Anakinra-treated Patients Research Articles

Transitions of blood immune endotypes and improved outcome by anakinra in COVID-19 pneumonia: an analysis of the SAVE-MORE randomized controlled trial

BackgroundEndotype classification may guide immunomodulatory management of patients with bacterial and viral sepsis. We aimed to identify immune endotypes and transitions associated with response to anakinra (human interleukin 1 receptor antagonist) in participants in the SAVE-MORE trial.MethodsAdult patients hospitalized with radiological findings of PCR-confirmed severe pneumonia caused by SARS-CoV-2 and plasma-soluble urokinase plasminogen activator receptor levels of ≥ 6 ng/ml in the SAVE-MORE trial (NCT04680949) were characterized at baseline and days 4 and 7 of treatment using a previously defined 33-messenger RNA classifier to assign an immunological endotype in blood. Endpoints were changes in endotypes and progression to severe respiratory failure (SRF) associated with anakinra treatment.ResultsAt baseline, 23.2% of 393 patients were designated as inflammopathic, 41.1% as adaptive, and 35.7% as coagulopathic. Only 23.9% were designated as the same endotype at days 4 and 7 compared to baseline, while all other patients transitioned between endotypes. Anakinra-treated patients were more likely to remain in the adaptive endotype during 7-day treatment (24.4% vs. 9.9%; p < 0.001). Anakinra also protected patients with coagulopathic endotype at day 7 against SRF compared to placebo (27.8% vs. 55.9%; p = 0.013).ConclusionWe identify an association between endotypes defined using blood transcriptome and anakinra therapy for COVID-19 pneumonia, with anakinra-treated patients shifting toward endotypes associated with a better outcome, mainly the adaptive endotype.Trial registration ClinicalTrials.gov, NCT04680949, December 23, 2020.

ESCAPE: An Open-Label Trial of Personalized Immunotherapy in Critically lll COVID-19 Patients

Background: Macrophage activation-like syndrome (MALS) and complex immune dysregulation (CID) often underlie acute respiratory distress (ARDS) in COVID-19. We aimed to investigate the effect of personalized immunotherapy on clinical improvement of critical COVID-19. Methods: In this open-label prospective trial, 102 patients with ARDS by SARS-CoV-2 were screened for MALS (ferritin >4,420 ng/mL) and CID (ferritin ≤4,420 ng/mL and low human leukocyte antigen (HLA)-DR expression on CD14-monocytes). Patients with MALS or CID with increased aminotransferases received intravenous anakinra; those with CID and normal aminotransferases received tocilizumab. The primary outcome was ≥25% decrease in the Sequential Organ Failure Assessment (SOFA) score and/or 50% increase in the respiratory ratio by day 8; 28-day mortality, change of SOFA score by day 28, serum biomarkers, and cytokine production by mononuclear cells were secondary endpoints. Results: The primary study endpoint was met in 58.3% of anakinra-treated patients and in 33.3% of tocilizumab-treated patients (p: 0.01). Most patients in both groups received dexamethasone as standard of care. No differences were found in secondary outcomes, mortality, and SOFA score changes. Ferritin decreased among anakinra-treated patients; interleukin-6, soluble urokinase plasminogen activator receptor, and HLA-DR expression increased among tocilizumab-treated patients. Survivors by day 28 who received anakinra were distributed to lower severity levels of the WHO clinical progression scale. Greater incidence of secondary infections was found with tocilizumab treatment. Conclusion: Immune assessment resulted in favorable anakinra responses among critically ill patients with COVID-19 and features of MALS.

IL-1 Receptor Antagonist Anakinra in the Treatment of COVID-19 Acute Respiratory Distress Syndrome: A Retrospective, Observational Study.

