Cryopyrin-associated periodic syndrome (CAPS) is due to gain-of-function mutations in the cryopyrin gene, which determines an overactive inflammatory response. AA amyloidosis is a complication of this syndrome. A 53-year-old man was referred to us because of lower limb edema. Past history: at the age of 20, he complained of arthralgia/arthritis and bilateral hypoacusis. At the age of 35, he presented posterior uveitis, several episodes of conjunctivitis, and progressive loss of visual acuity. Laboratory tests disclosed nephrotic syndrome, and renal biopsy showed AA amyloidosis. He was given anakinra with improvement of arthritis. A genetic study revealed the p.D303N mutation in the cryopyrin gene, and he was diagnosed as having AA amyloidosis due to CAPS. Twenty-one months after starting anakinra, the arthritis has disappeared, although nephrotic-range proteinuria persisted. It is important to be aware of cryopyrin-associated periodic syndrome because it can cause irreversible complications, and there is effective therapy.

OBJECTIVES:

To report our experience with the efficacy and safety of anakinra for acute gouty arthritis in medically complex hospitalized patients

METHODS:

We reviewed the hospital charts of 26 patients treated with anakinra for crystal-induced arthritis since 2007. Demographics, co-morbid conditions, reason for Anakinra use, response to treatment and any adverse outcomes were recorded

RESULTS:

Twenty-six patients received 40 courses of anakinra therapy. In 67% of patients, pain improved significantly within 24 hours and complete resolution of signs and symptoms of gout occurred by day 5 in 72.5%. Seven patients receivedmultiple courses with no decrement in response with repeated treatments. Anakinra was well tolerated and no adverse outcomes were attributed to the drug. Only one patient appeared to be refractory to this form of IL-1 inhibition.

CONCLUSIONS:

Anakinra is an effective and safe alternative treatment for acute gouty arthritis in medically complex hospitalized patients who fail or cannot undergo more conventional therapy © 2013 by the American College of Rheumatology.

Variants of the multidrug resistance gene (MDR1/ABCB1) have been associated with increased susceptibility to severe ulcerative colitis (UC). In this study, we investigated the role of TLR/IL-1R signaling pathways including the common adaptor MyD88 in the pathogenesis of chronic colonic inflammation in MDR1A deficiency. Double- or triple-null mice lacking TLR2, MD-2, MyD88, and MDR1A were generated in the FVB/N background. Deletion of TLR2 in MDR1A deficiency resulted in fulminant pancolitis with early expansion of CD11b(+) myeloid cells and rapid shift toward TH1-dominant immune responses in the lamina propria. Colitis exacerbation in TLR2/MDR1A double-knockout mice required the unaltered commensal microbiota and the LPS coreceptor MD-2. Blockade of IL-1β activity by treatment with IL-1R antagonist (IL-1Ra; Anakinra) inhibited colitis acceleration in TLR2/MDR1A double deficiency; intestinal CD11b(+)Ly6C(+)-derived IL-1β production and inflammation entirely depended on MyD88. TLR2/MDR1A double-knockout CD11b(+) myeloid cells expressed MD-2/TLR4 and hyperresponded to nonpathogenic Escherichia coli or LPS with reactive oxygen species production and caspase-1 activation, leading to excessive cell death and release of proinflammatory IL-1β, consistent with pyroptosis. Inhibition of reactive oxygen species-mediated lysosome degradation suppressed LPS hyperresponsiveness. Finally, active UC in patients carrying the TLR2-R753Q and MDR1-C3435T polymorphisms was associated with increased nuclear expression of caspase-1 protein and cell death in areas of acute inflammation, compared with active UC patients without these variants. In conclusion, we show that the combined defect of two UC susceptibility genes, MDR1A and TLR2, sets the stage for spontaneous and uncontrolled colitis progression through MD-2 and IL-1R signaling via MyD88, and we identify commensally induced pyroptosis as a potential innate immune effector in severe UC pathogenesis.

Pre-treatment culture before islet transplantation represents a window of opportunity to amelioratethe pro-inflammatory profile expressed by human β-cells in duress. Anakinra (IL-1 receptorantagonist) and tocilizumab (monoclonal IL6-receptor antibody) are two known anti-inflammatoryagents successfully used in the treatment of inflammatory states like rheumatoid arthritis. Bothcompounds have also been shown to reduce blood glucose and glycosylated hemoglobin in diabeticpatients. We therefore sought to evaluate the impact of anakinra and tocilizumab on human β-cells.The islets were pre-cultured with or without anakinra or tocilizumab and then transplanted in amarginal mass model using human islets in immunodeficient mice. Islet viability was evaluated in anin vitro model. The pre-treatment culture lead to a significantly improved engraftment in treatedislets compared to vehicle. Anakinra and tocilizumab are not toxic to human islets and significantlyreduce markers of inflammation and cell death. These results strongly support a pre-treatmentculture with anakinra and tocilizumab prior to human islet transplantation.

