BLAU SYNDROME OR MONOGENOUS SARCOIDOSIS WITH EARLY ONSET: RUSSIAN COHORT OF PATIENTS

Blau syndrome (BS) is a rare monogenic granulomatous autoinflammatory disease (a variant of genetically determined sarcoidosis) caused by a mutation of the NOD2/CARD15 gene, transmitted in an autosomal dominant manner and manifested by a triad of signs: dermatitis, granulomatous arthritis with pronounced exudative component and involvement of periarticular tissues, uveitis. Objective of the study: to present the variants of the clinical picture and the type of pathogenic variants (mutations) in patients with a rare monogenic granulomatous autoinflammatory disease – BS – in the Russian Federation, the clinical picture of which can mimic juvenile idiopathic arthritis. Materials and methods of research: the observational study included patients with BS who were observed in the children's department of the V.A. Nasonova Research Institute of Rheumatology from 2014 to 2021, the diagnosis of which was confirmed by the detection of a pathogenic mutation in the NOD2/CARD15 gene. Results: the study included 8 children: 6 boys and 2 girls. Ethnic Russians were 5 patients, 1 Jew, 1 of mixed origin (peoples of Dagestan/Russians), 1 Tatar female. The age of onset of the disease is from the first days of life to 2,5 years. Skin lesions were observed in 6 (75%) patients. Atypical arthritis (boggy arthritis) was observed in all patients, in all cases the wrist, ankle and knee joints were involved in the pathological process. Uveitis developed after all other manifestations and was detected in 6 (75%) patients. At the onset, 5 patients had anterior uveitis, 2 of them with subsequent involvement of the posterior segment; in 1 child, the first ophthalmic manifestation was posterior uveitis. In 5 patients, there was no increase in acute phase markers (ESR, C-reactive protein). 5 (62,5%) patients had variant p.R334Q (c.1001G>A), 2 (25%) had variant p.R334W (c.1001G>A), 1 patient had variant p.M513T (c.1538T>C) of the NOD2/CARD15 gene. Conclusions: BS can be encountered in the practice of a pediatric rheumatologist in Russia and requires differentiation from polyarticular juvenile idiopathic arthritis. Identification of the pathogenic variant of the NOD2/CARD15 gene plays a decisive role in the diagnosis.

Genetic variation in NOD1/CARD4 and NOD2/CARD15 immune sensors and risk of osteoporosis

The present study was aimed to investigate the relationship between NOD1/CARD4 and NOD2/CARD15 gene polymorphisms and osteoporosis in the Turkish population. The first time we thought that the functional polymorphisms in NOD1/CARD4 and NOD2/CARD15 genes might have triggered the development of osteoporosis. The objective of our study was to determine the relationship between NOD1/CARD4 and NOD2/CARD15 SNPs and osteoporosis. The NOD1/CARD4 (rs5743336) and NOD2/CARD15 (rs2066847) SNPs were analyzed by PCR restriction fragment length polymorphism (PCR-RFLP) in 94 healthy controls and 164 subjects with osteoporosis. PCR products were digested with restriction enzymes AvaI for NOD1/CARD4 and ApaI for NOD2/CARD15. We found that NOD1/CARD4 genotype distribution of AA, GA and GG were 15, 44 and 41% for patients and 17, 46 and 37% for controls, respectively. NOD2/CARD15 mutation was found only in three patients (1.8%) as heterozygote. The results did not show any statistical difference between NOD1/CARD4 and NOD2/CARD15 genotype distribution of patients and healthy groups (χ2 = 1.740, P=0.187; χ2 = 1.311, P=0.519). However, the most frequent AG genotype (46%) of NOD1/CARD4 was observed in healthy controls, GG genotype (44%) of NOD1/CARD4 was observed as the most frequent in osteoporotic patients. NOD2/CARD15 WT/WT genotype, the most frequent genotype, was observed in both groups. Statistical analysis revealed that NOD1/CARD4 and NOD2/CARD15 polymorphisms are not associated with osteoporosis. However, a definite judgement is difficult to be made due to restricted number of patients and small size of control group. Further research is sorely warranted in this direction.