The IL-1 receptor antagonist, anakinra, may represent a therapeutic option for acute respiratory distress syndrome (ARDS) associated with coronavirus disease 2019 (COVID-19). In this study, COVID-19 ARDS patients admitted to the Azienda Socio Sanitaria Territoriale of Lecco, Italy, between March 5th to April 15th, 2020, and who had received anakinra off-label were retrospectively evaluated and compared with a cohort of matched controls who did not receive immunomodulatory treatment. The primary end point was survival at day 28. The population consisted of 112 patients (56 treated with anakinra and 56 controls). Survival at day 28 was obtained in 69 patients (61.6%) and was significantly higher in anakinra-treated patients than in the controls (75.0 versus 48.2%, p = 0.007). When stratified by continuous positive airway pressure support at baseline, anakinra-treated patients' survival was also significant compared with the controls (p = 0.008). Univariate analysis identified anakinra usage (odds ratio, 3.2; 95% confidence interval, 1.47-7.17) as a significant survival predictor. This was not supported by multivariate modeling. The rate of infectious-related adverse events was similar between groups. In conclusion, anakinra improved overall survival and invasive ventilation-free survival and was well tolerated in patients with ARDS associated with COVID-19.

Efficacy of anakinra for idiopathic and non-idiopathic pericarditis refractory or intolerant to conventional therapy.

Anakinra, a recombinant interleukin-1 receptor antagonist is effective in treatment of idiopathic recurrent pericarditis. However, its efficacy in non-idiopathic pericarditis (secondary to a diagnosed inflammatory condition, or other known etiology) is unclear. We evaluated the efficacy of anakinra in patients with non-idiopathic (secondary to a diagnosed inflammatory condition, or other known etiology) and idiopathic pericarditis, who were intolerant or refractory to conventional therapy (colchicine and corticosteroids). This was a single-center study in which we performed a retrospective chart review of consecutive adult patients hospitalized with pericarditis intolerant or refractory to conventional therapy who were treated with conventional therapy and anakinra between January 2016-October 2018. The control group included age-matched hospitalized pericarditis patients treated with conventional therapy only. Symptom relief at discharge, time to symptom relief and recurrence on treatment were compared. The effect of outpatient continuation of anakinra on post-treatment recurrence risk was assessed. Twelve patients received anakinra for pericarditis; 22 age-matched controls were identified. Ten patients (83.3%) in the conventional therapy and anakinra group and 13 patients (54.1%) in the conventional therapy groups had non-idiopathic pericarditis. All conventional therapy and anakinra patients and 16 of 22 patients in the conventional therapy group reported symptom relief at discharge (p=0.04). Time to symptom relief was decreased in the conventional therapy and anakinra group (3.75±1.87 vs 5.63±3.28 days, p=0.08). During treatment, all conventional therapy and anakinra-treated patients continued to be symptom free, while nine of 22 conventional therapy patients (40.9%) experienced recurrence (p=0.009). Recurrence risk after treatment discontinuation was similar in the conventional therapy and anakinra group and the conventional therapy group. In hospitalized patients with non-idiopathic or idiopathic pericarditis refractory, or intolerant to, conventional therapy, anakinra is associated with improved symptom relief and decreased recurrence risk during treatment.

Early identification of COVID-19 cytokine storm and treatment with anakinra or tocilizumab

ObjectiveTo examine outcomes among patients who were treated with the targeted anti-cytokine agents, anakinra or tocilizumab, for COVID-19 -related cytokine storm (COVID19-CS). MethodsWe conducted a retrospective cohort study of all SARS-coV2-RNA-positive patients treated with tocilizumab or anakinra in Kaiser Permanente Southern California. Local experts developed and implemented criteria to define COVID19-CS. All variables were extracted from electronic health records. ResultsAt tocilizumab initiation (n = 52), 50 (96.2%) were intubated, and only seven (13.5%) received concomitant corticosteroids. At anakinra initiation (n = 41), 23 (56.1%) were intubated, and all received concomitant corticosteroids. Fewer anakinra-treated patients died (n = 9, 22%) and more were extubated/never intubated (n = 26, 63.4%) compared to tocilizumab-treated patients (n = 24, 46.2% dead, n = 22, 42.3% extubated/never intubated). Patients who died had more severe sepsis and respiratory failure and met COVID-CS laboratory criteria longer (median = 3 days) compared to those extubated/never intubated (median = 1 day). After accounting for differences in disease severity at treatment initiation, this apparent superiority of anakinra over tocilizumab was no longer statistically significant (propensity score-adjusted hazards ratio 0.46, 95% confidence interval 0.18–1.20). ConclusionsPrompt identification and treatment of COVID19-CS before intubation may be more important than the specific type of anti-inflammatory treatment. Randomized controlled trials of targeted anti-cytokine treatments and corticosteroids should report the duration of cytokine storm in addition to clinical severity at randomization.

