IL-1 Antagonism Research Articles

Targeting the NLRP3 inflammasome-IL-1β pathway in type 2 diabetes and obesity.

Increased activity of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome-IL-1β pathway is observed in obesity and contributes to the development of type 2 diabetes and its complications. In this review, we describe the pathological activation of IL-1β by metabolic stress, ageing and the microbiome and present data on the role of IL-1β in metabolism. We explore the physiological role of the IL-1β pathway in insulin secretion and the relationship between circulating levels of IL-1β and the development of diabetes and associated diseases. We highlight the paradoxical nature of IL-1β as both a friend and a foe in glucose regulation and provide details on clinical translation, including the glucose-lowering effects of IL-1 antagonism and its impact on disease modification. We also discuss the potential role of IL-1β in obesity, Alzheimer's disease, fatigue, gonadal dysfunction and related disorders such as rheumatoid arthritis and gout. Finally, we address the safety of NLRP3 inhibition and IL-1 antagonists and the prospect of using this therapeutic approach for the treatment of type 2 diabetes and its comorbidities.

Recent advances and evolving concepts in Still's disease.

Still's disease is a rare inflammatory syndrome that encompasses systemic juvenile idiopathic arthritis and adult-onset Still's disease, both of which can exhibit life-threatening complications, including macrophage activation syndrome (MAS), a secondary form of haemophagocytic lymphohistiocytosis. Genetic insights into Still's disease involve both HLA and non-HLA susceptibility genes, suggesting the involvement of adaptive immune cell-mediated immunity. At the same time, phenotypic evidence indicates the involvement of autoinflammatory processes. Evidence also implicates the type I interferon signature, mechanistic target of rapamycin complex 1 signalling and ferritin in the pathogenesis of Still's disease and MAS. Pathological entities associated with Still's disease include lung disease that could be associated with biologic DMARDs and with the occurrence of MAS. Historically, monophasic, recurrent and persistent Still's disease courses were recognized. Newer proposals of alternative Still's disease clusters could enable better dissection of clinical heterogeneity on the basis of immune cell profiles that could represent diverse endotypes or phases of disease activity. Therapeutically, data on IL-1 and IL-6 antagonism and Janus kinase inhibition suggest the importance of early administration in Still's disease. Furthermore, there is evidence that patients who develop MAS can be treated with IFNγ antagonism. Despite these developments, unmet needs remain that can form the basis for the design of future studies leading to improvement of disease management.

Rethinking IL-1 Antagonism in Respiratory Viral Infections: A Role for IL-1 Signaling in the Development of Antiviral T Cell Immunity

IL-1R integrates signals from IL-1α and IL-1β, and it is widely expressed across tissues and immune cell types. While the expression pattern and function of IL-1R within the innate immune system is well studied, its role in adaptive immunity, particularly within the CD8 T cell compartment, remains underexplored. Here, we show that CD8 T cells dynamically upregulate IL-1R1 levels during priming by APCs, which correlates with their proliferation status and the acquisition of an effector phenotype. Notably, this IL-1 sensitivity persists in memory CD8 T cells of both mice and humans, influencing effector cytokine production upon TCR reactivation. Furthermore, our study highlights that antiviral effector and tissue-resident CD8 T cell responses against influenza A virus infection become impaired in the absence of IL-1 signaling. Altogether, these data support the exploitation of IL-1 activity in the context of T cell vaccination strategies and warrant consideration of the impact of clinical IL-1 inhibition on the rollout of T cell immunity.

Targeting of Notch, IL-1, and leptin has therapeutic potential in xenograft colorectal cancer.

