NOD2-associated Autoinflammatory Disease Research Articles

Susceptibility of nucleotide-binding oligomerization domain 2 mutations to Whipple's disease.

Whipple's disease (WD) results from infection of the bacteria Tropheryma whipplei (TW). This disease is characterized by macrophage infiltration of intestinal mucosa and primarily affects Caucasian males. Genetic studies of host susceptibility are scarce. Nucleotide-binding oligomerization domain containing protein 2 (NOD2) is an innate immune sensor, resides mainly in monocytes/macrophages and contributes to defence against infection and inflammatory regulation. NOD2 mutations are associated with autoinflammatory diseases. We report the association of NOD2 mutations with TW and WD for the first time. A multicentre, retrospective study of three patients with WD was conducted. Patients received extensive multidisciplinary evaluations and were cared for by the authors. NOD2 and its association with infection and inflammation were schematically represented. All patients were Caucasian men and presented with years of autoinflammatory phenotypes, including recurrent fever, rash, inflammatory arthritis, gastrointestinal symptoms and elevated inflammatory markers. All patients underwent molecular testing using a gene panel for periodic fever syndromes and were identified to carry NOD2 mutations associated with NOD2-associated autoinflammatory disease. Despite initially negative gastrointestinal evaluations, repeat endoscopy with duodenal tissue biopsy ultimately confirmed WD. After initial ceftriaxone and maintenance with doxycycline and/or HCQ, symptoms were largely controlled, though mild relapses occurred in follow-up. Both NOD2 and TW/WD are intensively involved in monocytes/macrophages. WD is regarded as a macrophage disease. NOD2 leucin-rich repeat-associated mutations in monocytes/macrophages cause functional impairment of these cells and consequently may make the host susceptible for TW infection and WD, especially in the setting of immunosuppression.

EP085: Phenotype of two old order Amish patients with NOD2 increased risk alleles

Nucleotide-binding oligomerization domain containing 2 (NOD2) is a member of a family of intracellular proteins involved in various inflammatory processes. NOD2 sequence variants have been associated with Crohn’s disease, Blau syndrome, and NOD2-associated autoinflammatory disease (NAID). Three main NOD2 variants (p.Arg702Trp, p.Gly908Arg and p.Leu1007Profs*2) (NM_022162.2) are linked not only to Crohn’s disease (CD) but also to NAID, which is a multisystem inflammatory disease. Dermatitis is a major feature of the NAID clinical phenotype and often presents as erythematous patches and plaques primarily occurring on the trunk.

Co-existence of Blau syndrome and NAID? Diagnostic challenges associated with presence of multiple pathogenic variants in NOD2 gene: a case report

BackgroundPediatric autoinflammatory diseases are rare and still poorly understood conditions resulting from defective genetic control of innate immune system, inter alia from anomalies of NOD2 gene. The product of this gene is Nod2 protein, taking part in maintenance of immune homeostasis. Clinical form of resultant autoinflammatory condition depends on NOD2 genotype; usually patients with NOD2 defects present with Blau syndrome, NOD2-associated autoinflammatory disease (NAID) or Crohn’s disease.Case presentationWe present the case of a 7-year-old girl with co-existing symptoms of two rare diseases, Blau syndrome and NAID. Overlapping manifestations of two syndromes raised a significant diagnostic challenge, until next-generation molecular test (NGS) identified presence of three pathogenic variants of NOD2 gene: P268S, IVS8+158, 1007 fs, and established the ultimate diagnosis.ConclusionPresence of multiple genetical abnormalities resulted in an ambiguous clinical presentation with overlapping symptoms of Blau syndrome and NAID. Final diagnosis of autoinflammatory disease opened new therapeutic possibilities, including the use of biological treatments.

A Systematic Analysis of Treatment and Outcomes of NOD2-Associated Autoinflammatory Disease

