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Paul M. Ridker - One of the best experts on this subject based on the ideXlab platform.

  • residual inflammatory risk associated with interleukin 18 and interleukin 6 after successful interleukin 1β inhibition with Canakinumab further rationale for the development of targeted anti cytokine therapies for the treatment of atherothrombosis
    European Heart Journal, 2020
    Co-Authors: Paul M. Ridker, Tom Thuren, Jean G Macfadyen, Peter Libby
    Abstract:

    AIMS The Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) established that targeting inflammation with interleukin-1β (IL-1β) inhibition can significantly reduce cardiovascular (CV) event rates in the absence of any beneficial effects on cholesterol. Yet, CANTOS participants treated with both high-intensity statins and Canakinumab remain at considerable risk for recurrent CV events. Both interleukin-18 (IL-18, which like IL-1β requires the NLRP3 inflammasome for activation) and interleukin-6 (IL-6, a pro-inflammatory cytokine downstream of IL-1) may contribute to the recurrent events that occur even on Canakinumab therapy, and thus represent novel targets for treating atherothrombosis. METHODS AND RESULTS Plasma samples from 4848 stable post-myocardial infarction patients who were assigned to active IL-1β inhibition or placebo within CANTOS underwent measurement of IL-18 and IL-6 both before and after initiation of Canakinumab using validated ELISA. All participants were followed over a median 3.7-year period (maximum 5 years) for recurrent major adverse cardiovascular events (MACE) and for all-cause mortality. Compared to placebo, Canakinumab significantly reduced IL-6 levels in a dose-dependent manner yielding placebo-subtracted median percent reductions in IL-6 at 3 months of 24.8%, 36.3%, and 43.2% for the 50, 150, and 300 mg doses, respectively (all P-values  0.05). Yet, despite these differential plasma effects, either baseline and on-treatment levels of IL-18 or IL-6 associated with rates of future CV events. For example, for MACE, each tertile increase in IL-18 measured 3 months after Canakinumab initiation associated with a 15% increase in risk [95% confidence interval (CI) 3-29%, P = 0.016], while each tertile increase in IL-6 measured 3 months after Canakinumab initiation associated with a 42% increase in risk (95% CI 26-59%, P < 0.0001). Similar effects were observed for MACE-plus, CV death, all-cause mortality, and the for the combination endpoint of all vascular events inclusive of revascularization procedures and hospitalization for congestive heart failure. In baseline as well as on-treatment analyses, risks were highest among those with the highest levels of both IL-18 and IL-6. CONCLUSION There remains substantial residual inflammatory risk related to both IL-18 and IL-6 after IL-1β inhibition with Canakinumab These data support further pharmacologic development of therapies for atherothrombosis that target IL-18 or IL-6 signalling, or that can simultaneously inhibit both IL-1β and IL-18 (such as NLRP3 inflammasome inhibitors). CLINICAL TRIAL REGISTRATION ClinicalTrials.gov NCT01327846.

  • modulation of the interleukin 6 signalling pathway and incidence rates of atherosclerotic events and all cause mortality analyses from the Canakinumab anti inflammatory thrombosis outcomes study cantos
    European Heart Journal, 2018
    Co-Authors: Paul M. Ridker, Tom Thuren, Brendan M. Everett, Peter Libby, Jean G Macfadyen, Wolfgang Koenig, Christie M Ballantyne, Francisco Antonio Helfenstein Fonseca, Hiroaki Shimokawa, Robert J. Glynn
    Abstract:

    Aims: Canakinumab, a monoclonal antibody targeting interleukin (IL)-1β, reduces rates of recurrent cardiovascular events without lowering lipids. It is uncertain, however, to what extent these beneficial cardiovascular outcomes are mediated through interleukin-6 (IL-6) signalling, an issue with substantial pathophysiologic consequences and therapeutic implications. Methods and results: A total of 4833 stable atherosclerosis patients in the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) had IL-6 levels measured before randomization and after treatment with placebo or one of three doses of Canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months. Participants were followed for up to 5 years (median follow-up 3.7 years). Compared with those allocated to placebo, CANTOS participants receiving Canakinumab who achieved on-treatment IL-6 levels below the study median value of 1.65 ng/L experienced a 32% reduction in major adverse cardiovascular events [MACE, multivariable adjusted hazard ratio (HRadj) 0.68, 95% confidence interval (CI) 0.56-0.82; P < 0.0001], a 30% reduction in MACE plus the additional endpoint of hospitalization for unstable angina requiring urgent revascularization (MACE+, HRadj 0.70, 95% CI 0.59-0.84; P < 0.0001), a 52% reduction in cardiovascular mortality (HRadj 0.48, 95% CI 0.34-0.68; P < 0.0001), and a 48% reduction in all-cause mortality (HRadj 0.52, 95% CI 0.40-0.68; P < 0.0001) with prolonged treatment. In contrast, those with on-treatment IL-6 levels equal to or above 1.65 ng/L after taking the first dose of Canakinumab had no significant benefit for any of these endpoints. These differential findings based on the magnitude of IL-6 response were seen in analyses alternatively based on tertiles of on-treatment IL-6 levels, and in analyses using a statistical inference approach to estimate the effect of treatment among individuals who would achieve a targeted IL-6 level. Conclusion: CANTOS provides proof of concept evidence in humans that modulation of the IL-6 signalling pathway, at least with Canakinumab, associates with reduced cardiovascular event rates, independent of lipid lowering. Clinical trial registration: ClinicalTrials.gov NCT01327846.

  • modulation of the interleukin 6 signalling pathway and incidence rates of atherosclerotic events and all cause mortality analyses from the Canakinumab anti inflammatory thrombosis outcomes study cantos
    European Heart Journal, 2018
    Co-Authors: Paul M. Ridker, Tom Thuren, Brendan M. Everett, Peter Libby, Jean G Macfadyen, Wolfgang Koenig, Christie M Ballantyne, Francisco Antonio Helfenstein Fonseca, Hiroaki Shimokawa, Robert J. Glynn
    Abstract:

    Aims Canakinumab, a monoclonal antibody targeting interleukin (IL)-1β, reduces rates of recurrent cardiovascular events without lowering lipids. It is uncertain, however, to what extent these beneficial cardiovascular outcomes are mediated through interleukin-6 (IL-6) signalling, an issue with substantial pathophysiologic consequences and therapeutic implications. Methods and results A total of 4833 stable atherosclerosis patients in the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) had IL-6 levels measured before randomization and after treatment with placebo or one of three doses of Canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months. Participants were followed for up to 5 years (median follow-up 3.7 years). Compared with those allocated to placebo, CANTOS participants receiving Canakinumab who achieved on-treatment IL-6 levels below the study median value of 1.65 ng/L experienced a 32% reduction in major adverse cardiovascular events [MACE, multivariable adjusted hazard ratio (HRadj) 0.68, 95% confidence interval (CI) 0.56-0.82; P < 0.0001], a 30% reduction in MACE plus the additional endpoint of hospitalization for unstable angina requiring urgent revascularization (MACE+, HRadj 0.70, 95% CI 0.59-0.84; P < 0.0001), a 52% reduction in cardiovascular mortality (HRadj 0.48, 95% CI 0.34-0.68; P < 0.0001), and a 48% reduction in all-cause mortality (HRadj 0.52, 95% CI 0.40-0.68; P < 0.0001) with prolonged treatment. In contrast, those with on-treatment IL-6 levels equal to or above 1.65 ng/L after taking the first dose of Canakinumab had no significant benefit for any of these endpoints. These differential findings based on the magnitude of IL-6 response were seen in analyses alternatively based on tertiles of on-treatment IL-6 levels, and in analyses using a statistical inference approach to estimate the effect of treatment among individuals who would achieve a targeted IL-6 level. Conclusion CANTOS provides proof of concept evidence in humans that modulation of the IL-6 signalling pathway, at least with Canakinumab, associates with reduced cardiovascular event rates, independent of lipid lowering. Clinical trial registration ClinicalTrials.gov NCT01327846.