Colorectal cancer (CRC) is a fatal malignancy type and its occurence still needs to be explored mechanistically. Notch, IL-1, and leptin crosstalk is reported to play a role in the proliferation, migration, and expression of proangiogenic molecules. In this study, we aimed to investigate the effect of inhibition of Notch, IL-1, and leptin on CRC. To generate colorectal cancer tumor xenografts, 1 × 107 cells from exponentially growing cultures of HCT-15 cells were injected subcutaneously, at the axillary region of the left and right rear flanks of forty NOD.CB17-Prkdcscid/J (NOD/SCID) female mice. The mice were then monitored for the development of tumors and were randomly divided into five groups when tumor sizes reached a volume of approximately 150 mm3. Mice were used to determine the effectiveness of the gamma-secretase inhibitor (DAPT, Notch inhibitor), the interleukin-1 receptor antagonist (Anakinra) and the leptin receptor antagonist (Allo aca) against tumor growth. The mice were euthanized by CO2 inhalation immediately after the treatments finished, and all efforts were made to minimize suffering. Tumors were excissed for RT-PCR and histological analysis. There is an intact Notch, IL-1, and leptin signaling axis, and in vivo antagonism of Notch, IL-1, and leptin affects mRNA and protein expression of inflammatory and angiogenic molecules. Present data suggest that targeting Notch, IL-1, and leptin may be possesses therapeutic potential in CRC.

DP23 Paraprotein negative Schnitzler syndrome: a new clinical entity?

Abstract Schnitzler syndrome (SchS) is a rare autoinflammatory condition with prominent cutaneous features. The genetic basis of the condition is not understood. The Strasbourg Criteria outline the clinical diagnosis of SchS, requiring an IgM or IgG monoclonal gammopathy and an urticarial rash (Simon A, Asli B, Braun-Falco M et al. Schnitzler’s syndrome: diagnosis, treatment, and follow-up. Allergy 2013; 68:562–8). We report two cases of SchS, the first with a 5-year delay in the development of a paraprotein and the second with complete absence of a paraprotein, despite 12 years of symptoms. Case one was a 47-year-old female who attended with a 4-year history of a dusky-red urticarial rash and polyarthralgia. Inflammatory markers were persistently raised, in the absence of any identified cause. Investigations demonstrated thrombocytosis, hypocomplementaemia and an isolated elevated IgM (3.07 g L–1), with no monoclonal band. Serum free light chain κ : λ ratio was normal. The patient had a working diagnosis of hypocomplementaemic urticarial vasculitis, despite skin biopsy demonstrating a lack of fibrinoid necrosis. She failed to improve symptomatically on high-dose antihistamines, corticosteroids or azathioprine and had minimal improvement with omalizumab. Repeat serum electrophoresis identified the development of a new IgM κ paraprotein 5 years after the initial symptom onset. Interleukin (IL)-1 blockade resulted in rapid clinical and biochemical improvement. Case 2 was a 55-year-old woman with a 4-year history of recurrent urticaria. A diagnosis of urticarial vasculitis was made; skin biopsy was incongruent but displayed a neutrophilic infiltrate. She had a poor response to high-dose antihistamines and withdrew from services for 3 years. Subsequent therapy with ciclosporin, azathioprine, omalizumab, dapsone and colchicine yielded no clinical benefit. Laboratory investigations repeatedly showed elevated inflammatory markers and an elevated IgA (3.9 g L–1) in the context of inflammatory bowel disease but no IgM or IgM paraprotein. Serum free light chain κ : λ ratio was normal. Clinical suspicion of an autoinflammatory condition was high given the longstanding treatment-resistant urticaria and systemic inflammation. A trial of IL-1 blockade led to immediate clinical and biochemical resolution. This treatment was continued and has resulted in the eradication of a cumulative 12 years of symptoms. There are several reports of SchS with no monoclonal band responding to IL-1 antagonism. As these cases do not fulfil the obligatory criteria for SchS, we propose a new clinical entity, paraprotein-negative IL-1-mediated inflammatory dermatosis (PANID). It is not yet clear if PANID is a precursor to SchS, although published cases demonstrating delayed paraprotein development could support this. Clinicians should consider this diagnosis in patients with treatment-refractory urticaria and systemic inflammation.