Anakinra for patients with COVID-19 - Authors' reply.

Anakinra for patients with COVID-19 - Authors' reply.

THU0148 EFFICACY OF IL-1 INHIBITION ON RHEUMATOID ARTHRITIS AND TYPE 2 DIABETES, LONG-TERM FINDINGS FROM TRACK STUDY, A MULTICENTRE, OPEN-LABEL, RANDOMISED CONTROLLED TRIAL

Background: The inflammatory contribution to type 2 diabetes (T2D) has suggested new therapeutic targets by using biologic DMARDs designed for rheumatoid arthritis (RA), and IL-1 would be a common pathogenic mediator, suggesting a possible common therapeutic target [1]. In TRACK study, a multicentre open-label, randomised controlled trial, anakinra, a human interleukin-1-receptor antagonist, showed to induce a significant improvement of metabolic alteration whereas TNFi did not show any significant improvement on that, after both 3 months and 6 months of therapy (crude difference of 0.93 of glycated haemoglobin, HbA1c% between groups) [2]. Concerning RA, a progressive reduction of disease activity was observed in both groups [2]. Objectives: Since TRACK study has been prematurely stopped for “early benefit” after 6 months of follow-up, in this work, we aimed at investigating how long lasted the improvement of HbA1c% and of RA disease activity, considering the original scheduled 24 months follow-up. We also assessed the rate of antidiabetic and anti-rheumatic therapies reduction and stoppage. Methods: This study was designed as a multicentre, open-label, randomised controlled trial, enrolled participants, with RA and T2D, in 12 Italian Rheumatologic Units, between 2013 to 2016. Participants were randomised to anakinra or to a TNFi and the primary endpoint was the change in HbA1c% (EudraCT: 2012-005370-62; ClinicalTrial.gov: NCT02236481). In this further evaluation, we assessed how long lasted the improvement of HbA1c% and of RA disease activity, considering the original scheduled 24 months follow-up, and the rate of antidiabetic and anti-rheumatic drugs, mainly focusing on steroids, reduction and stoppage. Results: In TRACK study, 39 participants with RA and T2D (age 62.72 ± 9.97, 74.4% female gender) were randomised to anakinra or to TNFi; the majority of participants had seropositive RA disease (rheumatoid factor and/or ACPA 70.2%) with active disease (DAS28: 5.54 ± 1.03; C-reactive protein 11.84 ±9.67 mg/L, respectively) and all participants had T2D (HbA1c%: 7.77 ±0.70, fasting plasma glucose: 139.13 ±42.17 mg). Considering the last available observation, a maintenance of reduced levels of HbA1c% was observed in anakinra-treated participants (Baseline: 7.73% ±0.67; 6 months: 6.70% ±0.67; last follow-up: 6.60% ±0.52). Paralleling with HbA1c%, a significant reduction of dosages of antidiabetic therapies was observed in anakinra-treated patients, with a percentage of patients who discontinued any anti-diabetic therapy. Conversely, an intensification of antidiabetic therapies was reported in TNFi-treated participants. Concerning RA, the clinical response was maintained during the whole follow-up, although a larger percentage of anakinra-treated participants discontinued the concomitant steroids therapy. Conclusion: In this study, we observed the benefit of IL-1 inhibition in patients with RA and T2D, reaching the therapeutic targets of both diseases, which lasted longer than first 6 months of follow-up. Although the limitations due to open-label design and the necessity of further confirmatory studies, our results could suggest the concept that IL-1 inhibition may be considered a targeted therapeutic strategy for RA and T2D.

Benefit of Anakinra in Treating Pediatric Secondary Hemophagocytic Lymphohistiocytosis.