  • Anti-Inflammatory Therapy with Canakinumab for the Prevention and Management of Diabetes
    Journal of the American College of Cardiology, 2018
    Co-Authors: Brendan M. Everett, Tom Thuren, Marc Y. Donath, Aruna D. Pradhan, Prem Pais, Jose C. Nicolau, Robert J. Glynn, Peter Libby, Paul M. Ridker
    Abstract:

    Abstract Background Subclinical inflammation mediated in part by interleukin (IL)-1β participates in peripheral insulin resistance and impaired pancreatic insulin secretion. Objectives The authors tested the hypothesis that the IL-1β inhibitor Canakinumab reduces incident diabetes. Methods The authors randomized 10,061 patients with prior myocardial infarction and high-sensitivity C-reactive protein (hsCRP) ≥2 mg/l to placebo or Canakinumab at doses of 50 mg, 150 mg, or 300 mg subcutaneously once every 3 months. The authors tested the effects of Canakinumab on major cardiovascular events in patients with and without diabetes at baseline, and evaluated as a pre-specified analysis whether Canakinumab would reduce the risk of adjudicated cases of new-onset type 2 diabetes among those with protocol-defined pre-diabetes at trial entry. The authors also evaluated the effect of Canakinumab on fasting plasma glucose and glycosylated hemoglobin (HbA1c) in patients with and without established diabetes. Results Of the participants, 4,057 (40.3%) had baseline diabetes, 4,960 (49.3%) had pre-diabetes, and 1,044 (10.4%) had normal glucose levels. Among those without diabetes, increasing tertiles of hsCRP at baseline associated with an increased risk of developing diabetes during the median follow-up period of 3.7 years (incidence rates 3.2, 4.1, and 4.4 per 100 person-years; p = 0.003). Canakinumab 150 mg as compared with placebo had similar magnitude effects on major cardiovascular event rates among those with diabetes (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.70 to 1.03), pre-diabetes (HR: 0.86; 95% CI: 0.70 to 1.06), and normoglycemia (HR: 0.81; 95% CI: 0.49 to 1.35). Despite large reductions in hsCRP and IL-6, Canakinumab did not reduce the incidence of new-onset diabetes, with rates per 100 person-years in the placebo, 50 mg, 150 mg, and 300 mg Canakinumab groups of 4.2, 4.2, 4.4, and 4.1, respectively (log-rank p = 0.84). The HR comparing all Canakinumab doses to placebo was 1.02 (95% CI: 0.87 to 1.19; p = 0.82). Canakinumab reduced HbA1c during the first 6 to 9 months of treatment, but no consistent long-term benefits on HbA1c or fasting plasma glucose were observed. Conclusions Although IL-1β inhibition with Canakinumab had similar effects on major cardiovascular events among those with and without diabetes, treatment over a median period of 3.7 years did not reduce incident diabetes. (Canakinumab Anti-inflammatory Thrombosis Outcomes Study [CANTOS]; NCT01327846)

  • Inhibition of Interleukin-1β by Canakinumab and Cardiovascular Outcomes in Patients With Chronic Kidney Disease
    Journal of the American College of Cardiology, 2018
    Co-Authors: Paul M. Ridker, Tom Thuren, Brendan M. Everett, Robert J. Glynn, Peter Libby, Jean G Macfadyen, Wolfgang Koenig, Martin P. Lefkowitz, Jan H. Cornel
    Abstract:

    Background Inflammation contributes to chronic kidney disease (CKD), in part mediated through activation of interleukin (IL)-1β by the NLRP3 inflammasome within the kidney. This process also likely contributes to the accelerated atherosclerosis associated with nephropathy. Objectives The authors hypothesized that Canakinumab, a human monoclonal antibody targeting IL-1β, might reduce cardiovascular event rates and improve renal function among post-myocardial infarction patients with CKD. Methods Stable post-myocardial infarction patients with high-sensitivity C-reactive protein (hsCRP) ≥ 2mg/l were randomly allocated to placebo or to 1 of 3 doses of Canakinumab (50, 150, or 300 mg) given subcutaneously once every 3 months. Participants were followed for incident myocardial infarction, stroke, hospitalization for unstable angina requiring urgent revascularization, cardiovascular death, or death from any cause over a median follow-up period of 3.7 years (maximum 5 years). All patients additionally had serial monitoring of estimated glomerular filtration rate (eGFR), creatinine, the urine albumin to creatinine ratio (uACR), and were monitored for adverse renal and urinary events. Results Of 10,061 participants, 1,875 (18.6%) had baseline eGFR Conclusions IL-1β inhibition with Canakinumab reduces major adverse cardiovascular event rates among high-risk atherosclerosis patients with CKD, particularly among those with a robust anti-inflammatory response to initial treatment. These cardiovascular benefits accrued with no adverse clinical renal events. (Canakinumab Anti-inflammatory Thrombosis Outcomes Study [CANTOS]; NCT01327846).

Jasmin B Kuemmerledeschner - One of the best experts on this subject based on the ideXlab platform.

  • long term safety and effectiveness of Canakinumab therapy in patients with cryopyrin associated periodic syndrome results from the β confident registry
    RMD Open, 2021
    Co-Authors: Ulrich A Walker, Philip N. Hawkins, Hal M Hoffman, Hugh H Tilson, Tom Van Der Poll, Stephanie Noviello, Jeremy Levy, Eleni Vritzali, Jasmin B Kuemmerledeschner
    Abstract:

    Objective To report the long-term safety and effectiveness of Canakinumab, a fully human anti-interleukin 1β monoclonal antibody, in patients with cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID), in a real-world setting. Methods From December 2009 to December 2015, the β-Confident Registry prospectively enrolled patients with CAPS and non-CAPS conditions who received Canakinumab per routine care and were prospectively followed for up to 6 years. The registry protocol did not mandate specific visits or procedures; however, all observed adverse events (AEs) and serious adverse events (SAEs) had to be recorded. Canakinumab effectiveness was evaluated by Physician’s Global Assessment (PGA). Results Of 288 patients enrolled, 3 were excluded due to missing informed consent. Among the remaining 285 patients, 243 (85.3%) were patients with CAPS and 42 (14.7%) had atypical CAPS (6.3%) or other conditions (8.4%). The median age was 26.6 years. Based on PGA, 58 of 123 (47.2%) patients with CAPS had no disease activity at 48 months, and 65 of 123 (52.8%) experienced mild/moderate disease activity at 48 months. Among CAPS phenotypes, AE incidence rates per 100 patient-years were lowest for FCAS (73.1; 95% CI 60.3 to 87.8) compared with those with MWS (105.0; 95% CI 97.2 to 113.2) or NOMID (104.6; 95% CI 86.6 to 125.2). One hundred twenty-eight SAEs were reported in 68 patients with CAPS (incidence rate/100 patient-years, 14.0; 95% CI 11.6 to 16.6). One death (metastatic rectal adenocarcinoma in a patient with MWS) was reported. Conclusions The response to Canakinumab was sustained for up to 6 years. Canakinumab demonstrated a favourable safety profile over long-term treatment in patients with CAPS. Trial registration number NCT01213641.