Serum IL-1ra Is Associated with but Has No Genetic Link to Type 1 Diabetes

Interleukin-1 antagonism is a proposed biomarker and potential therapy for the delay and/or treatment of type 1 diabetes (T1D). We evaluated the role of circulating interleukin-1 receptor antagonist (IL-1ra) in a prospectively monitored cohort of T1D patients. In order to determine a mechanistic association between IL-1ra and T1D, we performed co-localization analyses between serum IL-1ra protein quantitative trait loci and T1D genome-wide analysis studies. Adjusting for human leukocyte antigen (HLA) genotypes, first degree relative status, gender, and age, serum levels of IL-1ra were lower in subjects who progressed to T1D compared to the controls (p = 0.023). Our results suggest that females have higher levels of IL-1ra compared to males (p = 0.005). The 2q14.1 region associated with serum IL-1ra levels is not associated with a risk of developing T1D. Our data suggest that IL-1 antagonism by IL-1ra is not an effective therapy in T1D, but IL-1ra may be a biomarker for progression to T1D.

Effects of interleukin-1 antagonism and corticosteroids on fibroblast growth factor-21 in patients with metabolic syndrome

Fibroblast growth factor-21 (FGF21) is elevated in patients with the metabolic syndrome. Although the exact underlying mechanisms remain ill-defined, chronic low-grade inflammation with increased Interleukin-(IL)-1β expression may be responsible. The aim of this study was to investigate effects of two different anti-inflammatory treatments (IL-1 antagonism or high-dose corticosteroids) on FGF21 in patients with the metabolic syndrome. This is a secondary analysis of two interventional studies in patients with obesity and features of the metabolic syndrome. Trial A was an interventional trial (n = 73) investigating short-term effects of the IL-1 antagonist anakinra and of dexamethasone. Trial B was a randomized, placebo-controlled, double-blinded trial (n = 67) investigating longer-term effects of IL-1 antagonism. In total, 140 patients were included in both trials. Median age was 55 years (IQR 44–66), 26% were female and median BMI was 37 kg/m2 (IQR 34–39). Almost half of the patients were diabetic (45%) and had increased c-reactive protein levels of 3.4 mg/L. FGF21 levels correlated with fasting glucose levels, HOMA-index, C-peptide levels, HbA1c and BMI. Short-term treatment with anakinra led to a reduction of FGF21 levels by − 200 pg/mL (95%CI − 334 to − 66; p = 0.004). No effect was detectable after longer-term treatment (between-group difference: − 8.8 pg/mL (95%CI − 130.9 to 113.3; p = 0.89). Acute treatment with dexamethasone was associated with reductions of FGF21 by -175 pg/mL (95%CI − 236 to − 113; p < 0.001). Anti-inflammatory treatment with both, IL-1 antagonism and corticosteroids reduced FGF21 levels at short-term in individuals with the metabolic syndrome.Trial registration: ClinicalTrials.gov Identifiers NCT02672592 and NCT00757276.

S2153 Diffuse Gastrointestinal Hemorrhage Due to COVID-19 Macrophage Activation Syndrome