OBJECTIVE:

To perform a mechanistic study on the effect of interleukin (IL)-1 blockade by anakinra in patients with refractory myositis and to explore possible predictive biomarkers.

METHODS:

Fifteen patients with refractory myositis were treated with anakinra for 12 months. Clinical response was assessed by the six-item core set measures of disease activity International Myositis Assessment and Clinical Studies (IMACS) and functional index (FI). Repeated muscle biopsies were investigated for cellular infiltrates, IL-1α, IL-1β, IL-1Ra and major histocompatibility complex-class I by immunohistochemistry. Serum levels of IL-1Ra and granulocyte colony-stimulating factor (G-CSF) were measured by ELISA. T cell phenotype and functional assays were investigated by multicolour flow cytometry.

RESULTS:

Seven patients had clinical response according to IMACS, four of them also showed improved FI. Responders had higher baseline extramuscular score compared with non-responders. In muscle biopsies, baseline CD163 macrophages and IL-1α expression were inversely correlated with muscle performance after 6 months treatment; all responders had IL-1Ra expression in the post-treatment biopsies but only 3/8 non-responders. In serum, IL-1Ra levels were increased and G-CSF was decreased after 6 months treatment, but their levels and changes were not related to clinical response. For T cells, an inverse correlation between baseline frequency of CD4 activated/memory T cells and decreased creatine kinase levels was observed. Five of six patients demonstrated less IL-17A and more IFN-γ secreting CD4 T cells after 6 months treatment. Moreover, anakinra reduced IL-17A secretion in vitro.

CONCLUSIONS:

Patients with myositis may respond to anakinra. Extramuscular score, muscle CD163 macrophages and IL-1α expression, blood CD4 activated/memory T cells might associate with anakinra treatment response. Blocking the IL-1 receptor disfavoured Th17 cell differentiation both in vivo and in vitro.

Alcohol-induced neuroinflammation is mediated by proinflammatory cytokines, including IL-1β. IL-1β production requires caspase-1 activation by inflammasomes-multiprotein complexes that are assembled in response to danger signals. We hypothesized that alcohol-induced inflammasome activation contributes to increased IL-1β in the brain. WT and TLR4-, NLRP3-, and ASC-deficient (KO) mice received an ethanol-containing or isocaloric control diet for 5 weeks, and some received the rIL-1ra, anakinra, or saline treatment. Inflammasome activation, proinflammatory cytokines, endotoxin, and HMGB1 were measured in the cerebellum. Expression of inflammasome components (NLRP1, NLRP3, ASC) and proinflammatory cytokines (TNF-α, MCP-1) was increased in brains of alcohol-fed compared with control mice. Increased caspase-1 activity and IL-1β protein in ethanol-fed mice indicated inflammasome activation. TLR4 deficiency protected from TNF-α, MCP-1, and attenuated alcohol-induced IL-1β increases. The TLR4 ligand, LPS, was not increased in the cerebellum. However, we found up-regulation of acetylated and phosphorylated HMGB1 and increased expression of the HMGB1 receptors (TLR2, TLR4, TLR9, RAGE) in alcohol-fed mice. NLRP3- or ASC-deficient mice were protected from caspase-1 activation and alcohol-induced IL-1β increase in the brain. Furthermore, in vivo treatment with rIL-1ra prevented alcohol-induced inflammasome activation and IL-1β, TNF-α, and acetylated HMGB1 increases in the cerebellum. Conversely, intracranial IL-1β administration induced TNF-α and MCP-1 in the cerebellum. In conclusion, alcohol up-regulates and activates the NLRP3/ASC inflammasome, leading to caspase-1 activation and IL-1β increase in the cerebellum. IL-1β amplifies neuroinflammation, and disruption of IL-1/IL-1R signaling prevents alcohol-induced inflammasome activation and neuroinflammation. Increased levels of acetylated and phosphorylated HMGB1 may contribute to alcoholic neuroinflammation.