  • rapid and sustained long term efficacy and safety of Canakinumab in patients with cryopyrin associated periodic syndrome ages five years and younger
    Arthritis & Rheumatism, 2019
    Co-Authors: Paul Brogan, Jasmin B Kuemmerledeschner, Isabelle Konepaut, Michael Hofer, Joachim Roesler, Tilmann Kallinich, G Horneff, Inmaculada Calvo Penades, Belen Sevillaperez, L Goffin
    Abstract:

    Objective To assess long-term efficacy and safety of Canakinumab and the response to vaccination in children ages ≤5 years with cryopyrin-associated periodic syndrome (CAPS). Methods CAPS patients (ages ≤5 years) received 2 mg/kg Canakinumab subcutaneously every 8 weeks; patients with neonatal-onset multisystem inflammatory disease (NOMID) received a starting dose of 4 mg/kg in this open-label trial. Efficacy was evaluated using physician global assessment of disease activity and serum levels of C-reactive protein (CRP) and amyloid A (SAA). Adverse events (AEs) were recorded. Vaccination response was evaluated using postvaccination antibody titers at 4 and 8 weeks after immunization. Results Of the 17 patients enrolled, 12 (71%) had Muckle-Wells syndrome, 4 (24%) had NOMID, and 1 (6%) had familial cold autoinflammatory syndrome. All 17 patients had a complete response to Canakinumab. Disease activity improved according to the physician global assessment, and for 65% of the patients autoinflammatory disease was characterized as "absent" at the end of the study. Median CRP levels decreased over time. No such change was evident in SAA levels. During the extension study, postvaccination antibody titers increased above protective levels in 16 (94%) of 17 assessable vaccinations. Ten of the patients (59%) had AEs suspected to be related to Canakinumab; 8 (47%) experienced at least 1 serious AE (SAE). None of the AEs or SAEs required interruption of Canakinumab therapy. Conclusion Our findings indicate that Canakinumab effectively maintains efficacy through 152 weeks and appears to have no effect on the ability to produce antibodies against standard childhood non-live vaccines. The safety profile of Canakinumab was consistent with previous studies, supporting long-term use of Canakinumab for CAPS in children ≤5 years of age.

  • real life effectiveness of Canakinumab in cryopyrin associated periodic syndrome
    Rheumatology, 2016
    Co-Authors: Jasmin B Kuemmerledeschner, Norbert Blank, Tilmann Kallinich, Ferdinand Hofer, T Endres, Birgit Kortusgoetze, Elisabeth Weisbarthriedel, Catharina Schuetz, Karoline Krause, Christoph Rietschel
    Abstract:

    OBJECTIVE Cryopyrin-associated periodic syndrome (CAPS) is a heterogeneous group of diseases characterized by excessive IL-1β release resulting in severe systemic and organ inflammation. Canakinumab targets IL-1β and is approved at standard dose for children and adults with all CAPS phenotypes. Limited data are available for the real-life effectiveness of Canakinumab in patients living with CAPS. Therefore the aim of the study was to evaluate the real-life dosing and effectiveness of Canakinumab in CAPS. METHODS A multi-centre study of consecutive children and adults with CAPS treated with Canakinumab was performed. Demographics, CAPS phenotype and disease activity, inflammatory markers and Canakinumab treatment strategy were recorded. Treatment response was assessed using CAPS disease activity scores, CRP and/or serum amyloid A levels. Comparisons between age groups, CAPS phenotypes and centres were conducted. RESULTS A total of 68 CAPS patients at nine centres were included. All CAPS phenotypes were represented. Thirty-seven (54%) patients were females, the median age was 25 years and 27 (40%) were children, and the median follow-up was 28 months. Overall, complete response (CR) was seen in 72% of CAPS patients, significantly less often in severe (14%) than in mild CAPS phenotypes (79%). Only 53% attained CR on standard dose Canakinumab. Dose increase was more commonly required in children (56%) than in adults (22%). Centres with a treat-to-target approach had significantly higher CR rates (94 vs 50%). CONCLUSION Real-life effectiveness of Canakinumab in CAPS was significantly lower than in controlled trials. Treat-to-target strategies may improve the outcome of children and adults living with CAPS.

  • treatment of muckle wells syndrome analysis of two il 1 blocking regimens
    Arthritis Research & Therapy, 2013
    Co-Authors: Jasmin B Kuemmerledeschner, Assen Koitschev, Pascal N. Tyrrell, Sandra Hansmann, Katharina Ummenhofer, Peter Lohse, Ina Koetter, Fabian Reess, Helmut Wittkowski, Christoph Deuter
    Abstract:

    Objectives: Muckle-Wells syndrome (MWS) is an autoinflammatory disease characterized by excessive interleukin-1 (IL-1) release, resulting in recurrent fevers, sensorineural hearing loss, and amyloidosis. IL-1 inhibition with anakinra, an IL-1 receptor antagonist, improves clinical symptoms and inflammatory markers. Subclinical disease activity is commonly observed. Canakinumab, a fully human IgG1 anti-IL-1b monoclonal antibody, can abolish excess IL-1b. The study aim was to analyze the efficacy and safety of these two anti-IL-1 therapies. Methods: Two cohorts of patients with severe MWS and confirmed NLRP3 mutation were treated with anakinra and/or Canakinumab. Clinical and laboratory features including ESR, CRP, SAA, and the neutrophil marker S100A12 were determined serially. Disease activity was captured by MWS disease activity scores (MWS-DAS). Remission was defined as MWS-DAS ≤5 plus normal CRP and SAA. Treatment efficacy and safety were analyzed. Results: The study included 12 anakinra- and 14 Canakinumab-treated patients; the median age was 33.5 years (3.0 years to 72.0 years); 57% were female patients. Both treatment regimens led to a significant reduction of clinical disease activity and inflammatory markers. At last follow-up, 75% of anakinra-treated and 93% of Canakinumabtreated patients achieved remission. During follow-up, S100A12 levels mirrored recurrence of disease activity. Both treatment regimens had favorable safety profiles. Conclusions: IL-1 blockade is an effective and safe treatment in MWS patients. MWS-DAS in combination with MWS inflammatory markers provides an excellent monitoring tool set. Canakinumab led to a sustained control of disease activity even after secondary failure of anakinra therapy. S100A12 may be a sensitive marker to detect subclinical disease activity.

