Deficiency Of Interleukin-1 Receptor Antagonist Research Articles

Analysis of Anakinra Therapy for the Deficiency of Interleukin-1 Receptor Antagonist through Clinical Evidence.

Deficiency of interleukin-1 receptor antagonist (DIRA) is a rare life-threatening autosomal recessive autoinflammatory disease with symptoms including but not limited to osteomyelitis, periostitis, and systemic inflammation. DIRA is developed from the loss-of-function biallelic mutations of the IL1RN gene that encodes IL-1 receptor antagonist (IL-1RA), leading to the unchecked pro-inflammatory signaling and subsequent systemic inflammation. Thus, anakinra as the recombinant IL-1RA has become the primary drug to treat DIRA. Although anakinra has been effective for the complete remission of DIRA, it has also shown various side effects. To confirm the efficacy and safety issues associated with DIRA treatment, we conducted a literature review and secondary data analysis to enhance our understanding on this important topic. Through comprehensive literature search, we have identified 15 papers with 25 patients studied. The demographic, clinical, and genetic data were extracted, followed by statistical analysis to support the physiological mechanisms of anakinra treatment. Through the literature review and data analysis, it was found that 88% of patients had complete clinical remission of DIRA upon continual treatment with anakinra; patients had a mean improvement of Hemoglobin (+3.18 g/dL), Erythrocyte Sedimentation Rate (-53.4 mm/h), and C-reactive Protein (-135.45 mg/L) levels, suggesting that the improvement of hematopoietic function and inflammation is a mechanism for anakinra treatment. Various genetic variants were also identified from the patient data that cause the loss of function of IL-1RA, providing real patient genomic data to support the anakinra treatment. Considering the inconsistency and certain variations from clinical research influenced by specific conditions, this review along with the data analysis confirms the efficacy and safety of anakinra treatment for DIRA.

Accuracy of generative artificial intelligence models in differential diagnoses of familial Mediterranean fever and deficiency of Interleukin-1 receptor antagonist

With the increasing development of artificial intelligence, large language models (LLMs) have been utilized to solve problems in natural language processing tasks. More recently, LLMs have shown unique potential in numerous applications within medicine but have been particularly investigated for their ability in clinical reasoning. Although the diagnostic accuracy of LLMs in forming differential diagnoses has been reviewed in general internal medicine applications, much is unknown in autoinflammatory disorders. From the nature of autoinflammatory diseases, forming a differential diagnosis is challenging due to the overlapping symptoms between disorders and even more difficult without genetic screening. In this work, the diagnostic accuracy of the Generative Pre-Trained Transformer Model-4 (GPT-4), GPT-3.5, and Large Language Model Meta AI (LLaMa) were evaluated in clinical vignettes of Deficiency of Interleukin-1 Receptor Antagonist (DIRA) and Familial Mediterranean Fever (FMF). We then compared these models to a control group including one internal medicine physician. It was found that GPT-4 did not significantly differ in correctly identifying DIRA and FMF patients compared to the internist. However, the physician maintained a significantly higher accuracy than GPT-3.5 and LLaMa 2 for either disease. Overall, we explore and discuss the unique potential of LLMs in diagnostics for autoimmune diseases.

Cutaneous findings and treatments in deficiency of interleukin-36 receptor antagonist (DITRA): A review of the literature.