To assess the benefit of the recombinant human interleukin-1 receptor antagonist anakinra in treating pediatric patients with secondary hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) associated with rheumatic and nonrheumatic conditions. A retrospective chart review of all anakinra-treated patients with secondary HLH/MAS was performed at Children's of Alabama from January 2008 through December 2016. Demographic, clinical, laboratory, and genetic characteristics, outcomes data, and information on concurrent treatments were collected from the records and analyzed using appropriate univariate statistical approaches to assess changes following treatment and associations between patient variables and outcomes. Forty-four patients with secondary HLH/MAS being treated with anakinra were identified in the electronic medical records. The median duration of hospitalization was 15 days. The mean pretreatment serum ferritin level was 33,316 ng/ml and dropped to 14,435 ng/ml (57% decrease) within 15 days of the start of anakinra treatment. The overall mortality rate in the cohort was 27%. Earlier initiation of anakinra (within 5 days of hospitalization) was associated with reduced mortality (P = 0.046), whereas thrombocytopenia (platelet count <100,000/μl) and STXBP2 mutations were both associated with increased mortality (P = 0.008 and P = 0.012, respectively). In considering patients according to their underlying diagnosis, those with systemic juvenile idiopathic arthritis (JIA) had the lowest mortality rate, with no deaths among the 13 systemic JIA patients included in the study (P = 0.006). In contrast, those with an underlying hematologic malignancy had the highest mortality rate, at 100% (n = 3). These findings suggest that anakinra appears to be effective in treating pediatric patients with non-malignancy-associated secondary HLH/MAS, especially when it is given early in the disease course and when administered to patients who have an underlying rheumatic disease.

Long-term surveillance of biologic therapies in systemic-onset juvenile idiopathic arthritis: data from the German BIKER registry.

Using data from the German Biologics JIA Registry (BIKER), long-term safety of biologics for systemic-onset JIA with regard to adverse events of special interest was assessed. Safety assessments were based on adverse event reports after first dose through 90 days after last dose. Rates of adverse event, serious adverse event and 25 predefined adverse events of special interest were analysed. Incidence rates were compared for each biologic against all other biologics combined applying a mixed-effect Poisson model. Of 260 systemic-onset JIA patients in this analysis, 151 patients received etanercept, 109 tocilizumab, 71 anakinra and 51 canakinumab. Patients with etanercept had higher clinical Juvenile Arthritis Disease Activity Score 10 scores, active joint counts and steroid use at therapy start. Serious adverse events were reported with higher frequency in patients receiving canakinumab [20/100 patient years (PY)] and tocilizumab (21/100 PY). Cytopenia and hepatic events occurred with a higher frequency with tocilizumab and canakinumab. Medically important infections were seen more often in patients with IL-6 or IL-1 inhibition. Macrophage activation syndrome occurred in all cohorts with a higher frequency in patients with canakinumab (3.2/100 PY) and tocilizumab (2.5/100 PY) vs anakinra (0.83/100 PY) and etanercept (0.5/100 PY). After adjustment only an elevated risk for infections in anakinra-treated patients remained significant. Three definite malignancies were reported in patients ever exposed to biologics. Two deaths occurred in patients treated with etanercept. Surveillance of pharmacotherapy as provided by BIKER is an import approach especially for patients on long-term treatment. Overall, tolerance was acceptable. Differences between several biologics were noted and should be considered in daily patient care.

IL-1 Blockade in Patients With Heart Failure With Preserved Ejection Fraction.

Background Enhanced inflammation may lead to exercise intolerance in heart failure with preserved ejection fraction. The aim of the current study was to determine whether IL (interleukin)-1 blockade with anakinra improved cardiorespiratory fitness in heart failure with preserved ejection fraction. Methods and Results Thirty-one patients with heart failure with preserved ejection fraction and CRP (C-reactive protein) >2 mg/L were randomized to anakinra (100 mg subcutaneously daily, N=21) or placebo (N=10) for 12 weeks. We measured peak oxygen consumption (Vo2), ventilatory efficiency (VE/Vco2 slope), and high-sensitivity CRP and NT-proBNP (N-terminal pro-B-type natriuretic peptide) at 4, 12, and 24 weeks. Twenty-eight patients completed ≥2 visits, 18 women (64%), 27 (96%) obese. There were no differences in peak Vo2 or VE/Vco2 slope between groups at baseline. Peak Vo2 was not changed after 12 weeks of anakinra (from 13.6 [11.8-18.0] to 14.2 [11.2-18.5] mL·kg-1·min-1, P=0.89), or placebo (14.9 [11.7-17.2] to 15.0 [13.8-16.9] mL·kg-1·min-1, P=0.40), without significant between-group differences in changes at 12 weeks (-0.4 [95% CI, -2.2 to +1.4], P=0.64). VE/Vco2 slope was also unchanged with anakinra (from 28.3 [27.2-33.0] to 30.5 [26.3-32.8], P=0.97) or placebo (from 31.6 [27.3-36.9] to 31.2 [27.8-33.4], P=0.78), without significant between-group differences in changes at 12 weeks (+1.2 [95% CI, -1.8 to +4.3], P=0.97). Within the anakinra-treated patients, high-sensitivity CRP and NT-proBNP levels were lower at 4 weeks compared with baseline ( P=0.026 and P=0.022 versus placebo [between-group analysis], respectively). Conclusions Treatment with anakinra for 12 weeks failed to improve peak Vo2 and VE/Vco2 slope in a group of obese heart failure with preserved ejection fraction patients. The favorable trends in high-sensitivity CRP and NT-proBNP with anakinra deserve exploration in future studies. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT02173548.