  • sustained remission of symptoms and improved health related quality of life in patients with cryopyrin associated periodic syndrome treated with Canakinumab results of a double blind placebo controlled randomized withdrawal study
    Arthritis Research & Therapy, 2011
    Co-Authors: I Konepaut, Helen J Lachmann, Eric Hachulla, N Patel, Jasmin B Kuemmerledeschner, Kieron Leslie, Richard Mouy, Alberto Ferreira, K Lheritier, R Preiss
    Abstract:

    Introduction: To assess the effect of Canakinumab, a fully human anti-interleukin-1b antibody, on symptoms and health-related quality of life (HRQoL) in patients with cryopyrin-associated periodic syndrome (CAPS). Methods: In this 48-week, phase 3 study, patients with CAPS received Canakinumab 150 mg subcutaneously at 8week intervals. All patients (n = 35) received Canakinumab during weeks 1 through 8; weeks 9 through 24 constituted a double-blind placebo-controlled withdrawal phase, and weeks 24 through 48 constituted an openlabel phase in which all patients received Canakinumab. Patient and physician assessments of symptoms, levels of inflammatory markers, and HRQoL were performed. Results: Rapid symptom remission was achieved, with 89% of patients having no or minimal disease activity on day 8. Responses were sustained in patients receiving 8-weekly Canakinumab. Responses were lost during the placebo-controlled phase in the placebo group and were regained on resuming Canakinumab therapy in the open-label phase. Clinical responses were accompanied by decreases in serum levels of C-reactive protein, serum amyloid A protein, and interleukin-6. HRQoL scores at baseline were considerably below those of the general population. Improvements in all 36-item Short-Form Health Survey (SF-36) domain scores were evident by day 8. Scores approached or exceeded those of the general U.S. population by week 8 and remained stable during Canakinumab therapy. Improvements in bodily pain and role-physical were particularly marked, increasing by more than 25 points from baseline to week 8. Therapy was generally well tolerated. Conclusions: Canakinumab, 150 mg, 8-weekly, induced rapid and sustained remission of symptoms in patients with CAPS, accompanied by substantial improvements in HRQoL. Trial registration: Clintrials.gov NCT00465985

Tom Thuren - One of the best experts on this subject based on the ideXlab platform.

  • residual inflammatory risk associated with interleukin 18 and interleukin 6 after successful interleukin 1β inhibition with Canakinumab further rationale for the development of targeted anti cytokine therapies for the treatment of atherothrombosis
    European Heart Journal, 2020
    Co-Authors: Paul M. Ridker, Tom Thuren, Jean G Macfadyen, Peter Libby
    Abstract:

    AIMS The Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) established that targeting inflammation with interleukin-1β (IL-1β) inhibition can significantly reduce cardiovascular (CV) event rates in the absence of any beneficial effects on cholesterol. Yet, CANTOS participants treated with both high-intensity statins and Canakinumab remain at considerable risk for recurrent CV events. Both interleukin-18 (IL-18, which like IL-1β requires the NLRP3 inflammasome for activation) and interleukin-6 (IL-6, a pro-inflammatory cytokine downstream of IL-1) may contribute to the recurrent events that occur even on Canakinumab therapy, and thus represent novel targets for treating atherothrombosis. METHODS AND RESULTS Plasma samples from 4848 stable post-myocardial infarction patients who were assigned to active IL-1β inhibition or placebo within CANTOS underwent measurement of IL-18 and IL-6 both before and after initiation of Canakinumab using validated ELISA. All participants were followed over a median 3.7-year period (maximum 5 years) for recurrent major adverse cardiovascular events (MACE) and for all-cause mortality. Compared to placebo, Canakinumab significantly reduced IL-6 levels in a dose-dependent manner yielding placebo-subtracted median percent reductions in IL-6 at 3 months of 24.8%, 36.3%, and 43.2% for the 50, 150, and 300 mg doses, respectively (all P-values  0.05). Yet, despite these differential plasma effects, either baseline and on-treatment levels of IL-18 or IL-6 associated with rates of future CV events. For example, for MACE, each tertile increase in IL-18 measured 3 months after Canakinumab initiation associated with a 15% increase in risk [95% confidence interval (CI) 3-29%, P = 0.016], while each tertile increase in IL-6 measured 3 months after Canakinumab initiation associated with a 42% increase in risk (95% CI 26-59%, P < 0.0001). Similar effects were observed for MACE-plus, CV death, all-cause mortality, and the for the combination endpoint of all vascular events inclusive of revascularization procedures and hospitalization for congestive heart failure. In baseline as well as on-treatment analyses, risks were highest among those with the highest levels of both IL-18 and IL-6. CONCLUSION There remains substantial residual inflammatory risk related to both IL-18 and IL-6 after IL-1β inhibition with Canakinumab These data support further pharmacologic development of therapies for atherothrombosis that target IL-18 or IL-6 signalling, or that can simultaneously inhibit both IL-1β and IL-18 (such as NLRP3 inflammasome inhibitors). CLINICAL TRIAL REGISTRATION ClinicalTrials.gov NCT01327846.

  • effects of interleukin 1β inhibition on blood pressure incident hypertension and residual inflammatory risk a secondary analysis of cantos
    Hypertension, 2020
    Co-Authors: Tom Thuren, Peter Libby, Jean G Macfadyen, Alexander M K Rothman, Alastair J S Webb, David G Harrison, Tomasz J Guzik, Robert J. Glynn
    Abstract:

    While hypertension and inflammation are physiologically inter-related, the effect of therapies that specifically target inflammation on blood pressure is uncertain. The recent CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) afforded the opportunity to test whether IL (interleukin)-1β inhibition would reduce blood pressure, prevent incident hypertension, and modify relationships between hypertension and cardiovascular events. CANTOS randomized 10 061 patients with prior myocardial infarction and hsCRP (high sensitivity C-reactive protein) ≥2 mg/L to Canakinumab 50 mg, 150 mg, 300 mg, or placebo. A total of 9549 trial participants had blood pressure recordings during follow-up; of these, 80% had a preexisting diagnosis of hypertension. In patients without baseline hypertension, rates of incident hypertension were 23.4, 26.6, and 28.1 per 100-person years for the lowest to highest baseline tertiles of hsCRP (P>0.2). In all participants random allocation to Canakinumab did not reduce blood pressure (P>0.2) or incident hypertension during the follow-up period (hazard ratio, 0.96 [0.85-1.08], P>0.2). IL-1β inhibition with Canakinumab reduces major adverse cardiovascular event rates. These analyses suggest that the mechanisms underlying this benefit are not related to changes in blood pressure or incident hypertension. Clinical Trial Registration- URL: https://clinicaltrials.gov. Unique identifier: NCT01327846.