Deficiency of the interleukin-36 receptor antagonist (DITRA) is a rare autoinflammatory disorder caused by mutations in the IL36RN gene. This mutation leads to a lack of functional interleukin-36 receptor antagonists (IL-36Ra), which results in an overactive immune system and chronic inflammation. Despite its rarity, numerous case series and individual reports in the literature emphasize the importance of recognizing and managing DITRA. Early identification of the cutaneous signs of DITRA is crucial for accurate diagnosis and timely administration of appropriate treatment. This review article provides a comprehensive overview of the current understanding of the cutaneous, non-cutaneous and histopathological manifestations of DITRA, with a focus on reported treatments. The disease typically presents in early childhood, although the age of onset can vary. Patients with DITRA exhibit recurrent episodes of skin inflammation, often with a pustular or pustular psoriasis-like appearance. Additionally, non-cutaneous manifestations are common, with recurrent fevers and elevated acute-phase reactants being the most prevalent. The exact prevalence of DITRA is unknown. Some cases of loss-of-function mutations in the IL36RN gene, considered a hallmark for diagnosis, have been identified in patients with familial generalized pustular psoriasis (GPP). Biological therapies with inhibition of IL-12/23 and IL-17 are promising treatment options; paediatric patients with DITRA have shown complete response with mild relapses. New and emerging biologic therapeutics targeting the IL-36 pathway are also of interest in the management of this rare autoinflammatory disorder.

Deficiency of interleukin-36 receptor antagonist (DITRA): An analysis of 58 Chinese patients in a tertiary hospital in Taiwan.

DITRA, acronym for deficiency of interleukin-36 receptor antagonist (IL36RN), leads to unopposed pro-inflammatory signalling which typically manifests as pustular psoriasis. In Asian patients, c.115 + 6 T > C mutation is the most common and important single-nucleotide variant in DITRA. We present the largest case series consisting of 58 DITRA patients carrying heterozygous or homozygous c.115 + 6 T > C mutation. The mean age of onset (±SD) was 20.74 (±20.86), and the median age of onset was 13 years old. Twelve patients (20.7%) had disease onset before the age of two. Twenty-two patients (37.9%) had disease onset between the ages of 2-18. Main clinical phenotype was generalized pustular psoriasis (GPP) with systemic symptoms (33 patients, 56.9%), followed by acrodermatitis continua of Hallopeau (ACH) (16 patients, 27.6%). Nearly half of our patients (27 patients, 46.6%) ever had ACH, and only three of them are free of ACH currently, which indicates that the development of ACH is relatively persistent and irreversible. Thirty-four patients (58.6%) had recurrent GPP and 29 patients (50%) have been admitted due to GPP flare. Compared to those with heterozygous (C/T) mutation, more patients carrying homozygous mutation (C/C) have recurrent episodes of GPP (C/T vs. C/C: 25.53 vs. 76.47%, p=0.0367). Two patients with squamous cell carcinomas arising from the pustular psoriasis skin lesions were noted. Two patients had elevated serum IgG4 levels.

