Behcet Syndrome

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2019-09-22

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Drugs

Adalimumab ( CYLTEZO, AMGEVITA, AMSPARITY, HALIMATOZ, HEFIYA, HULIO, HUMIRA, HYRIMOZ, KROMEYA, IDACIO, IMRALDI ), Apremilast ( OTEZLA ), Colchicine ( COLCHICINE HOUDE, COLCHIMAX, COLCRYS )

Adalimumab ( CYLTEZO, AMGEVITA, AMSPARITY, HALIMATOZ, HEFIYA, HULIO, HUMIRA, HYRIMOZ, KROMEYA, IDACIO, IMRALDI ), Apremilast ( OTEZLA ), Colchicine ( COLCHICINE HOUDE, COLCHIMAX, COLCRYS ), Gevokizumab, Recombinant human residue 41 glutamic acid to glutamine variant of Interferon-alfa-2b, Recombinant humanised anti-human interleukin-1 beta monoclonal antibody

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Clinical Features

Goolamali et al. (1976) observed this syndrome of recurrent inflammatory lesions of the mouth, genitalia, and eyes in 5 persons in 4 generations of a family. Viral and autoimmune etiologies had been suggested. In the family reported, 2 brothers suffered from an unusual schizoaffective disorder and their mother, who also had Behcet syndrome, had severe alopecia areata, Raynaud phenomenon, and rheumatoid arthritis. Thus, this may be the familial aggregation recognized with other autoimmune diseases. Chamberlain (1978) found that first-degree relatives of patients with definite Behcet syndrome occasionally suffer from mouth and, less commonly, genital ulcerations, but not from uveitis and other features of severe disease. Spouses showed no abnormality.

Mizuki et al. (1997) noted that Behcet disease is characterized by 4 major symptoms: oral aphthous ulcers, skin lesions, ocular symptoms, and genital ulcerations, and occasionally by inflammation in tissues and organs throughout the body, including the gastrointestinal tract, central nervous system, vascular system, lungs, and kidneys.

Zamir et al. (2003) reported that in addition to oral and genital ulceration, conjunctival ulceration may also be found in patients with Behcet disease. This rare clinical sign, when accompanied by uveitis or orogenital ulcers, might suggest a diagnosis of Behcet disease.

Yoshida et al. (2004) compared clinical findings in Japanese patients with Behcet disease examined in 2 decades (1980s and 1990s) to determine whether there had been a shift toward the appearance of less severe disease. Age of onset, type of inflammation, incidence of secondary glaucoma, and surgical history for glaucoma and cataract did not differ between the 1980s and 1990s. In patients seen in the 1990s, the number of ocular attacks per year and the percentage of patients treated with cyclosporine or cyclophosphamide decreased significantly. The percentage of eyes with good visual acuity (20/30 or better) increased, and the percentage of eyes with poor visual acuity (worse than 20/200) decreased significantly at both the first and the last examinations. There was a trend for less bilateral disease and fewer genital ulcers in the 1990s as well.

Biochemical Features

Serum proinflammatory cytokines upregulate leptin (164160) levels and leptin itself directly induces nitric oxide production from endothelial cells with its specific receptors. Evereklioglu et al. (2002) measured changes of serum leptin concentrations in 35 patients with Behcet syndrome compared with age- and sex-matched healthy volunteers by enzyme-linked immunosorbent assay. They also investigated whether disease activity or the duration of Behcet syndrome correlated with leptin concentration. The mean serum leptin concentrations in patients with Behcet syndrome were significantly higher than in healthy control volunteers. Active Behcet syndrome patients had significantly higher leptin concentrations when compared with patients in inactive periods. In addition, patients with longer disease duration had also significantly higher leptin concentrations than those with shorter disease duration. Evereklioglu et al. (2002) concluded that leptin may have a role in modulating endothelial function and may be involved in mechanisms for vessel endothelium repair, during an exacerbation as well as in chronic disease.

Autoimmune response to retinal antigens is considered to be a cause of uveitis in Behcet disease. Okunuki et al. (2007) used proteomic techniques to compare retinal autoantigens recognized by sera from BD patients with uveitis or healthy donors. Six protein spots showing high reactivity with the serum from the BD patients were detected as candidate retinal autoantigens, and 3 of them were identified by mass spectrometry. Two of them had previously been identified as BD autoantigens, i.e., S-antigen (181031) and alpha-enolase (172430), and the other was selenium-binding protein (SELENBP1; 604188). Because anti-SELENBP1 antibody-positive patients showed more frequent ocular inflammation than the antibody-negative patient group, Okunuki et al. (2007) concluded that autoimmunity against this retinal antigen might contribute to the pathogenesis of uveitis in BD patients.