ObjectivesYao syndrome, formerly named NOD2-associated autoinflammatory disease, is a periodic disease characterized by fever, dermatitis, polyarthritis/leg swelling, and gastrointestinal and sicca-like symptoms associated with specific NOD2 sequence variants. Our aim was to evaluate the treatment and outcomes of the disease. MethodsA total of 52 adult patients with autoinflammatory disease phenotype were diagnosed with Yao syndrome and enrolled at the Cleveland Clinic between November 2009 and May 2015. All patients were genotyped for the NOD2 variants, and systematically studied for treatment outcomes. ResultsAmong the 52 Yao syndrome patients, all were white, and 72% were women. The mean age at diagnosis was 38.0 ± 12.0 years, and the disease duration was 8.8 ± 5.8 years. In the multi-organ disease, more common and typical manifestations were recurrent dermatitis and inflammatory arthritis with or without distal leg swelling besides recurrent fever. It was genotypically associated with the NOD2 IVS8+158 or R702W. Therapeutically, glucocorticoids markedly decreased the disease severity and duration of flares in 19 patients (36.6%), sulfasalazine treatment achieved a significant symptomatic improvement in 22 (42%) patients, and 3 patients received canakinumab or tocilizumab with benefits. Prognostically, 13% of the 52 patients had somewhat physical impairment, and there was no mortality during the follow-up. Associated comorbidities were fibromyalgia, asthma, renal stones, and ventricular hypertrophy. ConclusionsAs a systemic disease, Yao syndrome uncommonly affects the solid internal organs, but it can be complicated with chronic pain syndrome and even disability. Glucocorticoids or sulfasalazine may be considered as the first-line treatment option, and interleukin (IL)-1/IL-6 inhibitors may be tried for refractory cases. The potential associations between certain comorbidities and Yao syndrome deserve further study.

NOD2-associated autoinflammatory disease and immune deficiency

NOD2-associated autoinflammatory disease and immune deficiency

Granulomatous disease associated with NOD2 sequence variants and familial camptodactyly: An intermediate form of NOD2-associated diseases?

ObjectiveNucleotide-binding oligomerization domain-containing protein-2 (NOD2)-associated diseases may be a spectrum of disease. We report two families who exhibited an intermediate form of Blau syndrome and NOD2-associated autoinflammatory disease (NAID). MethodsWe identified two families with granulomatous disease. The clinical phenotypes and genotypes of these two families were reviewed and analyzed. ResultsThe proband in family 1 was a white 57-year-old woman, with camptodactyly (age 6 years), inflammatory polyarthritis and dermatitis (age of 30 years), and cough, dyspnea, dry eyes, parotid gland enlargement, and fever. A computerized tomography showed mediastinal lymphadenopathy without hilar involvement, and a mediastinal lymph node biopsy revealed non-caseating granuloma. Pedigree analysis suggested autosomal dominant inheritance, and genetic testing identified a NOD2 sequence variant IVS8+158. The proband in family 2 was a white 50-year-old woman with inflammatory polyarthritis and periarticular subcutaneous nodules. Skin biopsy showed non-necrotizing granuloma. There was a family history of camptodactyly, and genetic testing identified a NOD2 sequence variant R703C. ConclusionsBoth probands had granulomatous disease and autosomal dominant phenotype of familial camptodactyly coupled with the presence of the NOD2 sequence variants, IVS8+158, and R703C. Granulomatous disease associated with NOD2 variants may be an intermediate form between Blau syndrome and NAID.

PReS-FINAL-2201: A P268S NOD mutation in one Blau patient

Blau syndrome (BS) is a rare autosomal dominant, autoinflammatory syndrome characterized by the clinical triad of granulomatous, recurrent uveitis, dermatitis and symmetric arthritis. Arthritis is usually a polyarticular exuberant synovitis and tenosynovitis and represents the characteristic phenotypic feature. Uveitis occurs in most patients and commonly evolves to a panuveitis. In the majority of patients, the disease is characterized by early onset, usually before 3-4years of age. The gene responsible for BS has been identified in the caspase recruitment domain gene NOD2/CARD15, and the most common mutations were found in codon 334 (R334Q and R334W). NOD2 is a member of a family of intracellular proteins with N-terminal caspase recruitment domains (CARDs). Since the first report of an association of the NOD2 variants with Crohn disease by Hugot et al, extensive studies have been focused on an association of NOD2 with inflammatory bowel disease (IBD), pediatric Blau syndrome, NOD2-associated autoinflammatory disease (NAID) and rheumatic disease.