P43 A complicated road to diagnosis: Auto inflammatory bone disease

Introduction/BackgroundAuto inflammatory bone disorders are characterized by chronic non-infectious osteomyelitis and inflammation-induced bone resorption. It results from aberrant activation of components of the innate immune system. The auto inflammatory bone disorder includes chronic non-bacterial osteomyelitis (CNO) and its severe form chronic recurrent multifocal osteomyelitis (CRMO); synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome; Majeed syndrome; deficiency of interleukin-1 receptor antagonist (DIRA) and cherubism. The most common among this is CRMO/CNO. The disease can affect any part of the body but the metaphyseal region of the long bones, clavicle, and vertebra are the most commonly affected site.Description/MethodA 9 year old girl presented with five month history of swelling over right periocular and temporal region, associated with skin discoloration and difficulty in opening her eyes. She also reported headache more in the right frontal region. She had on and off exacerbations of skin discoloration and headaches. There was no history of fevers, weight loss, night sweats, skin lesions or arthritic symptoms. She did not have a personal or family history of inflammatory or autoimmune disorders. She is under ophthalmology elsewhere since the age of 3 months with a right divergent squint and history of right squint surgery at 6 years.Physical examination revealed swelling involving right infraorbital and temporal region, which was soft and not tender to touch with associated erythema in the same site. There were no signs of meningism or altered mental status. Musculoskeletal examination was unremarkable.Her blood test results showed mild increase in platelets (476 * 109), CRP 8mg/L, ESR (18mm/hr). IgG4 titres were mildly raised (1.16g/L). Other immunologic markers including rheumatoid factor, human leukocyte antigen B27, antinuclear antibody and anti-neutrophil cytoplasmic antibody were normal.Histopathological examination of bone and soft tissue of her right orbital rim showed low grade non-specific chronic inflammation with extensive appositional remodelling of bone suggestive of CRMO/SAPHO. No evidence of malignancy/infection.Later whole body MRI was performed to identify the extent of disease. MRI whole body was performed which showed multiple areas of bone marrow oedema and periostitis within the appendicular and axial skeleton, bilateral gluteal enthesitis and sacroilitis. There are some features that are atypical for CRMO (asymmetrical involvement, transphyseal involvement including epiphyseal involvement of the left humerus). Also noted to have right-sided periorbital oedema, oedema of the right masticator muscles and temporalis. Further planned to do dedicated MRI of left humerus with contrast.Discussion/ResultsIt can be difficult to consider what the problem is when a health care provider is presented with a group of seemingly disparate signs and symptoms with a history and time course that do not match classic (or commonly atypical) disease presentations. Common things happen commonly, so when symptoms occur without the usual co-occurring symptoms, unusual symptoms or time courses, it can be challenging.The current patient presented with periocular swelling with headache and skin discolouration. The differentials can be Langerhans cell histiocytosis, IgG4-related disease, osteoblastoma, and osteosarcoma. There were no hepatosplenomegaly, lymphadenopathy, also the mass was soft to palpate, and hence the above differentials were unlikely. Patient was initially evaluated at tertiary oncology centre and malignancy ruled out. The histopathology slides were reviewed and reported as mentioned above. In view of no skin manifestations, CRMO was the likely diagnosis considered. Hence MRI whole body performed.Barrani et al reported a similar type of unusual case of a 12-year-old girl with CRMO arising with recurrent episodes of left supraorbital headache, followed by the appearance of a periorbital dyschromia. Magnetic resonance imaging (MRI) of the skull and orbits revealed an important subacute inflammatory process. However, a few months later, the child presented a painful swelling of the left clavicle; the histological examination of the related biopsy allowed us to establish the diagnosis of CRMO.The follow up with our patient is quite a short duration and she might evolve later in the disease course giving more clarity!Key learning points/ConclusionIn evaluating a diagnostic dilemma, starting the laboratory evaluation helps to begin the process of trying to find an answer and can also help the families as “something is being done.”Chronic recurrent multifocal osteomyelitis can present with unifocal lesions, atypical locations or absence of recurrence.A high level of suspicion is paramount to avoid unnecessary biopsies and repeated antibiotic regimens.Families will often be quite concerned and support for them is also necessary and close communication and follow up is appropriate.

IL-1 receptor antagonist, MIS-C, and the peculiar autoimmunity of SARS-CoV-2

IL-1 receptor antagonist, MIS-C, and the peculiar autoimmunity of SARS-CoV-2

Towards a Treatment for Neuroinflammation in Epilepsy: Interleukin-1 Receptor Antagonist, Anakinra, as a Potential Treatment in Intractable Epilepsy.

Febrile Infection-Related Epilepsy Syndrome (FIRES) is a unique catastrophic epilepsy syndrome, and the development of drug-resistant epilepsy (DRE) is inevitable. Recently, anakinra, an interleukin-1 receptor antagonist (IL-1RA), has been increasingly used to treat DRE due to its potent anticonvulsant activity. We here summarized its effects in 38 patients (32 patients with FIRES and six with DRE). Of the 22 patients with FIRES, 16 (73%) had at least short-term seizure control 1 week after starting anakinra, while the remaining six suspected anakinra-refractory cases were male and had poor prognoses. Due to the small sample size, an explanation for anakinra refractoriness was not evident. In all DRE patients, seizures disappeared or improved, and cognitive function improved in five of the six patients following treatment. Patients showed no serious side effects, although drug reactions with eosinophilia and systemic symptoms, cytopenia, and infections were observed. Thus, anakinra has led to a marked improvement in some cases, and functional deficiency of IL-1RA was indicated, supporting a direct mechanism for its therapeutic effect. This review first discusses the effectiveness of anakinra for intractable epileptic syndromes. Anakinra could become a new tool for intractable epilepsy treatment. However, it does not currently have a solid evidence base.

