrospective observational study evaluating the efficacy and safety of IL-1 inhibitors in AOSD patients. A good response was noted at 3 months after therapy onset in both the ANA- and CAN-groups. Skin reaction may nevertheless represent a non-negligible AE during ANA treatment.

Autoinflammation: Canakinumab effective in HIDS treatment.

Autoinflammation: Canakinumab effective in HIDS treatment.

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Interleukin (IL)-1 inhibition with anakinra and canakinumab in Behçet's disease-related uveitis: a multicenter retrospective observational study.

This study aimed to evaluate the role of interleukin (IL)-1 inhibitors anakinra (ANA) and canakinumab (CAN) in the treatment of Behçet's disease (BD)-related uveitis. Multicenter retrospective observational study includes 19 consecutive BD patients (31 affected eyes) received treatment with anti-IL-1 agents. Data were analyzed at baseline and at 3 and 12months. The primary endpoint is the reduction of ocular inflammatory flares (OIF). The secondary endpoints are improvement of best corrected visual acuity (BCVA); reduction of macular thickness defined by optical coherence tomography (OCT) and of vasculitis identified with fluorescein angiography (FA); evaluation of statistically significant differences between patients treated with IL-1 inhibitors as monotherapy, subjects also administered with disease modifying anti-rheumatic drugs (DMARDs) and/or corticosteroids as well as between patients administered with IL-1 inhibitors as first line biologic treatment and those previously treated with TNF-α inhibitors. At 12months, OIF significantly decreased from 200episodes/100 patients/year to 48.87episodes/100 patients/year (p<0.0001). The frequency of retinal vasculitis identified by FA significantly decreased between baseline and 3- and 12-month follow-up visits (p<0.0001 and p=0.001, respectively). OIF rate was significantly higher in patients co-administered with DMARDs (81.8episodes/100 patients/year) than in patients undergoing IL-1 inhibitors as monotherapy (0.0episodes/100 patients/year) (p=0.03). No differences were identified on the basis of corticosteroid use and between patients administered with IL-1 inhibitors as first line biologic approach or second line. Steroid dosage was significantly decreased at 12-month visit compared to baseline (p=0.02). Treatment with IL-1 inhibitors is effective in the management of BD-related uveitis and provides a long-term control of ocular inflammation in refractory and long-lasting cases.

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A Snapshot on the On-Label and Off-Label Use of the Interleukin-1 Inhibitors in Italy among Rheumatologists and Pediatric Rheumatologists: A Nationwide Multi-Center Retrospective Observational Study.

Background: Interleukin (IL)-1 inhibitors have been suggested as possible therapeutic options in a large number of old and new clinical entities characterized by an IL-1 driven pathogenesis.Objectives: To perform a nationwide snapshot of the on-label and off-label use of anakinra (ANA) and canakinumab (CAN) for different conditions both in children and adults.Methods: We retrospectively collected demographic, clinical, and therapeutic data from both adult and pediatric patients treated with IL-1 inhibitors from January 2008 to July 2016.Results: Five hundred and twenty-six treatment courses given to 475 patients (195 males, 280 females; 111 children and 364 adults) were evaluated. ANA was administered in 421 (80.04%) courses, CAN in 105 (19.96%). Sixty-two (32.1%) patients had been treated with both agents. IL-1 inhibitors were employed in 38 different indications (37 with ANA, 16 with CAN). Off-label use was more frequent for ANA than CAN (p < 0.0001). ANA was employed as first-line biologic approach in 323 (76.7%) cases, while CAN in 37 cases (35.2%). IL-1 inhibitors were associated with corticosteroids in 285 (54.18%) courses and disease modifying anti-rheumatic drugs (DMARDs) in 156 (29.65%). ANA dosage ranged from 30 to 200 mg/day (or 1.0–2.0 mg/kg/day) among adults and 2–4 mg/kg/day among children; regarding CAN, the most frequently used posologies were 150mg every 8 weeks, 150mg every 4 weeks and 150mg every 6 weeks. The frequency of failure was higher among patients treated with ANA at a dosage of 100 mg/day than those treated with 2 mg/kg/day (p = 0.03). Seventy-six patients (14.4%) reported an adverse event (AE) and 10 (1.9%) a severe AE. AEs occurred more frequently after the age of 65 compared to both children and patients aged between 16 and 65 (p = 0.003 and p = 0.03, respectively).Conclusions: IL-1 inhibitors are mostly used off-label, especially ANA, during adulthood. The high frequency of good clinical responses suggests that IL-1 inhibitors are used with awareness of pathogenetic mechanisms; adult healthcare physicians generally employ standard dosages, while pediatricians are more prone in using a weight-based posology. Dose adjustments and switching between different agents showed to be effective treatment strategies. Our data confirm the good safety profile of IL-1 inhibitors.