INTRODUCTION: Gastrointestinal symptoms of SARS-CoV-2 infection common, but usually mild in severity. We describe a case of severe gastrointestinal bleeding (GIB) in a patient with a COVID-19 associated hyperinflammatory response. CASE DESCRIPTION/METHODS: A 25-year-old man with no significant medical history presented with 2 weeks of fevers, cough, dyspnea, and diarrhea. He tested positive for COVID-19 on nasopharyngeal PCR and imaging showed multifocal pneumonia. Initial labs were notable for markedly elevated CRP and ferritin, pancytopenia and acute kidney injury. He was treated for suspected COVID-19 associated hyperinflammatory syndrome with anakinra (5 mg/kg twice daily) and hydroxychloroquine. He became anuric requiring hemodialysis and renal biopsy complicated by retroperitoneal bleeding and emergent embolization of the left renal artery. He was intubated for worsening acute respiratory distress syndrome (ARDS) and developed hematemesis and melena leading to hemorrhagic shock. EGD showed diffuse inflammation, erosions and oozing from the esophagus to the proximal duodenum, non-bleeding gastric ulcers and petechiae (Figure 1A, B). Given clinical suspicion for COVID-19 associated macrophage activation syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis (sHLH), anakinra was restarted and intravenous immunoglobulin (IVIG, 1mg/kg) was given with clinical improvement. The patient continued to have melena. Repeat EGD showed severe esophagitis with large clots and sloughing mucosa, a focal 3–4 cm area of necrosis in the fundus, unresolved non-bleeding stomach ulcers and improved duodenitis from prior (Figure 1C, D). DISCUSSION: We describe a case of a young adult who developed catastrophic GIB as a complication of COVID-19. The pathogenesis of SARS-CoV2 infection is incompletely understood, but there is mounting evidence that it can induce a MAS/sHLH-like hyperinflammatory response. Several laboratory hallmarks of COVID-19 infection are also seen in MAS/sHLH including elevated CRP, ferritin, IL-1, and IL-6. This hyperinflammatory response can manifest in a variety of ways, including a Kawasaki-like presentation in pediatric patients responsive to IVIG and IL-1 antagonism. GIB is rare in COVID-19, occurring in 4% of cases, but can occur in up to 20% of MAS/sHLH cases. Clinicians should recognize that COVID-19 can provoke a MAS/sHLH-like hyperinflammatory syndrome with gastrointestinal involvement.Figure 1.: A. Esophagitis and B. gastric ulcers with surrounding petechiae on EGD. B Esophagitis with sloughing mucosa and B. focal gastric necrosis seen on repeat EGD.

IL (Interleukin)-1 Receptor Antagonist Increases Ang (Angiotensin [1-7]) and Decreases Blood Pressure in Obese Individuals.

IL (Interleukin)-1 antagonism decreases blood pressure in obese individuals. The underlying mechanisms are unknown. Based on experimental data, we hypothesized an effect of IL-1 antagonism via modulation of the renin-angiotensin-aldosterone system. In this explorative study, we examined shorter- (2 days) and longer-term effects (4 weeks) of IL-1 antagonism (anakinra/Kineret) on renin-angiotensin system peptide profiles and on hemodynamic parameters assessed by noninvasive measurement in obese (body mass index ≥30 kg/m2) individuals from 2 interventional trials (a prospective interventional trial [n=73] and a placebo controlled-double blinded interventional trial [n=67]). A total of 140 patients were included. Systolic blood pressure decreased after short-term (absolute difference -5.2 mm Hg [95% CI, -8.5 to -1.8]; P=0.0006) and after longer-term treatment with anakinra (absolute difference -3.9 mm Hg [95% CI, -7.59 to -0.21]; P=0.04), with no change in blood pressure in the placebo group. Upon IL-1 antagonism, equilibrium levels of Ang II (angiotensin II), Ang I, aldosterone, and renin remained unchanged. In contrast, Ang (1-7) peptide levels increased after 4 weeks (between-group difference 16.35 pmol/L [95% CI, 1.22-30.17], P=0.03), as well as the Ang (1-7)/Ang II ratio (between-group difference 0.42 [95% CI, 0.17-0.67], P=0.02) in comparison to placebo. Consistently, the stroke systemic vascular resistance index significantly decreased in the anakinra group (between-group difference of -62.65 dyn/sec per cm-5 per m2 [95% CI, -116.94 to -18.36], P=0.008, consistent with a 25% decrease). IL-1 antagonism increased the vasodilatory Ang (1-7) peptide after 4 weeks of treatment in obese individuals, paralleled by a decrease in peripheral vascular resistance. These findings point to an IL-1 mediated blood pressure-lowering mechanism via modulation of Ang (1-7). Registration- URL: https://www.clinicaltrials.gov. Unique identifiers: NCT02227420 and NCT02672592.