  • modulation of the interleukin 6 signalling pathway and incidence rates of atherosclerotic events and all cause mortality analyses from the Canakinumab anti inflammatory thrombosis outcomes study cantos
    European Heart Journal, 2018
    Co-Authors: Paul M. Ridker, Tom Thuren, Brendan M. Everett, Peter Libby, Jean G Macfadyen, Wolfgang Koenig, Christie M Ballantyne, Francisco Antonio Helfenstein Fonseca, Hiroaki Shimokawa, Robert J. Glynn
    Abstract:

    Aims: Canakinumab, a monoclonal antibody targeting interleukin (IL)-1β, reduces rates of recurrent cardiovascular events without lowering lipids. It is uncertain, however, to what extent these beneficial cardiovascular outcomes are mediated through interleukin-6 (IL-6) signalling, an issue with substantial pathophysiologic consequences and therapeutic implications. Methods and results: A total of 4833 stable atherosclerosis patients in the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) had IL-6 levels measured before randomization and after treatment with placebo or one of three doses of Canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months. Participants were followed for up to 5 years (median follow-up 3.7 years). Compared with those allocated to placebo, CANTOS participants receiving Canakinumab who achieved on-treatment IL-6 levels below the study median value of 1.65 ng/L experienced a 32% reduction in major adverse cardiovascular events [MACE, multivariable adjusted hazard ratio (HRadj) 0.68, 95% confidence interval (CI) 0.56-0.82; P < 0.0001], a 30% reduction in MACE plus the additional endpoint of hospitalization for unstable angina requiring urgent revascularization (MACE+, HRadj 0.70, 95% CI 0.59-0.84; P < 0.0001), a 52% reduction in cardiovascular mortality (HRadj 0.48, 95% CI 0.34-0.68; P < 0.0001), and a 48% reduction in all-cause mortality (HRadj 0.52, 95% CI 0.40-0.68; P < 0.0001) with prolonged treatment. In contrast, those with on-treatment IL-6 levels equal to or above 1.65 ng/L after taking the first dose of Canakinumab had no significant benefit for any of these endpoints. These differential findings based on the magnitude of IL-6 response were seen in analyses alternatively based on tertiles of on-treatment IL-6 levels, and in analyses using a statistical inference approach to estimate the effect of treatment among individuals who would achieve a targeted IL-6 level. Conclusion: CANTOS provides proof of concept evidence in humans that modulation of the IL-6 signalling pathway, at least with Canakinumab, associates with reduced cardiovascular event rates, independent of lipid lowering. Clinical trial registration: ClinicalTrials.gov NCT01327846.

  • modulation of the interleukin 6 signalling pathway and incidence rates of atherosclerotic events and all cause mortality analyses from the Canakinumab anti inflammatory thrombosis outcomes study cantos
    European Heart Journal, 2018
    Co-Authors: Paul M. Ridker, Tom Thuren, Brendan M. Everett, Peter Libby, Jean G Macfadyen, Wolfgang Koenig, Christie M Ballantyne, Francisco Antonio Helfenstein Fonseca, Hiroaki Shimokawa, Robert J. Glynn
    Abstract:

    Aims Canakinumab, a monoclonal antibody targeting interleukin (IL)-1β, reduces rates of recurrent cardiovascular events without lowering lipids. It is uncertain, however, to what extent these beneficial cardiovascular outcomes are mediated through interleukin-6 (IL-6) signalling, an issue with substantial pathophysiologic consequences and therapeutic implications. Methods and results A total of 4833 stable atherosclerosis patients in the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) had IL-6 levels measured before randomization and after treatment with placebo or one of three doses of Canakinumab (50 mg, 150 mg, or 300 mg) given subcutaneously once every 3 months. Participants were followed for up to 5 years (median follow-up 3.7 years). Compared with those allocated to placebo, CANTOS participants receiving Canakinumab who achieved on-treatment IL-6 levels below the study median value of 1.65 ng/L experienced a 32% reduction in major adverse cardiovascular events [MACE, multivariable adjusted hazard ratio (HRadj) 0.68, 95% confidence interval (CI) 0.56-0.82; P < 0.0001], a 30% reduction in MACE plus the additional endpoint of hospitalization for unstable angina requiring urgent revascularization (MACE+, HRadj 0.70, 95% CI 0.59-0.84; P < 0.0001), a 52% reduction in cardiovascular mortality (HRadj 0.48, 95% CI 0.34-0.68; P < 0.0001), and a 48% reduction in all-cause mortality (HRadj 0.52, 95% CI 0.40-0.68; P < 0.0001) with prolonged treatment. In contrast, those with on-treatment IL-6 levels equal to or above 1.65 ng/L after taking the first dose of Canakinumab had no significant benefit for any of these endpoints. These differential findings based on the magnitude of IL-6 response were seen in analyses alternatively based on tertiles of on-treatment IL-6 levels, and in analyses using a statistical inference approach to estimate the effect of treatment among individuals who would achieve a targeted IL-6 level. Conclusion CANTOS provides proof of concept evidence in humans that modulation of the IL-6 signalling pathway, at least with Canakinumab, associates with reduced cardiovascular event rates, independent of lipid lowering. Clinical trial registration ClinicalTrials.gov NCT01327846.

  • Anti-Inflammatory Therapy with Canakinumab for the Prevention and Management of Diabetes
    Journal of the American College of Cardiology, 2018
    Co-Authors: Brendan M. Everett, Tom Thuren, Marc Y. Donath, Aruna D. Pradhan, Prem Pais, Jose C. Nicolau, Robert J. Glynn, Peter Libby, Paul M. Ridker
    Abstract:

    Abstract Background Subclinical inflammation mediated in part by interleukin (IL)-1β participates in peripheral insulin resistance and impaired pancreatic insulin secretion. Objectives The authors tested the hypothesis that the IL-1β inhibitor Canakinumab reduces incident diabetes. Methods The authors randomized 10,061 patients with prior myocardial infarction and high-sensitivity C-reactive protein (hsCRP) ≥2 mg/l to placebo or Canakinumab at doses of 50 mg, 150 mg, or 300 mg subcutaneously once every 3 months. The authors tested the effects of Canakinumab on major cardiovascular events in patients with and without diabetes at baseline, and evaluated as a pre-specified analysis whether Canakinumab would reduce the risk of adjudicated cases of new-onset type 2 diabetes among those with protocol-defined pre-diabetes at trial entry. The authors also evaluated the effect of Canakinumab on fasting plasma glucose and glycosylated hemoglobin (HbA1c) in patients with and without established diabetes. Results Of the participants, 4,057 (40.3%) had baseline diabetes, 4,960 (49.3%) had pre-diabetes, and 1,044 (10.4%) had normal glucose levels. Among those without diabetes, increasing tertiles of hsCRP at baseline associated with an increased risk of developing diabetes during the median follow-up period of 3.7 years (incidence rates 3.2, 4.1, and 4.4 per 100 person-years; p = 0.003). Canakinumab 150 mg as compared with placebo had similar magnitude effects on major cardiovascular event rates among those with diabetes (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.70 to 1.03), pre-diabetes (HR: 0.86; 95% CI: 0.70 to 1.06), and normoglycemia (HR: 0.81; 95% CI: 0.49 to 1.35). Despite large reductions in hsCRP and IL-6, Canakinumab did not reduce the incidence of new-onset diabetes, with rates per 100 person-years in the placebo, 50 mg, 150 mg, and 300 mg Canakinumab groups of 4.2, 4.2, 4.4, and 4.1, respectively (log-rank p = 0.84). The HR comparing all Canakinumab doses to placebo was 1.02 (95% CI: 0.87 to 1.19; p = 0.82). Canakinumab reduced HbA1c during the first 6 to 9 months of treatment, but no consistent long-term benefits on HbA1c or fasting plasma glucose were observed. Conclusions Although IL-1β inhibition with Canakinumab had similar effects on major cardiovascular events among those with and without diabetes, treatment over a median period of 3.7 years did not reduce incident diabetes. (Canakinumab Anti-inflammatory Thrombosis Outcomes Study [CANTOS]; NCT01327846)

Helen J Lachmann - One of the best experts on this subject based on the ideXlab platform.