PURPOSE:

Tumor necrosis factor (TNFα) is a proinflammatory cytokine and has been a target for intervention in human sepsis. However, inhibition of TNF-α with a high dose of a TNF-receptor fusion protein in patients with septic shock worsened patient survival. This study was designed to investigate whether blocking TNF-α enhances mortality in infected burn mice through the induction of IL-1β.

METHODS:

WT or Tnfrsf1a(-/-) mice received Pseudomonas aeruginosa injection in the back at 8h after burn injury. The animals were sacrificed at 24h after burn and lung tissues were harvested and examined for determining myeloperoxidase (MPO) activity, pulmonary microvascular dysfunction, NF-κB DNA binding activity, and IL-1β expression. Also, the lung and blood were harvested for bacterial count assay.

RESULT:

Thermal injury alone induced NF-κB DNA binding activity and neutrophil infiltration in the lung in WT but not in Tnfrsf1a(-/-) mice. A 50% total body surface area (TBSA) burn induced a significant increase of mortality in WT compared with Tnfrsf1a(-/-) mice. In contrast, P. aeruginosa injection with a 30% TBSA burn pretreatment enhanced IL-1β expression, bacterial counts in lung and blood, pulmonary microvascular dysfunction, and mortality in Tnfrsf1a(-/-) mice compared with WT mice. Injection of the IL-1 receptor antagonist, Anakinra, reduced P. aeruginosa infection with burn pretreatment-induced blood bacterial counts, IL-1β levels as well as permeability of lung, and mortality in Tnfrsf1a(-/-) mice.

CONCLUSIONS:

Our findings suggest that thermal injury induces lung NF-κB activation and neutrophil sequestration through TNFα signaling. However, blocking TNF-α enhances P. aeruginosa infection-induced lung damage in burn mice via induction of IL-1β. Using an IL-1 receptor antagonist combined with the neutralization of TNF-α could be a useful strategy for decreasing P. aeruginosa infection-induced mortality in burn patients.

IMPORTANCE The immunopathogenic mechanisms of dry eye disease (DED), one of the most common ophthalmic conditions, is incompletely understood. Data from this prospective, double-masked, randomized trial demonstrate that targeting interleukin 1 (IL-1) by topical application of an IL-1 antagonist is efficacious in significantly reducing DED-related patient symptoms and corneal epitheliopathy.

OBJECTIVE

To evaluate the safety and efficacy of treatment with the topical IL-1 receptor antagonist anakinra (Kineret; Amgen Inc) in patients having DED associated with meibomian gland dysfunction. DESIGN AND SETTING Prospective phase 1/2, randomized, double-masked, vehicle-controlled clinical trial. PARTICIPANTS Seventy-five patients with refractory DED. INTERVENTIONS Participants were randomized to receive treatment with topical anakinra, 2.5% (n = 30), anakinra, 5% (n = 15), or vehicle (1% carboxymethylcellulose) (n = 30) 3 times daily for 12 weeks. MAIN OUTCOMES AND MEASURES Primary outcomes were corneal fluorescein staining (CFS), complete bilateral CFS clearance, dry eye-related symptoms as measured by the Ocular Surface Disease Index, tear film breakup time, and meibomian gland secretion quality.

RESULTS

Topical anakinra was well tolerated compared with vehicle, with no reports of serious adverse reactions attributable to the therapy. After 12 weeks of therapy, participants treated with anakinra, 2.5%, achieved a 46% reduction in their mean CFS score (P = .12 compared with vehicle and P < .001 compared with baseline); participants treated with anakinra, 5%, achieved a 17% reduction in their mean CFS score (P = .88 compared with vehicle and P = .33 compared with baseline); and patients treated with vehicle achieved a 19% reduction in their mean CFS score (P = .11). Complete bilateral CFS clearance was noted in 8 of 28 patients (29%) treated with anakinra, 2.5%, vs in 2of 29 patients (7%) treated with vehicle (P = .03). By week 12, treatment with anakinra, 2.5%, and treatment with anakinra, 5%, led to significant reductions in symptoms of 30% and 35%, respectively (P = .02 and P = .01, respectively, compared with vehicle); treatment with vehicle led to a 5% reduction in symptoms.

CONCLUSIONS

AND RELEVANCE Treatment with topical anakinra, 2.5%, for 12 weeks was safe and significantly reduced symptoms and corneal epitheliopathy in patients with DED. These data suggest that the use of an IL-1 antagonist may have a role as a novel therapeutic option for patients with DED. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00681109.