NOD2-associated autoinflammatory disease: an exploratory study of its pathogenesis

NOD2-associated autoinflammatory disease: an exploratory study of its pathogenesis

P03-012 - A P268S NOD2 mutation in one Blau patient

Blau syndrome (BS) is a rare autosomal dominant, autoinflammatory syndrome characterized by the clinical triad of granulomatous, recurrent uveitis, dermatitis and symmetric arthritis. The arthritis is usually a polyarticular exuberant synovitis and tenosynovitis and represents the characteristic phenotypic feature. Uveitis occurs in most patients and commonly evolves to a panuveitis. In the majority of patients, the disease is characterized by early onset, usually before 3-4 years of age. The gene responsible for BS has been identified in the caspase recruitment domain gene NOD2/CARD15, and the most common mutations were found in codon 334 (R334Q and R334W) [1]. NOD2 is a member of a family of intracellular proteins with N-terminal caspase recruitment domains (CARDs). Since the first report of an association of the NOD2 variants with Crohn disease by Hugot et al. [2], extensive studies have been focused on an association of NOD2 with inflammatory bowel disease (IBD), pediatric Blau syndrome, NOD2-associated autoinflammatory disease (NAID) and rheumatic disease [3].

Ocular Myositis Occurring with NOD2-associated Autoinflammatory Disease

NOD2-associated autoinflammatory disease (NAID) is an emerging disease1. We report a patient with ocular myositis (OM) whose clinical phenotype was consistent with NAID. A 34-year-old white woman developed eyelid swelling, pain on eye movement, and color vision loss 3 years ago. There was right eye pain with adduction and abduction with normal visual acuity and color vision on examination. A magnetic resonance imaging study revealed …

Distal lower extremity swelling as a prominent phenotype of NOD2-associated autoinflammatory disease

Distal lower extremity swelling as a prominent phenotype of NOD2-associated autoinflammatory disease

Nucleotide-binding oligomerization domain containing 2: Structure, function, and diseases

ObjectivesTo systematically review literature about the structure and function of nucleotide-binding oligomerization domain containing 2 (NOD2) and its disease association. MethodsThe English literature was searched using keywords “NOD2” and “disease”. Relevant original and review articles were reviewed. ResultsNOD2 is an intracellular protein and shares similar molecular structure with NOD1, pyrin, and cryopyrin. There are more than 100 NOD2 gene mutations, some of which have been linked to diseases such as Crohn disease, Blau syndrome, and NOD2-associated autoinflammatory disease (NAID). The NOD2 variants located in the leucine-rich repeat (LRR) region are susceptible to Crohn disease, and the variants in the nucleotide-binding domain (NBD) and in between the NBD and LRR are associated with Blau syndrome and NAID, respectively. No disease association with the gene variants has been found in rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, psoriasis/psoriatic arthritis, adult sarcoidosis, granulomatous polyangiitis, or multiple sclerosis. The potential association of the NOD2 variants with graft-versus-host-disease remains controversial. NOD2 functions mainly through RICK or RIP2 to activate p38 mitogen-activated protein kinases and NF-κB, resulting in inflammatory response, and enhanced autophagic activity. Biologic therapy may be beneficial for NOD2-associated diseases, and new drug development may be realized based upon the signaling pathways. ConclusionsNOD2 gene mutations are associated with several diseases, and some of the mutations are of diagnostic value in Blau disease and NAID. To understand the NOD2 function, disease association, and its pathogenesis is important given the ever increasing clinical significance of NOD2.

Dermatitis as a characteristic phenotype of a new autoinflammatory disease associated with NOD2 mutations

We sought to characterize a new category of autoinflammatory disease associated with nucleotide-binding oligomerization domain 2 (NOD2) gene mutations. A total of 22 patients were identified, inclusive of those reported previously. All had autoinflammatory phenotypes and NOD2 gene mutations that were prospectively studied between January 2009 and February 2012. All 22 patients were non-Jewish whites (13 women and 9 men). The mean age at diagnosis was 40.1 years (range 17-72), with a mean disease duration of 4.7 years (range 1-13). Three female patients were siblings. Common clinical features were weight loss (13/22), episodic self-limiting fever (13/22), dermatitis (19/22), and inflammatory polyarthritis/polyarthralgia (20/22). Gastrointestinal symptoms occurred in 13 patients, sicca-like symptoms in 9, and recurrent chest pain in 5. All patients carried the NOD2 gene mutations, with the intervening sequence 8(+158) variant in 21 and the R702W variant in 8. The NOD2 allelic frequency may need to be examined in a larger population with systemic autoimmune diseases. The characteristic clinical phenotype, notably dermatitis, coupled with certain NOD2 variants constitutes a new autoinflammatory disease entity, which we have named as NOD2-associated autoinflammatory disease.