Spectrum of Systemic Auto-Inflammatory Diseases in India: A Multi-Centric Experience.

Background: Systemic autoinflammatory diseases (SAID) are rare inherited disorders involving genes regulating innate immune signaling and are characterized by periodic or chronic multi-systemic inflammation.Objective: To describe spectrum of clinical, immunological, molecular features, and outcomes of patients with SAID in India.Methods: Request to share data was sent to multiple centers in India that are involved in care and management of patients with Inborn Errors of Immunity. Six centers provided requisite data that were compiled and analyzed.Results: Data on 107 patients with SAID were collated—of these, 29 patients were excluded due to unavailability of complete information. Twelve patients (15%) had type 1 interferonopathies, 21 (26%) had diseases affecting inflammasomes, 30 patients (41%) had non-inflammasome related conditions and 1five patients (19%) had Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA). Type1 interferonopathies identified in the cohort included patients with Deficiency of Adenosine Deaminase 2 (DADA2) (six patients; five families); STING-associated vasculopathy infantile-onset (SAVI) (three patients, one family); Spondyloenchondro-dysplasia with Immune Dysregulation (SPENCD) (two patients). Diseases affecting inflammasomes include Mevalonate Kinase Deficiency (eight patients); Cryopyrin-Associated Periodic Syndromes (CAPS) (seven patients); NLR Family, Pyrin domain-containing 12 (NLRP12) (two patients); Familial Mediterranean fever (FMF) (two patients); Autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) (two patients). TNF receptor-associated periodic syndrome (TRAPS) (three patients); A20 haploinsufficiency (four patients); Deficiency of Interleukin 1 Receptor Antagonist (DIRA) (two patients) were categorized as non-inflammasome related conditions. There were significant delays in diagnosis Corticosteroids and other immunosuppressive agents were used for treatment as anti-IL-1 drugs and other biological agents were and still are not available in India. Eight (16.3%) patients had so far succumbed to their illness.Conclusions: This is the first nationwide cohort of patients with SAID from India. Clinical manifestations were diverse. Overlapping of clinical features with other relatively common rheumatological disorders often resulted in delays in diagnosis. More nationwide efforts are needed to enhance awareness of SAID among health care professionals and there is an urgent need to make targeted immunotherapies universally available.

Deficiency of Interleukin-1 Receptor Antagonist: New Genetic Autoinflammatory Disease as a Diagnostic Challenge for Pediatricians.

Deficiency of interleukin-1 receptor antagonist is a rare autoinflammatory disease that affects infants early in life. It often presents with systemic inflammation, skin and bone involvement. We present a 5-month-old boy who was hospitalized due to generalized erythematous pustular eruption with secondary impetigo, cellulitis, bronchiolitis, and elevated inflammatory markers. The patient was unresponsive to multiple courses of intravenous antibiotics, systemic, and topical steroid medications. The patient was evaluated by dermatology and rheumatology services among other subspecialities. Skin biopsy showed changes consistent with psoriasiform dermatitis, while bone scans showed multifocal osteomyelitis. The patient was started empirically on anakinra with improvement at 72 hours upon administration. This is one of the youngest reported case in the literature to be started on anakinra empirically prior to genetic confirmation of the mutation. A comprehensive literature review revealed that approximately 20 genetically confirmed patients, including our patient, have been reported with this genetic disease. It is imperative to recognize this disease early to achieve adequate response and remission. Therefore, clinical symptoms and the associated differential diagnosis for this disease should be constantly reassessed and reviewed by pediatricians and subspecialists to detect the disease as early as possible and reduce the high morbidity and mortality associated with delayed diagnosis and treatment.

Genetic diagnosis of autoinflammatory disease patients using clinical exome sequencing.