  • retrospective case series describing the efficacy safety and cost effectiveness of a vial sharing programme for Canakinumab treatment for paediatric patients with cryopyrin associated periodic syndrome
    Pediatric Rheumatology, 2019
    Co-Authors: Abdulkadir A Elmi, Helen J Lachmann, Philip N. Hawkins, Karen Wynne, Iek Cheng, Despina Eleftheriou, Paul Brogan
    Abstract:

    Cryopyrin-associated periodic syndrome (CAPS) is a rare autoinflammatory disease, caused by gain of function mutation in NLRP3 resulting in excess production of interleukin-1 (IL-1). Canakinumab is a human monoclonal antibody against Interleukin-1 beta (IL-1β), licensed for the treatment of CAPS. The objective of the study was to describe the feasibility and cost-effectiveness of a Canakinumab vial-sharing programme for paediatric patients with CAPS. Retrospective case series and clinical service description of a national specially commissioned CAPS clinic at Great Ormond Street Hospital (GOSH). Effectiveness was assessed using a CAPS disease activity score (DAS) and serum amyloid A protein (SAA). Adverse events were collected to determine safety. The number of Canakinumab vials saved was considered when investigating the cost-effectiveness of vial-sharing. Nineteen/20 (95%) of our paediatric patients achieved minimally active clinical disease activity with Canakinumab monotherapy; and 75% achieved both minimally active clinical disease and serological remission using a pre-specified definition based on the CAPS DAS and SAA level. Canakinumab was well tolerated, with only one child developing an infection requiring hospitalisation during the study. Canakinumab vial sharing resulted in 117 vials of Canakinumab saved over a 24-month period, equating to a direct drug-related cost saving of £1,385,821, and a conservative estimated 5-year cost-saving of £3,464,552.50. We provide further evidence for the effectiveness and safety of Canakinumab in children with CAPS, and highlight the cost-effectiveness of a vial-sharing programme for this high cost medicine. We suggest that this could have important implications for the delivery of other high cost medicines used in paediatric practice.

  • Canakinumab for the treatment of autoinflammatory recurrent fever syndromes
    The New England Journal of Medicine, 2018
    Co-Authors: Fabrizio De Benedetti, Marco Gattorno, Helen J Lachmann, I Konepaut, Jordi Anton, Eldad Benchetrit, Joost Frenkel, Hal M Hoffman, Seza Ozen
    Abstract:

    BACKGROUND: Familial Mediterranean fever, mevalonate kinase deficiency (also known as the hyperimmunoglobulinemia D syndrome), and the tumor necrosis factor receptor-associated periodic syndrome (TRAPS) are monogenic autoinflammatory diseases characterized by recurrent fever flares. METHODS: We randomly assigned patients with genetically confirmed colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, or TRAPS at the time of a flare to receive 150 mg of Canakinumab subcutaneously or placebo every 4 weeks. Patients who did not have a resolution of their flare received an add-on injection of 150 mg of Canakinumab. The primary outcome was complete response (resolution of flare and no flare until week 16). In the subsequent phase up to week 40, patients who had a complete response underwent a second randomization to receive Canakinumab or placebo every 8 weeks. Patients who underwent a second randomization and had a subsequent flare and all other patients received open-label Canakinumab. RESULTS: At week 16, significantly more patients receiving Canakinumab had a complete response than those receiving placebo: 61% vs. 6% of patients with colchicine-resistant familial Mediterranean fever (P<0.001), 35% versus 6% of those with mevalonate kinase deficiency (P=0.003), and 45% versus 8% of those with TRAPS (P=0.006). The inclusion of patients whose dose was increased to 300 mg every 4 weeks yielded a complete response in 71% of those with colchicine-resistant familial Mediterranean fever, 57% of those with mevalonate kinase deficiency, and 73% of those with TRAPS. After week 16, an extended dosing regimen (every 8 weeks) maintained disease control in 46% of patients with colchicine-resistant familial Mediterranean fever, 23% of those with mevalonate kinase deficiency, and 53% of those with TRAPS. Among patients who received Canakinumab, the most frequently reported adverse events were infections (173.3, 313.5, and 148.0 per 100 patient-years among patients with colchicine-resistant familial Mediterranean fever, those with mevalonate kinase deficiency, and those with TRAPS, respectively), with a few being serious infections (6.6, 13.7, and 0.0 per 100 patient-years). CONCLUSIONS: In this trial, Canakinumab was effective in controlling and preventing flares in patients with colchicine-resistant familial Mediterranean fever, mevalonate kinase deficiency, and TRAPS. (Funded by Novartis; CLUSTER ClinicalTrials.gov number, NCT02059291 .).

  • Canakinumab treatment for patients with active recurrent or chronic TNF receptor-associated periodic syndrome (TRAPS): An open-label, phase II study
    Annals of the Rheumatic Diseases, 2017
    Co-Authors: Marco Gattorno, Vincent Tormey, Antonio Speziale, Suraj G. Bhansali, Ken Abrams, Nicole Davis, Laura Obici, Marco Cattalini, Alberto Martini, Helen J Lachmann
    Abstract:

    OBJECTIVE To evaluate the efficacy of Canakinumab, a high-affinity human monoclonal anti-interleukin-1β antibody, in inducing complete or almost complete responses in patients with active tumour necrosis factor receptor-associated periodic syndrome (TRAPS). METHODS Twenty patients (aged 7-78 years) with active recurrent or chronic TRAPS were treated with Canakinumab 150 mg every 4 weeks for 4 months (2 mg/kg for those ≤40 kg) in this open-label, proof-of-concept, phase II study. Canakinumab was then withdrawn for up to 5 months, with reintroduction on relapse, and 4 weekly administration (subsequently increased to every 8 weeks) for 24 months. The primary efficacy variable was the proportion of patients achieving complete or almost complete response at day 15, defined as clinical remission (Physician's Global Assessment score ≤1) and full or partial serological remission. RESULTS Nineteen patients (19/20, 95%; 95% CI 75.1% to 99.9%) achieved the primary efficacy variable. Responses to Canakinumab occurred rapidly; median time to clinical remission 4 days (95% CI 3 to 8 days). All patients relapsed after Canakinumab was withdrawn; median time to relapse 91.5 days (95% CI 65 to 117 days). On reintroduction of Canakinumab, clinical and serological responses were similar to those seen during the first phase, and were sustained throughout treatment. Canakinumab was well tolerated and clinical responses were accompanied by rapid and sustained improvement in health-related quality of life. Weight normalised pharmacokinetics of Canakinumab, although limited, appeared to be consistent with historical Canakinumab data. CONCLUSIONS Canakinumab induces rapid disease control in patients with active TRAPS, and clinical benefits are sustained during long-term treatment. TRIAL REGISTRATION NUMBER NCT01242813; Results.

