Clinical and Genetic Features of Korean Patients with Recurrent Fever and Multi-System Inflammation without Infectious or Autoimmune Evidence

Autoinflammatory disease (AID) is a newly proposed category of disorders characterized by unprovoked episodes of inflammation without any infectious or autoimmune evidence. We aimed to characterize the clinical and genetic features of patients who had recurrent fever and multi-system inflammation but remain unclassified for any established AIDs. Medical records of 1,777 patients who visited our Rheumatology Clinic between March 2009 and December 2010 were reviewed to identify those who met the following criteria; 1) presence of fever, 2) inflammation in two or more organ systems, 3) recurrent nature of fever or inflammation, 4) no evidence of infection or malignancy, 5) absence of high titer autoantibodies, and 6) failure to satisfy any classification criteria for known AIDs. Genotyping was performed for common missense variants in MEFV, NOD2/CARD15, and TNFRSF1A. A small number of patients (17/1,777, 0.95%) were identified to meet the above criteria. Muco-cutaneous and musculoskeletal features were most common, but there was a considerable heterogeneity in symptom combination. Although they did not satisfy any established classification criteria for AIDs, substantial overlap was observed between the clinical spectrum of these patients and known AIDs. According to the newly proposed Eurofever criteria for periodic fevers, eleven of them were classified as TNF receptor-associated periodic syndrome and two as mevalonate kinase deficiency. However, no examined genetic variants including those in TNFRSF1A were found in these patients. A new set of classification criteria needs to be developed and validated for Asian patients with unclassified AIDs.

Clinical and Genetic Features of Korean Patients with Recurrent Fever and Multi-System Inflammation without Infectious or Autoimmune Evidence

Autoinflammatory disease (AID) is a newly proposed category of disorders characterized by unprovoked episodes of inflammation without any infectious or autoimmune evidence. We aimed to characterize the clinical and genetic features of patients who had recurrent fever and multi-system inflammation but remain unclassified for any established AIDs. Medical records of 1,777 patients who visited our Rheumatology Clinic between March 2009 and December 2010 were reviewed to identify those who met the following criteria; 1) presence of fever, 2) inflammation in two or more organ systems, 3) recurrent nature of fever or inflammation, 4) no evidence of infection or malignancy, 5) absence of high titer autoantibodies, and 6) failure to satisfy any classification criteria for known AIDs. Genotyping was performed for common missense variants in MEFV, NOD2/CARD15, and TNFRSF1A. A small number of patients (17/1,777, 0.95%) were identified to meet the above criteria. Muco-cutaneous and musculoskeletal features were most common, but there was a considerable heterogeneity in symptom combination. Although they did not satisfy any established classification criteria for AIDs, substantial overlap was observed between the clinical spectrum of these patients and known AIDs. According to the newly proposed Eurofever criteria for periodic fevers, eleven of them were classified as TNF receptor-associated periodic syndrome and two as mevalonate kinase deficiency. However, no examined genetic variants including those in TNFRSF1A were found in these patients. A new set of classification criteria needs to be developed and validated for Asian patients with unclassified AIDs.

[NOD2 novel mutations in Iranian Crohn's patients]

Despite the reported role of three common mutations of the CARD15/NOD2 gene including R702W, G908R and 1007fs in Crohn's disease [CD], only about 30% of Iranian CD patients carry one of these three variants [R702W]. The aim of this study was to screen the hot points of NOD2 gene to find any novel sequence variations in Iranian patients with CD. Eighty non-related Crohn's patients from Iranian origin, referred to a tertiary center in a three-year period [2006-2009], were enrolled in this study. The hot points of NOD2 gene [including exons 4 and 8] were evaluated by direct sequencing after amplification of related sequences with polymerase chain reaction [PCR]. A total of 17 sequence variations were identified among these exons of NOD2 gene including 7 novel ones. Three of these new mutations had an allele frequency more than 5%. All new mutations were a consequence of a single nucleotide change, 4 resulted in an aminoacid change while one formed a stop coden. No deletion or insertion mutation was observed in this part of the gene. This study demonstrated the existence of uncommon NOD2 variants in Iranian patients with CD. It is possible that these mutations play a role in susceptibility to CD in Iranian population

frequency of three common mutations of CARD15/NOD2 gene in Iranian IBD patients

CARD15/NOD2 gene, located on the pericentromeric region of chromosome 16 [IBD1] has been reported to have an association with IBD, especially Crohn's disease [CD]. Many independent studies have shown a variable association between three common mutations of CARD 15, with Crohn's disease in different ethnic groups. Thus, raising the hypothesis that genetic and / or allelic heterogeneity may influence the relationship between CARD 15 and Crohn's disease. In the present study, we have investigated the frequency of three main mutations of CARD 15 gene [Arg 702 Trp, Gly 908 Arg and Leu 1007 fsinsC] in Iranian IBD patients and compared it with healthy control population. For this case-control study, 100 ulcerative colitis [UC], 40 Crohn's disease patients and 100 sex- age- and ethnicity-matched controls were enrolled from a teaching hospital during a one year period [2003-2004]. All three mutations were assessed on DNA of leukocyte cells, by PCR [Polymerase Chain Reaction] and RFLP [Restriction Fragment Length Polymorphism] methods. The mean age of UC, CD and healthy controls were 38.6 +/- 14.3, 36.6 +/- 14.1, and 38.6 +/- 14.2 years. Among the three evaluated CARD 15 gene mutations, the frequency of Arg702Trp mutation was significantly higher in Iranian patients with Crohn's disease [OR19.2; 95%CI:4.2-87.3, p<0.001]. None of these mutations were associated with ulcerative colitis. This study showed that Arg702Trp mutation of CARD 15 gene is probably associated with Crohn's disease in Iranian population; indicating that genetic polymorphisms may differ between populations