Postprandial Hypoglycemia in Patients after Gastric Bypass Surgery Is Mediated by Glucose-Induced IL-1β

Postprandial hypoglycemia is a disabling complication of the treatment of obesity by gastric bypass surgery. So far, no therapy exists, and the underlying mechanisms remain unclear. Here, we hypothesized that glucose-induced IL-1β leads to an exaggerated insulin response in this condition. Therefore, we conducted a placebo-controlled, randomized, double-blind, crossover study with the SGLT2-inhibitor empagliflozin and the IL-1 receptor antagonist anakinra (clinicaltrials.govNCT03200782; n= 12). Both drugs reduced postprandial insulin release and prevented hypoglycemia (symptomatic events requiring rescue glucose: placebo= 7/12, empagliflozin= 2/12, and anakinra= 2/12, pvallikelihood ratio test (LRT) = 0.013; nadir blood glucose for placebo= 2.4mmol/L, 95% CI2.18-2.62, empagliflozin= 2.69mmol/L, 95% CI 2.31-3.08, and anakinra= 2.99mmol/L, 95% CI 2.43-3.55, pvalLRT= 0.048). Moreover, analysis of monocytes exvivo revealed a hyper-reactive inflammatory state that has features of an exaggerated response to a meal. Our study proposes a role for glucose-induced IL-1β in postprandial hypoglycemia after gastric bypass surgery and suggests that SGLT2-inhibitors and IL-1 antagonism may improve this condition.

Postprandial Hypoglycemia in Patients after Bariatric Surgery is Mediated by Glucose-Induced Il-1β

Postprandial hypoglycemia is a disabling complication of the treatment of obesity by bariatric surgery. So far, no therapy exists, and the underlying mechanisms remain unclear. Here, we hypothesized that glucose-induced IL-1β leads to an exaggerated insulin response in this condition. Therefore, we conducted a placebo-controlled, randomized, double-blind, cross-over study with the SGLT2-inhibitor empagliflozin and the IL-1 receptor antagonist anakinra. Both drugs reduced postprandial insulin release and prevented hypoglycemia. Moreover, analysis of monocytes ex vivo revealed a hyper-reactive inflammatory state that resembles an exaggerated response to a meal. Our study proposes a role for glucose-induced IL-1β in postprandial hypoglycemia after bariatric surgery and suggests that SGLT2-inhibitors and IL-1 antagonism may improve this condition.

1830-P: Empagliflozin as Well as Anakinra Reduces Symptomatic Postprandial Hypoglycemia after Gastric Bypass

Background: Postprandial hypoglycemia (PPH) is a debilitating complication after bariatric surgery, due to an exaggerated hyperinsulinemic response after carbohydrate ingestion. Recent studies have shown that IL-1β contributes to the postprandial stimulation of insulin. Similarly, lowering hyperglycemic peak by SGLT2-inhibition may reduce insulin secretion. We investigated whether the IL-1 receptor antagonist anakinra or empagliflozin influence PPH in patients after gastric bypass. Methods: We included 12 subjects with PPH after gastric bypass in a placebo controlled, double-blind, randomized, cross-over proof-of-concept study. Subjects received on each of the 3 study days either empagliflozin, anakinra or the respective placebos followed by a mixed-meal-test (MMT) with assessment of hypoglycaemia. Results: Treatment with empagliflozin reduced glycaemia at 30 (11.2 vs. 10.1 mmol/l), 60 (9.1 vs. 6.9 mmol/l) and 90 (4.5 vs. 3.5 mmol/l) minutes of the MMT compared to placebo and was followed by a significant reduction of hypoglycemic events (n = 2, 16.6%) compared to placebo (n = 8, 61.5%). Treatment with anakinra showed a similar glucose curve as placebo, but was also followed by a significantly reduced rate of hypoglycemic events (n = 2, 16.6%). Both treatment interventions showed lowered insulin and c-peptide levels compared to placebo (p&amp;lt;0.001). Conclusion: Empagliflozin as well as Anakinra significantly reduced hypoglycemic episodes in patients after gastric bypass by decreased insulin secretion. Therefore, empagliflozin and IL-1 antagonism, could be promising novel therapeutic options for patients with refractory PPH after gastric bypass. Disclosure M. Hepprich: None. B. Schelker: None. S.J. Wiedemann: None. B. Trinh: None. M. Böni-Schnetzler: None. M.Y. Donath: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Merck &amp; Co., Inc., Novartis AG, Novo Nordisk A/S, Sanofi. Funding University of Basel