  • efficacy and safety of Canakinumab therapy in paediatric patients with cryopyrin associated periodic syndrome a single centre real world experience
    Rheumatology, 2014
    Co-Authors: Ricardo Russo, Helen J Lachmann, Karen Wynne, Despina Eleftheriou, Pn Hawkins, Sonia Melogomes, Kaukab Rajput, Clive Edelsten, Paul A Brogan
    Abstract:

    Objective. The aim of this study was to determine the short- and long-term efficacy and safety of 8-weekly Canakinumab therapy in children with cryopyrin-associated periodic syndromes (CAPS) in routine clinical practice. Methods. A single-centre observational study was performed. Patients were assessed every 8 weeks at a dedicated clinic. Standardized assessments were the 10-domains DAS for CAPS, acute phase reactants (APRs), physician’s global assessment of disease activity, Child Health Assessment Questionnaire (CHAQ) and Child Health Questionnaire Parent Form 28 (CHQPF-28). The primary endpoint was clinical improvement, defined as a reduction of DAS score 8 weeks after commencing therapy. Secondary endpoints included sustained clinical improvement in APRs, relapses, CHAQ score and CHQPF-28 score. Results. Ten children with CAPS [eight Muckle-Wells syndrome (MWS), two chronic infantile cutaneous neurological articular (CINCA); median age 6.3 years] received 8-weekly Canakinumab treatments at 28.7 mg/kg for a median of 21 months (range 1231 months). Nine of 10 patients improved after the first dose: baseline median DAS of 7.5/20 decreased to 3.5/20 at 8 weeks (P = 0.04). This clinical improvement was sustained at a median follow-up of 21 months (range 1231 months). Children with CINCA required higher doses of Canakinumab than those with MWS. CHAQ and CHQ scores indicated improvement in functioning and health-related quality of life (HRQoL). Treatment was well tolerated, with no injection site reactions and no serious infections. Conclusion. Canakinumab, although costly, is a safe and effective treatment for CAPS in children, leading to sustained improvement in disease activity, serological markers, functional ability and HRQoL.

  • sustained remission of symptoms and improved health related quality of life in patients with cryopyrin associated periodic syndrome treated with Canakinumab results of a double blind placebo controlled randomized withdrawal study
    Arthritis Research & Therapy, 2011
    Co-Authors: I Konepaut, Helen J Lachmann, Eric Hachulla, N Patel, Jasmin B Kuemmerledeschner, Kieron Leslie, Richard Mouy, Alberto Ferreira, K Lheritier, R Preiss
    Abstract:

    Introduction: To assess the effect of Canakinumab, a fully human anti-interleukin-1b antibody, on symptoms and health-related quality of life (HRQoL) in patients with cryopyrin-associated periodic syndrome (CAPS). Methods: In this 48-week, phase 3 study, patients with CAPS received Canakinumab 150 mg subcutaneously at 8week intervals. All patients (n = 35) received Canakinumab during weeks 1 through 8; weeks 9 through 24 constituted a double-blind placebo-controlled withdrawal phase, and weeks 24 through 48 constituted an openlabel phase in which all patients received Canakinumab. Patient and physician assessments of symptoms, levels of inflammatory markers, and HRQoL were performed. Results: Rapid symptom remission was achieved, with 89% of patients having no or minimal disease activity on day 8. Responses were sustained in patients receiving 8-weekly Canakinumab. Responses were lost during the placebo-controlled phase in the placebo group and were regained on resuming Canakinumab therapy in the open-label phase. Clinical responses were accompanied by decreases in serum levels of C-reactive protein, serum amyloid A protein, and interleukin-6. HRQoL scores at baseline were considerably below those of the general population. Improvements in all 36-item Short-Form Health Survey (SF-36) domain scores were evident by day 8. Scores approached or exceeded those of the general U.S. population by week 8 and remained stable during Canakinumab therapy. Improvements in bodily pain and role-physical were particularly marked, increasing by more than 25 points from baseline to week 8. Therapy was generally well tolerated. Conclusions: Canakinumab, 150 mg, 8-weekly, induced rapid and sustained remission of symptoms in patients with CAPS, accompanied by substantial improvements in HRQoL. Trial registration: Clintrials.gov NCT00465985

Isabelle Konepaut - One of the best experts on this subject based on the ideXlab platform.

  • rapid and sustained long term efficacy and safety of Canakinumab in patients with cryopyrin associated periodic syndrome ages five years and younger
    Arthritis & Rheumatism, 2019
    Co-Authors: Paul Brogan, Jasmin B Kuemmerledeschner, Isabelle Konepaut, Michael Hofer, Joachim Roesler, Tilmann Kallinich, G Horneff, Inmaculada Calvo Penades, Belen Sevillaperez, L Goffin
    Abstract:

    Objective To assess long-term efficacy and safety of Canakinumab and the response to vaccination in children ages ≤5 years with cryopyrin-associated periodic syndrome (CAPS). Methods CAPS patients (ages ≤5 years) received 2 mg/kg Canakinumab subcutaneously every 8 weeks; patients with neonatal-onset multisystem inflammatory disease (NOMID) received a starting dose of 4 mg/kg in this open-label trial. Efficacy was evaluated using physician global assessment of disease activity and serum levels of C-reactive protein (CRP) and amyloid A (SAA). Adverse events (AEs) were recorded. Vaccination response was evaluated using postvaccination antibody titers at 4 and 8 weeks after immunization. Results Of the 17 patients enrolled, 12 (71%) had Muckle-Wells syndrome, 4 (24%) had NOMID, and 1 (6%) had familial cold autoinflammatory syndrome. All 17 patients had a complete response to Canakinumab. Disease activity improved according to the physician global assessment, and for 65% of the patients autoinflammatory disease was characterized as "absent" at the end of the study. Median CRP levels decreased over time. No such change was evident in SAA levels. During the extension study, postvaccination antibody titers increased above protective levels in 16 (94%) of 17 assessable vaccinations. Ten of the patients (59%) had AEs suspected to be related to Canakinumab; 8 (47%) experienced at least 1 serious AE (SAE). None of the AEs or SAEs required interruption of Canakinumab therapy. Conclusion Our findings indicate that Canakinumab effectively maintains efficacy through 152 weeks and appears to have no effect on the ability to produce antibodies against standard childhood non-live vaccines. The safety profile of Canakinumab was consistent with previous studies, supporting long-term use of Canakinumab for CAPS in children ≤5 years of age.