Autoinflammatory diseases comprise a wide range of syndromes caused by dysregulation of the innate immune response. They are difficult to diagnose due to their phenotypic heterogeneity and variable expressivity. Thus, the genetic origin of the disease remains undetermined for an important proportion of patients. We aim to identify causal genetic variants in patients with suspected autoinflammatory disease and to test the advantages and limitations of the clinical exome gene panels for molecular diagnosis. Twenty-two unrelated patients with clinical features of autoinflammatory diseases were analyzed using clinical exome sequencing (~4800 genes), followed by bioinformatic analyses to detect likely pathogenic variants. By integrating genetic and clinical information, we found a likely causative heterozygous genetic variant in NFKBIA (p.D31N) in a North-African patient with a clinical picture resembling the deficiency of interleukin-1 receptor antagonist, and a heterozygous variant in DNASE2 (p.G322D) in a Spanish patient with a suspected lupus-like monogenic disorder. We also found variants likely to increase the susceptibility to autoinflammatory diseases in three additional Spanish patients: one with an initial diagnosis of juvenile idiopathic arthritis who carries two heterozygous UNC13D variants (p.R727Q and p.A59T), and two with early-onset inflammatory bowel disease harbouring NOD2 variants (p.L221R and p.A728V respectively). Our results show a similar proportion of molecular diagnosis to other studies using whole exome or targeted resequencing in primary immunodeficiencies. Thus, despite its main limitation of not including all candidate genes, clinical exome targeted sequencing can be an appropriate approach to detect likely causative variants in autoinflammatory diseases.

Designation of Autoinflammatory Skin Manifestations With Specific Genetic Backgrounds.

“Autoinflammatory disease (AiD)” has first been introduced in 1999 when the responsible gene for the familial Hibernean fever or autosomal dominant-type familial Mediterranean fever-like periodic fever syndrome was reportedly identified as tumor necrosis factor receptor superfamily 1. Linked with the rapid research progress in the field of innate immunity, “autoinflammation” has been designated for dysregulated innate immunity in contrast to “autoimmunity” with dysregulated acquired immunity. As hereditary periodic fever syndromes represent the prototype of AiD, monogenic systemic diseases are the main members of AiD. However, skin manifestations provide important clinical information and there are even some AiDs originating from skin diseases. Recently, AiD showing psoriasis and related keratinization diseases have specifically been designated as “autoinflammatory keratinization diseases (AiKD)” and CARD14-associated psoriasis and deficiency of interleukin-36 receptor antagonist previously called as generalized pustular psoriasis are included. Similarly, a number of autoinflammatory skin diseases can be proposed; autoinflamatory urticarial dermatosis (AiUD) such as cryopyrin-associated periodic syndrome; autoinflammatory neutrophilic dermatosis (AiND) such as pyogenic sterile arthritis, pyoderma gangrenosm, and acne syndrome; autoinflammatory granulomatosis (AiG) such as Blau syndrome; autoinflammatory chilblain lupus (AiCL) such as Aicardi-Goutieres syndrome; autoinflammatory lipoatrophy (AiL) such as Nakajo-Nishimura syndrome; autoinflammatory angioedema (AiAE) such as hereditary angioedema; and probable autoinflammatory bullous disease (AiBD) such as granular C3 dermatosis. With these designations, skin manifestations in AiD can easily be recognized and, even more importantly, autoinflammatory pathogenesis of common skin diseases are expected to be more comprehensive.

Woronoff Ring in Deficiency of Interleukin-36 Receptor Antagonist (DITRA).

Woronoff Ring in Deficiency of Interleukin-36 Receptor Antagonist (DITRA).