SAT-066 Effect Of Interleukin-1-receptor Antagonist On Hemodynamics And Renin-angiotensin-aldosterone System In Obese Individuals

Background: Interleukin (IL)-1 antagonism led to a decrease of systolic blood pressure (5mmHg) in obese individuals. The underlying mechanism is unknown. Based on experimental data in animals we hypothesised a blood-pressure lowering effect of IL-1-antagonism via modulation of the Renin-Angiotensin-Aldosterone System (RAAS). Methods: In this post-hoc explorative study, we examined short- (2 days) and long-term effects (4 weeks) of IL-1 antagonism (anakinra/Kineret®) on RAAS-peptide-profiles and on hemodynamic parameters assessed by a non-invasive measurement using HOTMAN® system in 128 obese (BMI > 30kg/m2) individuals with at least one feature of the metabolic syndrome from two previous interventional trials (CortIL trial a prospective interventional trial (n= 61) and TestIL trial, a placebo controlled-double blinded interventional trial (n=67)). Results: Upon IL-1 antagonism circulating levels of angiotensin II, angiotensin I, aldosterone and renin remained unchanged after short- and long-term treatment, respectively. In contrast, the vasodilatory angiotensin 1-7 peptide significantly increased after 4 weeks compared to placebo (in between group difference 16.35 pmol/L [1.22 to 30.17], p=0.028), without short-term effect on day 2. Non-invasive hemodynamic measurement revealed a decrease in the stroke systemic vascular resistance index (SSVRI) with an in between group difference of -62.65 dyn.sec.cm-5.m2 [95%CI -116.94 to -18.36], p=0.008 (consistent with a 25%-decrease) after 4 weeks of treatment compared to baseline. Conclusion: IL-1 antagonism in obese individuals with features of the metabolic syndrome led to an increase of the vasodilatory angiotensin 1-7 peptide and a decrease in peripheral vascular resistance, reflected by the SSVRI after 4 weeks of treatment. These findings point to a possible blood pressure lowering mechanism via modulation of the RAAS-system of IL-1 antagonism.

IL-1 Antagonism in Men With Metabolic Syndrome and Low Testosterone: A Randomized Clinical Trial.

Hypogonadism is highly prevalent among obese men with metabolic syndrome. Chronic low-grade inflammation is suspected to be a major cause for low testosterone levels in obese individuals. To test the inflammatory hypothesis of testosterone deficiency in metabolic syndrome. In this randomized, placebo-controlled, double-blind trial involving men with metabolic syndrome, we randomly assigned 33 patients to receive 100 mg of anakinra (recombinant human IL-1 receptor antagonist) subcutaneously twice daily for 4 weeks and 34 patients to receive placebo. The primary endpoint was the change from baseline in total testosterone levels after 4 weeks. The mean age was 54 years and baseline total testosterone levels were 9.3 nmol/L (95% CI, 8.7 to 10.0). At 4 weeks, total testosterone levels increased by 1.2 nmol/L (95% CI, 0.3 to 2.0; P = 0.01) in the anakinra group as compared with no change in the placebo group (0.01 nmol/L; 95% CI, -0.5 to 0.5; P = 0.99), resulting in a between-group difference of 0.96 nmol/L (95% CI, 0.3 to 1.9; P = 0.04). The effects were most pronounced with baseline C-reactive protein >2 mg/L (between-group difference 2.14 nmol/L; 95% CI, 0.11 to 4.17; P = 0.04) and body mass index >40 kg/m2 (between-group difference 2.64 nmol/L; 95% CI, 0.19 to 5.09; P = 0.04). Anakinra treatment did not exert benefits on fatigue and sexual dysfunction, but it improved grip strength of nondominant hand by 3.5 kg (95% CI 0.23 to 6.81; P = 0.04) and reduced mean arterial blood pressure by 2.9 mm Hg (95% CI, -5.99 to 0.19; P = 0.07). Anti-inflammatory treatment with an antagonist of IL-1 led to an increase in testosterone levels in obese men with testosterone deficiency.