Effect of Interleukin-1 Blockade on Left Ventricular Systolic Performance and Work: A Post Hoc Pooled Analysis of 2 Clinical Trials.

Interleukin-1 (IL-1) blockade seems to improve anaerobic exercise in patients with systolic heart failure through improved left ventricular (LV) systolic performance. However, it is unclear whether IL-1 blockade affects LV systolic performance. We pooled data from 2 clinical trials of patients with systolic heart failure who were randomized to IL-1 blockade or placebo. We estimated changes in LV systolic performance (LV ejection fraction [LVEF] and end-systolic elastance [LVEes]) and pressure-volume area (PVA), a surrogate of oxygen consumption, after 14 days of treatment. LVEF increased from 30% (24%-38%) to 36% (29%-43%) between baseline and day 14 only in anakinra-treated patients (P = 0.03 for within-group change and P = 0.02 for between-group change compared with placebo). LVEes increased from 1.0 mm Hg/mL (0.7-1.5) to 1.3 mm Hg/mL (0.8-1.6) in anakinra-treated patients between baseline and day 14 but not in placebo-treated patients (P = 0.03 for within-group change and P = 0.08 for between-group change). A change in PVA between baseline and 14 days was not detected in either anakinra or placebo patients. In this post hoc analysis, LVEes and LVEF increased significantly in patients treated with an IL-1 blocker but not in placebo-treated patients. An effect of IL-1 blockade on calculated PVA was not detected.

Effect of Biologic Therapy on Clinical and Laboratory Features of Macrophage Activation Syndrome Associated With Systemic Juvenile Idiopathic Arthritis.

To assess performance of the 2016 macrophage activation syndrome (MAS) classification criteria for patients with systemic juvenile idiopathic arthritis (JIA) who develop MAS while treated with biologic medications. A systematic literature review was performed to identify patients with MAS while being treated with interleukin (IL)-1 and IL-6 blocking agents. Clinical and laboratory information was compared to a large previously compiled historical cohort. 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%, 78.5%, and 84%, respectively; P < 0.01). Patients who developed MAS while treated with canakinumab trended towards lower ferritin at MAS onset than the historical cohort (4,050 versus 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 levels (1,152 versus 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. These findings show substantial alterations in MAS features that may limit utility of defined criteria for diagnosis of systemic JIA patients treated with biologic agents.

Leukocyte activity in patients with ST-segment elevation acute myocardial infarction treated with anakinra.

Anakinra, the recombinant form of the human interleukin (IL)-1 receptor antagonist, blunts the acute systemic inflammatory response in patients with ST-segment elevation myocardial infarction (STEMI), by determining a fall in peripheral blood leukocyte and plasma C-reactive protein levels. The aim of the present study was to determine the effects of anakinra on the activity of leukocytes measured ex vivo. Blood was collected 72 h after admission in 17 patients enrolled in the Virginia Commonwealth University-Anakirna Remodeling Trial (2) (VCU-ART2) and randomly treated with anakinra (N=7) or placebo (N=10). Whole blood was cultured at 37°C for 24 h to measure spontaneous production of IL-6 or stimulated with Escherichia coli lipopolysaccharide (LPS) for toll-like receptor (TLR)-4 or heat-killed Staphylococcus epidermidis (SE) for TLR-2 activation. The cultures of anakinra-treated patients produced significantly less IL-6 spontaneously (71 pg/mL [27-114]) compared with placebo-treated patients (290 pg/mL [211-617], p=0.005). LPS- or SE-induced IL-6 production, on the other hand, was not statistically different between anakinra-versus placebo-treated patients (344 pg/mL [94-560] versus 370 pg/mL [306-991], p=0.32 for LPS, and 484 pg/mL [77-612] versus 615 pg/mL [413-871], p=0.31 for SE, respectively). IL-1 blockade with anakinra in STEMI patients results in reduced spontaneous leukocyte activity ex vivo without impairing the responsiveness to bacterial stimuli.