Deficiency of Interleukin-1 Receptor Antagonist: A Case with Late Onset Severe Inflammatory Arthritis, Nail Psoriasis with Onychomycosis and Well Responsive to Adalimumab Therapy

DIRA (deficiency of the IL-1Ra) is a rare condition that usually presents in the neonatal period. Patients with DIRA present with systemic inflammation, respiratory distress, joint swelling, pustular rash, multifocal osteomyelitis, and periostitis. Previously, we reported a patient with a novel mutation in IL1RN with a healthy neonatal period, a late-onset of pustular dermatosis, inflammatory arthritis, and excellent response to canakinumab treatment. Herein, we are presenting a new case of late-onset DIRA syndrome, carrying a different mutation and showing different clinical findings. This patient is the first one in the literature with the inflammatory arthritis, nail psoriasis, and onychomycosis and with her remarkable response to monoclonal antibodies. The case responded well and fully recovered after treatment with adalimumab, but not with canakinumab. The DIRA disease can lead to death from multiple organ failures and if recognized early, the treatment with replacement of the deficient protein with biologic agents induces rapid and complete remission. Therefore, clinical symptoms should be learned exactly by the pediatricians, pediatric rheumatologists, and immunologists; and molecular analysis targeting this defect must be performed as early as possible.

Aberrant intestinal microbiota due to IL-1 receptor antagonist deficiency promotes IL-17- and TLR4-dependent arthritis

BackgroundPerturbation of commensal intestinal microbiota has been associated with several autoimmune diseases. Mice deficient in interleukin-1 receptor antagonist (Il1rn−/− mice) spontaneously develop autoimmune arthritis and are susceptible to other autoimmune diseases such as psoriasis, diabetes, and encephalomyelitis; however, the mechanisms of increased susceptibility to these autoimmune phenotypes are poorly understood. We investigated the role of interleukin-1 receptor antagonist (IL-1Ra) in regulation of commensal intestinal microbiota, and assessed the involvement of microbiota subsets and innate and adaptive mucosal immune responses that underlie the development of spontaneous arthritis in Il1rn−/− mice.ResultsUsing high-throughput 16S rRNA gene sequencing, we show that IL-1Ra critically maintains the diversity and regulates the composition of intestinal microbiota in mice. IL-1Ra deficiency reduced the intestinal microbial diversity and richness, and caused specific taxonomic alterations characterized by overrepresented Helicobacter and underrepresented Ruminococcus and Prevotella. Notably, the aberrant intestinal microbiota in IL1rn−/− mice specifically potentiated IL-17 production by intestinal lamina propria (LP) lymphocytes and skewed the LP T cell balance in favor of T helper 17 (Th17) cells, an effect transferable to WT mice by fecal microbiota. Importantly, LP Th17 cell expansion and the development of spontaneous autoimmune arthritis in IL1rn−/− mice were attenuated under germ-free condition. Selective antibiotic treatment revealed that tobramycin-induced alterations of commensal intestinal microbiota, i.e., reduced Helicobacter, Flexispira, Clostridium, and Dehalobacterium, suppressed arthritis in IL1rn−/− mice. The arthritis phenotype in IL1rn−/− mice was previously shown to depend on Toll-like receptor 4 (TLR4). Using the ablation of both IL-1Ra and TLR4, we here show that the aberrations in the IL1rn−/− microbiota are partly TLR4-dependent. We further identify a role for TLR4 activation in the intestinal lamina propria production of IL-17 and cytokines involved in Th17 differentiation preceding the onset of arthritis.ConclusionsThese findings identify a critical role for IL1Ra in maintaining the natural diversity and composition of intestinal microbiota, and suggest a role for TLR4 in mucosal Th17 cell induction associated with the development of autoimmune disease in mice.

A Brief History of IL-1 and IL-1 Ra in Rheumatology.