The role of IL-1 in postprandial fatigue

ObjectivesCytokines such as IL-1 seems to play a role in the pathogenesis of fatigue associated with some chronic diseases and anti-inflammatory treatment has been shown to reduce these symptoms.Ingestion of a calorie rich meal leads to postprandial fatigue, and is associated with increased systemic concentrations of cytokines, which is more pronounced in obese than lean subjects.We investigated whether postprandial fatigue is regulated by IL-1, and therefore reduced by IL-1 antagonism, in lean and obese subjects. MethodsIn a double-blind, crossover study in 8 lean and 8 obese male subjects, randomized to receive either saline (placebo) or the IL-1 receptor antagonist anakinra, we investigated whether postprandial fatigue was regulated by IL-1. To promote postprandial fatigue, subjects ran 30 min prior to a high-fat, high-carbohydrate meal. Fatigue was determined using the Stanford Sleepiness Scale and blood samples were drawn at baseline and after the intervention. ResultsIL-1 antagonism led to a reduction in postprandial fatigue and this effect was more pronounced in obese than lean individuals. ConclusionsWe conclude that IL-1 is involved in the regulation of postprandial fatigue under physiologic conditions in lean and obese individuals. It remains to be shown whether this effect translates into clinical relevant effects.

Monocytes, Macrophages, and Microglia and the Role of IL-1 in Autoimmune Inner Ear Disease (AIED)

Purpose of Review Autoimmune inner ear disease (AIED) is a rare disease of unknown etiology characterized by a sudden decline in hearing. Although AIED is initially responsive to corticosteroid therapy, this response is lost over time. We recently demonstrated in a small cohort of corticosteroid-resistant AIED patients that IL-1 was overexpressed in the plasma and that IL-1 antagonism led to hearing improvement and reduction in circulating IL-1. Autoinflammatory diseases, such as Muckle-Wells syndrome (MWS), are diseases of the innate immune system whose phenotype includes sensorineural hearing loss. Monocytes are the primary cells orchestrating the inflammatory response in this family of diseases, due to a gain-of-function mutation that causes excessive IL-1 release.

Interleukin-1 Antagonism Decreases Cortisol Levels in Obese Individuals.

Increased cortisol levels in obesity may contribute to the associated metabolic syndrome. In obesity, the activated innate immune system leads to increased interleukin (IL)-1β, which is known to stimulate the release of adrenocorticotropin hormone (ACTH). We hypothesized that in obesity IL-1 antagonism would result in downregulation of the hypothalamo-pituitary-adrenal axis, leading to decreased cortisol levels. In this prospective intervention study, we included 73 patients with obesity (body mass index [BMI] ≥30 kg/m2) and at least one additional feature of the metabolic syndrome. The primary end point was change in morning cortisol from baseline to after the administration of the IL-1 receptor antagonist (anakinra/Kineret®, total dose 3 × 100 mg). Secondary end points were effects on salivary cortisol and ACTH. Median age was 56 years, 50.7% of patients were female, and median BMI was 36.3 kg/m2. Median morning serum cortisol levels (nmol/L) decreased significantly after IL-1 antagonism [from baseline, 452 to 423; absolute difference, -38.7; 95% confidence interval (CI), -64 to -13.4; P = 0.0019]. Similar effects were found for salivary cortisol levels (-2.8; 95% CI, -4.4 to -1.3; P = 0.0007), ACTH levels (-2.2; 95% CI; -4.2 to -0.1; P = 0.038), systolic blood pressure (-5.2, 95% CI, -8.5 to -1.8; P = 0.0006), and heart rate (-2.9; 95% CI, -4.7 to -1.0; P = 0.0029). IL-1 antagonism in obese individuals with features of the metabolic syndrome leads to a decrease in serum cortisol, salivary cortisol, and ACTH levels along with a reduction in systolic blood pressure and heart rate.