Inheritance

A positive family history was noted by Forbes and Robson (1960), Fowler et al. (1968), Mason and Barnes (1969), among others. Behcet disease is most frequent in Turkey and Japan. HLA-B5 (see 142830) has been found to predominate in cases. Dundar et al. (1985) reported 7 families with multiple cases. In 1 family, 3 sibs, including twins, were affected. Father and son were affected in another. They found HLA-B5 in the 3 families tested.

Bird Stewart (1986) analyzed 15 families from the U.K. and 9 from Turkey, finding 27 affected persons. There were no affected parents. The author concluded that the data were incompatible with a simple mendelian pattern of inheritance and specifically incompatible with autosomal recessive inheritance. No definite HLA association was found.

Kone-Paut et al. (1999) conducted a retrospective study to analyze data collected from 572 patients with Behcet disease in whom the diagnosis was made with criteria defined by the International Study Group for BD. The age of 'attaining criteria,' i.e., the age at which the patient met the study group criteria, was evaluated for each patient. Recurrence risks were calculated for the pediatric group from information provided by 45 families. Of the 505 patients from whom the age of attaining criteria could be ascertained, 106 showed definitive BD before the age of 16 years and were considered pediatric patients with BD; the other 399 were classified as nonpediatric patients. Thirteen of the 106 pediatric patients (12.3%) and only 9 of the 399 nonpediatric patients (2.2%) had relatives affected by BD. This difference was significant (p less than 0.0001). Moreover, the mean age of attaining criteria in familial cases (17.95 years) was significantly lower than in sporadic cases (27.28 years). The recurrence risk among sibs and parents who had met the International Study Group criteria was 10%.

Molinari et al. (2003) performed segregation analysis of 67 nuclear families with pediatric Behcet disease and 37 with nonpediatric Behcet disease according to the criteria established by the International Study Group for BD. They found data consistent with autosomal recessive inheritance in the families with pediatric Behcet disease (estimated mendelian segregation ratio = 0.248) but not in the nonpediatric families (estimated segregation ratio = 0.08). Molinari et al. (2003) stated that this was the first evidence of genetic heterogeneity in Behcet disease.

Molecular Genetics

Behcet disease is associated with the HLA-B51 (see 142830) molecule, which is relatively frequent, ranging from 45 to 60% in many different ethnic groups including Asian and Eurasian populations from Japan and the Middle East (Ohno et al., 1982). However, it was not certain whether HLA-B51 itself or a closely linked gene is responsible for susceptibility to Behcet disease. Mizuki et al. (1997) presented evidence that the primary association of Behcet disease may be not with HLA-B, but with polymorphism in the MICA gene (600169) located about 40 kb centromeric to the HLA-B gene. They discovered a triplet repeat (GCT/AGC) microsatellite polymorphism in the transmembrane region of the MICA gene. In investigations of 77 Japanese patients with Behcet disease, they found that the microsatellite allele of MICA consisting of 6 repetitions of GCT/AGC was present at significantly higher frequencies in the patient population (Pc = 0.00055) than in a control population. Furthermore, the (GCT/AGC)6 allele was present in all B51-positive patients and in an additional 13 B51-negative patients. These results suggested the possibility of a primary association of Behcet disease with MICA rather than HLA-B.

Mizuki et al. (2000) studied the localization of the pathogenic gene of Behcet disease using microsatellite analysis of 3 different populations: Japanese, Greek, and Italian. In genotypic differentiation between patients and controls, the authors found that only HLA-B51 was significantly associated with BD in all 3 populations. These results suggested that the pathogenic gene of BD is HLA-B51 itself and not other genes located in the vicinity of HLA-B.

Remmers et al. (2010) performed a genomewide association study with 311,459 SNPs in 1,215 individuals with Behcet disease (cases) and 1,278 healthy controls from Turkey. Remmers et al. (2010) confirmed the known association of Behcet disease with HLA-B*51 and identified a second, independent association within the MHC class I region. The authors also identified an association with IL10 (124092) (rs1518111, p = 1.88 x 10(-8)). Using a metaanalysis from an additional 5 cohorts from Turkey, the Middle East, Europe, and Asia, comprising a total of 2,430 cases and 2,660 controls, Remmers et al. (2010) identified associations at IL10 (rs1518111, p = 3.54 x 10(-18), odds ratio = 1.45, 95% confidence interval 1.34-1.58) and the IL23R (607562)-IL12RB2 (601642) locus (rs924080, p = 6.69 x 10(-9), odds ratio = 1.28, 95% confidence interval 1.18-1.39). The disease-associated IL10 variant (the rs1518111 A allele) was associated with diminished mRNA expression and low protein production.