The history of what, in 1979, was called interleukin-1 (IL-1), orchestrator of leukocyte inter-communication, began many years before then, initially by the observation of fever induction via the endogenous pyrogen (EP) (1974) and then in rheumatology on the role in tissue destruction in rheumatoid diseases via the induction of collagenase and PGE2 in human synovial cells by a mononuclear cell factor (MCF) (1977). Since then, the family has exploded to presently 11 members as well as many membrane-bound and soluble receptor forms. The discovery of a natural Interleukin-1 receptor antagonist (IL-1Ra) in human biological fluids has highlighted the importance of IL-1 and IL-1Ra in human diseases. Evidence delineating its role in autoinflammatory syndromes and the elucidation of the macromolecular complex referred to as “inflammasome” have been instrumental to our understanding of the link with IL-1. At present, the IL-1blockade as therapeutic approach is crucial for many hereditary autoinflammatory diseases, as well as for adult-onset Still’s disease, crystal-induced arthropathies, certain skin diseases including neutrophil-triggered skin diseases, Behçet’s disease and deficiency of IL-1Ra and other rare fever syndromes. Its role is only marginally important in rheumatoid arthritis and is still under debate with regard to osteoarthritis, type 2 diabetes mellitus, cardiovascular diseases and cancer. This brief historical review focuses on some aspects of IL-1, mainly IL-1β and IL-Ra, in rheumatology. There are many excellent reviews focusing on the IL-1 family in general or with regard to specific diseases or biological discoveries.

Vasculitis in the autoinflammatory diseases.

This article addresses the prevalence and relationship between autoinflammatory diseases and vasculitis. Autoimmune diseases (AIDs) are a group of syndromes characterized by episodes of unprovoked inflammation due to dysregulation of the innate immune system. Despite the common occurrence of rashes and other skin lesions in these diseases, vasculitis is reported in only a few. On the other hand, neutrophilic dermatoses are more prevalent. Large vessel vasculitis is reported in patients with Behcet's and Blau's syndromes. Small and medium size vasculitides are reported in familial Mediterranean fever mainly as Henoch-Schonlein purpura and polyarteritis nodosa, respectively. It is rarely described in hyper IgD with periodic fever syndrome, cryopyrin associated periodic syndromes, TNF receptor-associated periodic syndrome, deficiency of interleukin-1 receptor antagonist and pyoderma gangrenosum and acne syndrome. In most AID where bones and skin are mainly involved (CRMO, Majeed syndrome, Cherubism and DITRA) - vasculitis has not been described at all. In AID small vessel vasculitis affects mainly the skin with no involvement of internal organs. In AID, neutrophilic dermatoses are more common and prominent than vasculitis. This may reflect a minor role for interleukin-1 in the pathogenesis of vasculitis. The rarity of vasculitis in AID suggests that in most reported cases its occurrence has been probably coincidental rather than being an integral feature of the disease.

Serum levels of innate immunity cytokines are elevated in dogs with metaphyseal osteopathy (hypertrophic osteodytrophy) during active disease and remission

Metaphyseal osteopathy (MO) (hypertrophic osteodystrophy) is a developmental disorder of unexplained etiology affecting dogs during rapid growth. Affected dogs experience relapsing episodes of lytic/sclerotic metaphyseal lesions and systemic inflammation. MO is rare in the general dog population; however, some breeds (Weimaraner, Great Dane and Irish Setter) have a much higher incidence, supporting a hereditary etiology. Autoinflammatory childhood disorders of parallel presentation such as chronic recurrent multifocal osteomyelitis (CRMO), and deficiency of interleukin-1 receptor antagonist (DIRA), involve impaired innate immunity pathways and aberrant cytokine production. Given the similarities between these diseases, we hypothesize that MO is an autoinflammatory disease mediated by cytokines involved in innate immunity. To characterize immune dysregulation in MO dogs we measured serum levels of inflammatory markers in 26 MO and 102 control dogs. MO dogs had significantly higher levels (pg/ml) of serum Interleukin-1beta (IL-1β), IL-18, IL-6, Granulocyte-macrophage colony stimulating factor (GM-CSF), C-X-C motif chemokine 10 (CXCL10), tumor necrosis factor (TNF), and IL-10. Notably, recovered MO dogs were not different from dogs during active MO disease, providing a suggestive mechanism for disease predisposition. This is the first documentation of elevated immune markers in MO dogs, uncovering an immune profile similar to comparable autoinflammatory disorders in children.