Anti-inflammatory panacea? The expanding therapeutics of interleukin-1 blockade.

Blockade of interleukin (IL)-1 signaling is one of the oldest biologic therapies, yet the use of these agents is on the rise as the role of IL-1 activation is being recognized in a wide spectrum of inflammatory disorders. This review will cover established and emerging uses of IL-1 antagonism in rheumatic diseases. Expanding off-label indications for IL-1 blockade include neutrophil-dominant skin diseases, including pyoderma gangrenosum, hidradenitis supperativa, and pustular psoriasis. There is also increasing evidence for the use of IL-1 blockade in heart failure associated with rheumatic diseases. Somatic mosaicism in NLRP3 may explain the onset of later-in-life presentations of periodic fevers which are responsive to IL-1 blockade. Of importance, clinical response to anti-IL-1 therapy does not always denote protection from autoinflammatory disease complications such as macrophage activation syndrome or amyloidosis. Indications for IL-1 blocking therapies will likely continue to broaden, but given the rarity of many rheumatic diseases which respond to such treatment, rigorous, large clinical trials for each indication are unlikely to occur. Thus, recommended use of these medications will often fall to the discretion of the astute physician. However, medication cost and hurdles of insurance approval, rather than drug efficacy, may be the primary limitation for more widespread use.

Interleukin-1 signaling contributes to acute islet compensation.

IL-1β is a well-established inducer of both insulin resistance and impaired pancreatic islet function. Despite this, findings examining IL-1 receptor deficiency or antagonism in in vivo animal models, as well as in clinical studies of type 2 diabetic (T2D) patients, have led to conflicting results, suggesting that the actions of IL-1β on glycemic control may be pleiotropic in nature. In the present work, we find that the ability of IL-1β to amplify glucose-stimulated insulin secretion from human islets correlates with donor BMI. Islets from obese donors are sensitized to the insulinotropic effects of this cytokine, whereas the stimulatory effects of IL-1β are lost in islets from obese T2D patients, suggesting a role for IL-1 signaling in islet compensation. Indeed, mice deficient in IL-1 receptor type I become glucose intolerant more rapidly than their WT littermates and have impaired secretory responses during the acute stages of inflammatory and metabolic stress induced by LPS and high-fat diet, respectively. IL-1β directly enhances β cell insulin secretion by increasing granule docking and soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) complex formation at the plasma membrane. Together, our study highlights the importance of IL-1β signaling in islet compensation to metabolic and inflammatory stress.

A large family having Muckle Wells Syndrome

CAPS is a rare autoinflammatory disease associated with mutations in the NLRP3 gene that result in overactivation of the inflammasome, increased secretion of IL-1beta and IL-18, and systemic inflammation. Mutations in the NLRP3 gene on chromosome 1q44 causes cryopyrinopathies. These are autosomal dominant disorders with varying penetrance, which may also present de novo. MWS is an intermediate phenotype characterized by chronic or intermittent episodes of fever, headache, urticarial rash, arthralgias or arthritis, CNS involvement, ocular disorders and progressive deafness. Treatment is based on IL-1 antagonism, which usually results in prompt clinical response and may prevent amyloidosis.