Anakinra: A safe and effective first-line treatment in systemic onset juvenile idiopathic arthritis (SoJIA)

Systemic onset juvenile idiopathic arthritis (SoJIA) is a rare inflammatory disorder. It can result in disease and treatment-related disability. SoJIA is characterized by remitting fevers, evanescent rash, generalized lymphadenopathy, hepatomegaly/splenomegaly, and/or serositis. Non-responsiveness to standard therapy with corticosteroids and disease modifying antirheumatic drugs is not uncommon. IL-1β has been shown to be a main contributor to the pathogenesis of SoJIA. Anakinra, a recombinant IL-1β receptor antagonist, was shown to be effective in small cohorts of therapy-resistant adult and pediatric Still's patients. In order to assess the efficacy and safety of first-line anakinra treatment in SoJIA, we reviewed the charts of all SoJIA patients in our institution from 2005 to 2010, searching for first-line anakinra-treated patients. We report the clinical and laboratory course of four SoJIA patients. The mean follow-up was 13.5 (range: 2-50) months. Anakinra was started at doses from 1.5 to 4 mg/kg for a median duration of 3 (range: 3-18) months. Two patients responded to anakinra mono-therapy; two cases required corticosteroids. Normalized body temperatures and the absence of evanescent rashes were achieved after a median of 4 (range: 2-10) days. We did not see treatment-related adverse reactions other than local injection site inflammation. This is the first single-center series, reporting anakinra as first-line treatment in SoJIA. We show rapid efficacy of anakinra in early SoJIA with reduced treatment-related side effects. A subset of patients remains corticosteroid dependent. Further studies are warranted to follow larger cohorts and to assess long-term safety.

Preliminary studies related to anti-interleukin-1β therapy in children with newly diagnosed type 1 diabetes

Interleukin-1β (IL-1β) may play a role in the pathogenesis of type 1 diabetes, but there are no data regarding the efficacy of agents antagonizing IL-1β in patients with this disorder. We characterized the effects of IL-1β on gene expression in peripheral blood mononuclear cells (PBMC) and the clinical and gene expression effects of a short course of recombinant IL-1 receptor antagonist protein, anakinra, on children with newly diagnosed diabetes. PBMC from healthy adult volunteers were exposed to IL-1β for 24 h in vitro. Gene expression was analyzed via microarray. Fifteen children within 1 wk of diagnosis of type 1 diabetes received daily anakinra for 28 d and were followed for 6 months. Blood was drawn for microarray analysis before and after anakinra treatment. Insulin secretory capacity was assessed by mixed-meal tolerance testing (MMTT) at 3-4 wk and 7 months after diagnosis. Hemoglobin A1c (HbA1c) and insulin doses were periodically recorded. Data were compared with two historical control groups of children with newly diagnosed diabetes. Although in vitro exposure to IL-1β caused many changes in PBMC gene expression, gene expression did not change significantly after anakinra therapy in diabetes patients. Anakinra-treated patients had similar HbA1c and MMTT responses, but lower insulin requirements 1 and 4 months after diagnosis compared to controls, and lower insulin-dose-adjusted A1c 1 month after diagnosis. Anakinra therapy is well tolerated in children with newly diagnosed type 1 diabetes. Further studies are needed to demonstrate biological effects.