Deficiency of Interleukin-1 Receptor Antagonist (DIRA): Report of the First Indian Patient and a Novel Deletion Affecting IL1RN

Purpose Deficiency of interleukin-1 receptor antagonist (DIRA) is a rare life-threatening autoinflammatory disease caused by autosomal recessive mutations in IL1RN. DIRA presents clinically with early onset generalized pustulosis, multifocal osteomyelitis, and elevation of acute phase reactants. We evaluated and treated an antibiotic-unresponsive patient with presumed DIRA with recombinant IL-1Ra (anakinra). The patient developed anaphylaxis to anakinra and was subsequently desensitized.

Abstract 13025: Deficiency of Interleukin-1 Receptor Antagonist Promotes Angiotensin II-induced Aortic Inflammation and Aneurysm

Introduction: Angiotensin II (AngII) increases arterial pressure and induces inflammation. Although interleukin-1 receptor antagonist (IL-1Ra) is one of the most important anti-inflammatory cytokines, the role of IL-1Ra in AngII-induced aortic inflammation and aneurysm remains unknown. Methods and Results: To determine the contrition of IL-1Ra to AngII-induced aortic inflammation, male wild-type (WT) (n=18) and IL-1Ra-deficient (IL-1Ra-/-) (n=18) mice were infused with AngII (3000ng/kg per minute) using subcutaneous osmotic pumps for 28 days. 7 days after infusion, real-time PCR of abdominal aorta in IL-1Ra-/- mice revealed significantly increased mRNA levels of IL-6 (2.1-fold, p<0.01), TNF-α (4.1-fold, p<0.01), and MMP-9 (20.3-fold, p<0.05) compared with WT mice. 14 days after infusion, both systolic blood pressure (178±21 vs 135±21 mmHg, p<0.01)and abdominal aortic width (1.02±0.12 vs 0.82±0.05 mm, p<0.01) in IL-1Ra-/- mice significantly increased compared with WT mice. Moreover, AngII infusion into IL-1Ra-/- mice also led to a significant increased occurrence of fatal aortic rupture (IL-1Ra-/-: 89% vs WT: 6%, p<0.01). Next, WT (n=6) and IL-1Ra-/- (n=6) mice were infuse with AngII for only 14 days, and histological analyses were performed at 28 days after operation. Interestingly, the abdominal aortic width in IL-1Ra-/- mice more significantly increased than those in WT mice (1.57±0.34 vs 0.80±0.04 mm, p<0.01), although IL-1Ra-/- and WT mice did not differ with regard to systolic blood pressure (105±15 vs 109±13 mmHg, p=0.61) at 28 days after operation. Histological analyses revealed there were numerous inflammatory cells around the abdominal aorta in IL-1Ra-/- mice, but not in WT mice. Furthermore, elastin staining showed destruction of the elastic lamina of abdominal aorta in IL-1Ra-/- mice. TNF-α protein expression also increased significantly in IL-1Ra-/- mice compared to WT mice at 28days. Conclusions: The present study shows that IL-1Ra deficiency in mice led to increase inflammation and the development of aortic aneurysm after AngII infusion. Furthermore, our results also showed IL-1Ra deficiency continued the AngII-induced inflammation even though blood pressure was improved after cessation of AngII infusion.

IL36RN mutations define a severe autoinflammatory phenotype of generalized pustular psoriasis

Safia Hussain, BSc, Dorottya M Berki, BSc, Siew-Eng Choon, MRCP, A David Burden, MD, FRCP, Michael H Allen, PhD, Juan I Arostegui, MD, PhD, Antonio Chaves, MD, Michael Duckworth, Alan D Irvine, MD, Maja Mockenhaupt, MD, PhD, Alexander A Navarini, MD, PhD, Marieke MB Seyger, MD, PhD, Pere Soler-Palacin, MD, PhD, Christa Prins, MD, Laurence Valeyrie-Allanore, MD, M Asuncion Vicente, MD, Richard C Trembath, FMedSci, Catherine H Smith, MD, FRCP, Jonathan N Barker, MD, FRCP,* Francesca Capon, PhD,*