Mizuki et al. (2010) conducted a genomewide association study in a Japanese cohort including 612 individuals with Behcet disease and 740 unaffected individuals (controls). They identified 2 suggestive associations on chromosomes 1p31.3 (IL23R-IL12RB2, rs12119179, p = 2.7 x 10(-8)) and 1q32.1 (IL10, rs1554286, p = 8.0 x 10(-8)). A metaanalysis of these 2 loci with results from additional Turkish and Korean cohorts showed genomewide significant associations (rs1495965 in IL23R-IL12RB2, p = 1.9 x 10(-11), odds ratio = 1.35; rs1800871 in IL10, p = 1.0 x 10(-14), odds ratio = 1.45).

Kirino et al. (2013) performed a genomewide association study of 779,465 SNPs with imputed genotypes in 1,209 Turkish individuals with Behcet disease and 1,278 controls and identified associations at CCR1 (601159), STAT4 (600558), and KLRC4 (602893). Additionally, 2 SNPs in ERAP1 (606832), encoding asp575 to asn (rs10050860) and arg725 to gln (rs17482078) alterations, recessively conferred disease risk. These findings were replicated in 1,468 independent Turkish and/or 1,352 Japanese samples (combined metaanalysis p less than 2 x 10(-9)). Kirino et al. (2013) also found evidence for interaction between HLA-B*51 and ERAP1 (p = 9 x 10(-4)). In an analysis restricted to HLA-B*51-positive individuals, the ERAP1 rs17482078TT genotype had an odds ratio of 3.78 (95% CI = 1.94-7.35), whereas in the HLA-B*51-negative individuals the rs17482078TT genotype odds ratio was 1.48 (95% CI = 0.78-2.80).

Hughes et al. (2013) genotyped 8,572 variants in the extended HLA locus and carried out imputation and metaanalysis of 24,834 variants in 2 independent Behcet disease cohorts from 2 ancestry groups. Genotyped SNPs were used to infer classical HLA alleles in the HLA-A, HLA-B, HLA-C, HLA-DQA1, HLA-DQB1, and HLA-DRB1 loci. The data suggest that the robust HLA-B*51 association in Behcet disease is explained by a variant located between the HLA-B and MICA genes (rs116799036; OR = 3.88, p = 9.42 x 10(-50)). Three additional independent genetic associations, within PSORS1C1 (rs12525170; OR = 3.01, p = 3.01 x 10(-26)), upstream of HLA-F-AS1 (rs114854070; OR = 1.95, p = 7.84 x 10(-14)), and with HLA-Cw*1602 (OR = 5.38, p = 6.07 x 10(-18)), were also identified and replicated.

Takeuchi et al. (2017) analyzed 1,900 Turkish Behcet disease cases and 1,779 controls genotyped with SNP microarray. The most significantly associated SNP was rs1050502, a tag SNP for HLA-B*51 (see 142830). In the Turkish discovery set, the authors identified 3 new risk loci, IL1A (147760)-IL1B (147720), IRF8 (601565), and CEBPB (189965)-PTPN1 (176885), with genomewide significance (p less than 5 x 10(-8)) by direct genotyping, and ADO (611392)-EGR2 (129010) by imputation. Takeuchi et al. (2017) replicated the ADO-EGR2, IRF8, and CEBPB-PTPN1 loci by genotyping 969 Iranian cases and 826 controls. Imputed data in 608 Japanese cases and 737 controls further replicated ADO-EGR2 and IRF8, and metaanalysis additionally identified RIPK2 (603455) and LACC1 (613409). The disease-associated allele of rs4402765, the lead marker at IL1A-IL1B, was associated with both decreased IL1-alpha and increased IL1-beta production. ABO nonsecretor genotypes for 2 ancestry-specific FUT2 (182100) SNPs showed strong disease association (p = 5.89 x 10(-15)). Takeuchi et al. (2017) concluded that their findings extended the list of susceptibility genes shared with Crohn disease and leprosy and implicated mucosal factors and the innate immune response to microbial exposure in Behcet disease susceptibility.