  • effect of biologic therapy on clinical and laboratory features of macrophage activation syndrome associated with systemic juvenile idiopathic arthritis
    Arthritis Care and Research, 2018
    Co-Authors: Grant S Schulert, Daniel J. Lovell, Isabelle Konepaut, Francesca Minoia, John F Bohnsack, Randy Q Cron, Soah Hashad, Mikhail Kostik, Despoina Maritsi, Peter A Nigrovic
    Abstract:

    Objective: To assess performance of the 2016 macrophage activation syndrome (MAS) classification criteria for patients with systemic juvenile idiopathic arthritis (systemic JIA) who develop MAS while treated with biologic medications. Methods: A systematic literature review was performed to identify patients with MAS while treated with IL-1 and IL-6 blocking agents. Clinical and laboratory information was compared to a large previously compiled historical cohort. Results: Eighteen publications were identified, and after removing duplicates 35 patients treated with Canakinumab and 49 patients with tocilizumab were available for analysis; 5 anakinra-treated patients were excluded due to limited numbers. MAS classification criteria were less likely to classify tocilizumab treated patients as having MAS compared to the historical cohort or Canakinumab treated patients (56.7% vs. 78.5% and 84%, p<0.01). Patients who developed MAS while treated with Canakinumab trended towards lower ferritin at MAS onset than the historical cohort (4,050 vs. 5,353 ng/ml, p=0.18) but had no differences in other cardinal clinical or laboratory features. In comparison, patients who developed MAS while treated with tocilizumab were less likely febrile, and had notably lower ferritin (1,152 vs. 5,353 ng/ml, p<0.001). Other features of MAS were more pronounced in patients treated with tocilizumab, including lower platelet counts, lower fibrinogen and higher aspartate aminotransferase levels. Mortality rates for patients with MAS treated with tocilizumab or Canakinumab were not significantly different from the historical cohort. Conclusions: These findings show substantial alterations in MAS features that may limit utility of defined criteria for diagnosis of systemic JIA patients treated with biologics. This article is protected by copyright. All rights reserved.

  • real world experience and impact of Canakinumab in cryopyrin associated periodic syndrome results from a french observational study
    Arthritis Care and Research, 2017
    Co-Authors: Isabelle Konepaut, Pierre Quartier, O. Fain, G. Grateau, P. Pillet, F. Bonnet, V. Despert, Le P Blay, K Stankovicstojanovic, L. Willemin
    Abstract:

    Objective The ENVOL study was designed to assess the psychosocial impact of disease and therapy in a French cohort of cryopyrin-associated periodic syndromes (CAPS) patients (and caregivers) treated with Canakinumab. Methods The ENVOL study was a multicenter, observational study of CAPS patients given ≥1 Canakinumab dose. Data were collected before treatment, at 6 and 12 months afterward, and at the last visit. Patients and caregivers completed questionnaires assessing changes from the 12 months of pretreatment to 12 months prior to interview. Data were analyzed retrospectively. Results The study included 10 physicians and 68 patients (53 adults, 15 children). Sixty-five patients (95.6%) were still receiving Canakinumab at the last visit (median 5 years after starting therapy). The mean ± SD score for patient-reported general health increased from 7 ± 2.9 before Canakinumab to 2.7 ± 2.7 after treatment (P  40% of respondents. Caregivers spent a median of 3 versus 0.5 hours/week on care in the 12 months of pretreatment versus 12 months prior to interview (P < 0.001). Following treatment, patients required fewer consultations with general practitioners (mean ± SD per patient per year: 5.2 ± 7.4 versus 8.5 ± 7.2 pretreatment), internists/rheumatologists/dermatologists (2.0 ± 2.1 versus 3.7 ± 3.9), and pediatricians (1.8 ± 1.5 versus 4.4 ± 4.2). Conclusion Long-term treatment with Canakinumab achieves a highly relevant improvement in the physical, emotional, and social lives of patients with CAPS, accompanied by a marked reduction in support required from caregivers and in health care consultations.

  • longterm followup of quality of life in patients with cryopyrin associated periodic syndrome treated with Canakinumab an anti interleukin 1β monoclonal antibody
    The Journal of Rheumatology, 2014
    Co-Authors: Celine Marsaud, Isabelle Marie, Isabelle Konepaut
    Abstract:

    To the Editor: Cryopyrin-associated periodic syndrome (CAPS) is an inherited autoinflammatory disorder that comprises a clinical spectrum of 3 distinct phenotypes increasing in severity: familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and chronic infantile neurological cutaneous and articular syndrome (CINCA). Urticarial rash, fever, arthralgia, and intense fatigue are the main clinical signs1. CINCA is the most severe form, with mental and physical disability. Some patients are difficult to classify because they present intermediate phenotypes. The effect of CAPS on quality of life is significant in all phenotypes, with limitation in ability to work (78%) and in participation in outdoor activities (95%)2. The NOD-like receptor 3 (NLPR3) gene mutation is responsible for overproduction of interleukin 1β (IL-1β)3. Three IL-1 inhibitors have shown efficacy in CAPS: anakinra, rilonacept, and Canakinumab4. The approval of Canakinumab by the US Food and Drug Administration was based on a 48-week, double-blinded study showing rapid and sustained remission of symptoms under treatment5. Our objective with this monocentric longitudinal study was to evaluate quality of life and socioprofessional effects of … Address correspondence to Dr. C. Marsaud, Department of Pediatrics and Pediatric Rheumatology, Bicetre University Hospital, Paris XI University, 78 rue du General Leclerc, 94270 Le Kremlin Bicetre, Paris, France. E-mail: celine.marsaud{at}bct.aphp.fr

  • sustained remission of symptoms and improved health related quality of life in patients with cryopyrin associated periodic syndrome treated with Canakinumab results of a double blind placebo controlled randomized withdrawal study
    Arthritis Research & Therapy, 2011
    Co-Authors: Isabelle Konepaut, Helen J Lachmann, Kieron S. Leslie, Eric Hachulla, N Patel, Jasmin B Kuemmerledeschner, Richard Mouy, Alberto Ferreira, K Lheritier, R Preiss
    Abstract:

    To assess the effect of Canakinumab, a fully human anti-interleukin-1β antibody, on symptoms and health-related quality of life (HRQoL) in patients with cryopyrin-associated periodic syndrome (CAPS). In this 48-week, phase 3 study, patients with CAPS received Canakinumab 150 mg subcutaneously at 8-week intervals. All patients (n = 35) received Canakinumab during weeks 1 through 8; weeks 9 through 24 constituted a double-blind placebo-controlled withdrawal phase, and weeks 24 through 48 constituted an open-label phase in which all patients received Canakinumab. Patient and physician assessments of symptoms, levels of inflammatory markers, and HRQoL were performed. Rapid symptom remission was achieved, with 89% of patients having no or minimal disease activity on day 8. Responses were sustained in patients receiving 8-weekly Canakinumab. Responses were lost during the placebo-controlled phase in the placebo group and were regained on resuming Canakinumab therapy in the open-label phase. Clinical responses were accompanied by decreases in serum levels of C-reactive protein, serum amyloid A protein, and interleukin-6. HRQoL scores at baseline were considerably below those of the general population. Improvements in all 36-item Short-Form Health Survey (SF-36) domain scores were evident by day 8. Scores approached or exceeded those of the general U.S. population by week 8 and remained stable during Canakinumab therapy. Improvements in bodily pain and role-physical were particularly marked, increasing by more than 25 points from baseline to week 8. Therapy was generally well tolerated. Canakinumab, 150 mg, 8-weekly, induced rapid and sustained remission of symptoms in patients with CAPS, accompanied by substantial improvements in HRQoL. Clintrials.gov NCT00465985