IL-1 receptor antagonism and muscle gene expression in patients with type 2 diabetes

We have previously reported that systemic blockade of IL-1beta in patients with type 2 diabetes with anakinra (a recombinant human interleukin-1-receptor antagonist, IL-1Ra), lowered glycated hemoglobin improved beta-cell function and reduced circulating levels of IL-6 and CRP (7). To investigate the effects of IL-1Ra in insulin-sensitive tissue, gene expression levels in skeletal muscle from type 2 diabetic patients treated with IL-1Ra were analysed. Gene expression profiles in vastus lateralis muscle biopsies from five obese patients (BMI >27) were determined before and after 13 weeks of treatment with IL-1Ra (anakinra) using Affymetrix U133Plus2.0 GeneChips. Microarray data were normalized and analysed independently using four different algorithms; RMA, GCRMA, dChip and GCOS. Hypothesis tests were applied to the microarray data for each gene, and protein network analysis was used to identify biological networks/pathways affected by the treatment. Gene expression levels for candidate genes (COL1A1, CDKN1C, HSP70, HLA-A, IL-1 and IL-6) were determined by qRT-PCR in muscles of placebo- (n = 12) and anakinra-treated patients (n = 11). The concordance of the variations of the transcripts identified as significantly regulated after IL-1Ra treatment was low. No significantly altered expression levels could be demonstrated after false discovery rate correction. The protein interaction network did not reveal any altered networks/pathways. None of the candidate genes, quantified by qRT-PCR, were significantly altered when comparing the number of transcripts before and after treatment for each individual. conclusion: Treatment with IL-1Ra did not significantly affect gene expression levels in skeletal muscle in this limited and selected sample of obese patients with type 2 diabetes. Larger studies might confirm the lack of effect of anakinra on muscle tissue gene expression.

Lowering interleukin-1 activity with anakinra improves myocardial deformation in rheumatoid arthritis

Objective:Inhibition of interleukin-1 activity improves nitro-oxidative stress, endothelial and coronary function. The authors investigated (a) the association of nitro-oxidative stress and endothelial function with myocardial deformation, (b) the effects of...

Effect of ultrasound‐guided, peritendinous injections of adalimumab and anakinra in chronic Achilles tendinopathy: a pilot study

A new review suggested that an inflammatory process may be related to the development of tendinopathy and that the inflammation may also play a role in chronic tendinopathy. Hitherto, peritendinous injections of glucocorticosteroids have been used to reduce the inflammation. In an attempt to reduce the possible side effects and the high frequency of relapse of symptoms after local treatments with glucocorticosteroids, new anti-inflammatory treatments were tested. Ultrasound-guided, peritendinous injections of adalimumab (tumor necrosis factor -alpha blocker) and anakinra (interleukin-1 receptor antagonist) were evaluated with regard to reducing pain, tendon thickness, and the blood flow in chronic Achilles tendinopathy. We found in this small pilot study that peritendinous injections of adalimumab had a significant effect on pain sensation at rest in chronic Achilles tendinopathy. Adalimumab had no effect on tendon thickness and contrary to all expectation, the tendon thickness in the anakinra-treated patients increased significantly after 12 weeks. Adalimumab showed a significant tendency to reduce the blood flow in the tendon over 12 weeks, whereas anakinra had no effect on the blood flow.

Durability and Rapidity of Response to Anakinra in Patients with Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic and progressive inflammatory disease that ultimately leads to disability and functional decline. Because patients usually develop RA in mid-life, they may experience its consequences for 20-30 years or longer. Proinflammatory cytokines, notably interleukin (IL)-1 and tumour necrosis factor-alpha, are believed to play significant pathophysiological roles. Clinical trials of biologicals that block these cytokines confirm their importance.Anakinra, a recombinant human IL-1 receptor antagonist, improves clinical signs and symptoms, and slows radiographic progression in patients with active RA. In clinical trials, patients receiving anakinra doses >1 mg/kg, whether administered alone or in combination with methotrexate, were two to three times more likely than patients receiving placebo to achieve a sustained ACR20 (American College of Rheumatology criteria) response. Notably, bone erosion slows to a greater extent and shows accelerated benefit when anakinra treatment is continued for periods beyond 24 weeks. Anakinra has a rapid onset of action, with substantial improvements in biochemical indices (C-reactive protein) seen within 1 week and clinical responses (ACR20 or joint counts) seen within 4 weeks of starting treatment. Anakinra is generally well tolerated, with injection site reactions being the most common adverse event. These reactions are generally mild and typically resolve within 2-3 weeks of treatment. The anakinra product labelling does include a warning regarding an increased risk of infections of 2% in anakinra-treated patients versus <1% in patients receiving placebo.