AB0996 FAMILY CASE OF BLAU SYNDROME IN 3 CHILDREN, INITIALLY DIAGNOSED AS JUVENILE IDIOPATHIC ARTHRITIS

Background:Juvenile Idiopathic Arthritis (JIA) is heterogeneous group of diseases which may include genetically determined conditions. Extremely rare monogenic hereditary autoinflammatory disease, such as Blau syndrome (BS) is usually difficult to recognize and JIA is initially established. BS is caused by a mutation in the NOD2/CARD5 gene and phenotypically characterized by triad of granulomatosis polyarthritis, uveitis and skin rash.Objectives:To present the family case of genetically confirmed BS in 2 siblings, initially diagnosed as patients with JIA.Methods:Two brothers of 15 and 3 years old were examined in our clinic. Additional genetic assay was performed because of unusual clinical picture.Results:Case report.Older brother, 15 y.o. developed arthritis of both wrist joints at the age of two. There was erythematous maculo-micropapular scaly rash on the trunk and extremities before the onset of arthritis. By 2009 (5 y.o.), the knees, ankles, and three PIP joints of the left hand were involved. Polyarthritis was characterized by severe effusion and periarticular tissues swallowing. He was treated in regional hospital by NSAID, methotrexate, cyclosporine A without significant positive effect. Since 2012 etanercept was added for treatment with variable result. Inactive status of the disease is never reached. Repeated intra-articular GC injections were needed from 4 to 10 times per year. The patient was admitted to our clinic in November 2019. He was suffering from severe polyarthritis and uveitis de novo (granulomatous chorioretinitis) was detected. At the same time his younger 3 y. o. brother with recently started disease was hospitalized in our clinic. He had polyarthritis with typical features of “boggy” synovitis and tenosynovitis of wrists, ankles and knees, anterior uveitis was determined. The onset of arthritis was preceded by a small-spotted rash with desquamation. This classical clinical features in younger brother let us suggest the BS. There was no increasing of ESR and CRP in both sibs throughout the course of the disease. A molecular genetic study of the NOD2/CARD15 gene in both brothers revealed the same mutation of c.1001G>A (p. Arg334Gln). Because of the absence of specific treatment for this disease and due to insufficient effect of etanercept with uveitis de novo therapy was changed to golimumab and good initial effect is reached. The youngest brother has started his therapy by methotrexate. It should be noted that the family has the eldest brother (20 y.o.), who has been suffering from arthritis since an early childhood with similar clinical picture. We are going to perform genetic analysis of the NOD2/CARD15 gene for the eldest brother.Conclusion:Our clinical case shows that extremely rare BS may be misdiagnosed as JIA. Lack of efficacy of the etanercept therapy and uveitis de novo developing may be caused by genetic (non-idiopathic) nature of disease. Classic triad of boggy-arthritis, granulomatous uveitis and/or skin lesions without acute phase markers is required to perform genetic assay for the detection of a pathogenic mutation of the NOD2/CARD15 gene. This case is remarkable by the presence of BS in two (or 3) children of the family.References:[1]Wouters C.H, Maes A, Foley K, et al. Blau Syndrome, the prototypic auto-inflammatory granulomatous disease. Pediatric Rheumatology. 2014; 12: 33.Disclosure of Interests:None declared

The role of NOD2/CARD15 gene of antigen-presenting system in functioning of various organs and systems

The article presents the literature review devoted to NOD2/CARD15 gene. Genetic variability affects the susceptibility and development of certain human diseases such as autoimmune diseases and infections, affecting numerous cellular processes, and thus modulating the response to environmental and internal factors. The NOD2/CARD15 gene plays a major role in the development and course of various diseases such as Grohn's disease, Blau syndrome, as well as the risk of developing severe complications of the graft versus host reaction after allogeneic stem cell transplantation. NOD (Nucleotide Oligomerization Domain) is the domain of nucleotide oligomerization. NOD-like receptors play an important regulatory role in the response on infectious agents and at activation of the adaptive immune response. It is known that the mechanism of action of NOD-like receptors is based on the response to the pathogen of associated molecular patterns mainly of bacterial origin, which leads to the formation and activation of inflammasome. Recently, another NOD-like receptor activation mechanism has been revealed that provides innate virus recognition. The review presents Toll-like receptors, which are part of the innate immune system. Innate immunity is an inherited system of protection of the body against pathogenic and non-pathogenic microorganisms. The mechanisms of innate immunity develop very quickly. In newborns, the immune system is mainly dependent on components of the innate or antigen-independent immune system including phagocytes, natural killer cells, antigen-presenting cells, humoral inflammatory mediators and complement system.

Despite Genetic and Proteomic Arguments, the Three Common Variants of NOD2/ CARD15 Genes: Pemphigus Foliaceus

Background: Knowledge about the pathogenesis of Pemphigus Foliaceus (PF), an autoimmune disorder of the skin natural barrier, is still modest. Genetic susceptibility factors have been widely studied, while environmental factors remain still ambiguous. NOD2/CARD15 gene encodes an intracytoplasmic receptor involved in recognition of microbial components and NF-κB inflammatory signaling pathway. Three common CD-associated variations (R702W, G908R and 1007fs) cause a "loss of function" of the molecule and lead to a chronic inflammation in the intestinal epithelial barrier. The aim of this study is to analyze NOD2/CARD15 gene polymorphisms in Tunisian endemic PF. Methods and Results:A case-control study including 79 PF patients and 160 controls was conducted using PCR-RFLP and direct sequencing. Our results showed that the three SNPs are not polymorphic in both patients and controls (allelic frequencies were 0.63% vs 1.25%, 0.63% vs 1.87% and 0% vs 0.62%, respectively). There was no association of mutant alleles with the disease. Conclusions: Our results suggest that the three common variants of NOD2/CARD15 gene are not involved in susceptibility to Tunisian PF. The alteration of the molecule's functionality caused by these mutations seems to not interfere with the development of the disease.