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Background: It has been well documented that Takayasu arteritis (TAK) and ulcerative colitis (UC) coexist in the same patients. HLA-B*52 characterizes the co-occurrence, which is one of the common genetic features between these two diseases, indicating shared underlying pathologic mechanisms. Anti-integrin αvβ6 antibody (Ab) is present in sera of UC patients in a highly specific manner. We investigated if there were any associations between anti-integrin αvβ6 Ab and TAK, considering the risk HLA alleles., Methods: A total of 227 Japanese TAK patients were recruited in the current study and their serum samples were subjected to measurement of anti-integrin αvβ6 Ab by ELISA. The clinical information, including the co-occurrence of UC, was collected. The HLA allele carrier status was determined by Luminex or genotype imputation., Results: The information about the presence of UC was available for 165 patients, among which eight (4.84%) patients had UC. Anti-integrin αvβ6 antibody was identified in 7 out of 8 TAK subjects with UC (87.5%) while only 5 out of 157 (3.18%) TAK subjects without UC had the antibody (OR 121, p=7.46×10 -8 ). A total of 99 out of 218 (45.4%) patients were HLA-B*52 carriers. There was no significant association between the presence of anti-integrin αvβ6 Ab and HLA-B*52 carrier status in those without UC (OR 2.01, 95% CI 0.33-12.4, p = 0.189)., Conclusions: The prevalence of anti-integrin αvβ6 Ab was high in TAK patients with UC, but not in the absence of concomitant UC. The effect of HLA-B*52 on anti-integrin αvβ6 Ab production would be minimal., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ishikawa, Yoshida, Yoshifuji, Ohmura, Origuchi, Ishii, Mimori, Morinobu, Shiokawa and Terao.)

HLA-B*52 is an established genetic factor in Takayasu arteritis (TAK). Recently, single nucleotide polymorphisms (SNPs) in IL12B (rs6871626) and LILRA3 (rs103294) were newly identified as non-HLA susceptibility loci in TAK. Here, we examined how these SNPs contribute to clinical characteristics and vascular damage in TAK. We retrospectively reviewed the medical records of 99 TAK patients enrolled in our previous genome-wide association study, and whose genotypes for IL12B rs6871626, LILRA3 rs103294, and HLA-B*52 were available. Incidence of aortic regurgitation (AR) was significantly associated with the A allele (risk allele) of IL12B rs6871626 (CC 42%, AC 61%, AA 81%; p = 0.0052; odds ratio [OR] 2.45), as well as with the incidence of hypertension (p = 0.049; OR 1.82) and the proportion of patients who underwent aortic valve replacement (p = 0.023; OR 3.64). Regarding vascular damage, there was positive correlation between the Takayasu Arteritis Damage Score and the A allele of IL12B rs6871626 (CC 3.42 ± 2.71, AC 4.06 ± 3.25, AA 6.00 ± 2.81; p = 0.0035; β = 1.35) and between the Vasculitis Damage Index and the A allele (CC 3.47 ± 1.98, AC 4.33 ± 2.40, AA 5.37 ± 2.22; p = 0.0054; β = 0.96). Contrarily, no correlation was found between LILRA3 rs103294 and vascular damage. In the present study, IL12B rs6871626 was associated with vascular damage in TAK, whereas LILRA3 rs103294 was not. Genotyping of IL12B rs6871626 may help to identify patients at risk of disease progression.

Objectives: Biologics have been used to treat refractory Takayasu arteritis (TAK), but their efficacy and safety have not been sufficiently evaluated., Methods: We extracted clinical information from medical records for TAK patients who were treated with biologics including ustekinumab (UST) at Kyoto University Hospital. We also analysed the patient's genetic backgrounds., Results: Of 163 cases, 12 (7.4%) were treated with infliximab, tocilizumab, or UST (n = 3). Erythrocyte sedimentation rate (ESR), C-reactive protein levels (CRP), and prednisolone (PSL) dose were significantly decreased 12 months after the initiation of biologics. When compared with the 15 patients who were only treated with immunosuppressants (IS group), the change in ESR from baseline was significantly lower in the biologics group than in the IS group (-2 mm/h, p  = .005). The proportion of patients with HLA-B*52 and the risk-type alleles of the SNP were similar in both groups. Among the biologics, TCZ showed the highest continuation rate. UST exhibited marginal effects on reducing ESR, CRP levels, and PSL dose. No adverse events were observed in patients with UST for approximately 3 years., Conclusions: Biological treatments resulted in a reduction in inflammatory markers and PSL dose in refractory TAK patients.

Takayasu arteritis (TAK) is a systemic vasculitis with severe complications that affects the aorta and its large branches. HLA-B*52 is an established susceptibility locus to TAK. To date, there are still only a limited number of reports concerning non-HLA susceptibility loci to TAK. We conducted a genome-wide association study (GWAS) and a follow-up study in a total of 633 TAK cases and 5,928 controls. A total of 510,879 SNPs were genotyped, and 5,875,450 SNPs were imputed together with HLA-B*52. Functional annotation of significant loci, enhancer enrichment, and pathway analyses were conducted. We identified four unreported significant loci, namely rs2322599, rs103294, rs17133698, and rs1713450, in PTK2B , LILRA3 / LILRB2 , DUSP22 , and KLHL33 , respectively. Two additional significant loci unreported in non-European GWAS were identified, namely HSPA6 / FCGR3A and chr21q.22. We found that a single variant associated with the expression of MICB , a ligand for natural killer (NK) cell receptor, could explain the entire association with the HLA-B region. Rs2322599 is strongly associated with the expression of PTK2B Rs103294 risk allele in LILRA3 / LILRB2 is known to be a tagging SNP for the deletion of LILRA3 , a soluble receptor of HLA class I molecules. We found a significant epistasis effect between HLA-B*52 and rs103294 ( P = 1.2 × 10 -3 ). Enhancer enrichment analysis and pathway analysis suggested the involvement of NK cells ( P = 8.8 × 10 -5 , enhancer enrichment). In conclusion, four unreported TAK susceptibility loci and an epistasis effect between LILRA3 and HLA-B*52 were identified. HLA and non-HLA regions suggested a critical role for NK cells in TAK., Competing Interests: Conflict of interest statement: Editor Tasuku Honjo and several authors are affiliated with Kyoto University but do not have any active collaborations.

Background: A previous study revealed the association between susceptibility to Takayasu arteritis (TAK) and a single nucleotide polymorphism (SNP) rs6871626 located in IL12B, which encodes interleukin (IL)-12p40, a common component of IL-12p70 and IL-23. We investigated the expression of these cytokines in patients with TAK, stratifying them into those with or without the risk allele at the rs6871626 SNP., Methods: Plasma levels of IL-12p40, IL-12p70, and IL-23 were quantified in 44 patients with TAK and 19 healthy controls (HCs) by enzyme-linked immunosorbent assays. Monocytes were obtained from 20 patients with TAK and 14 HCs, treated with interferon-γ (IFN-γ) and lipopolysaccharide, and then supernatant cytokines were quantified. In addition, the ratio of IFN-γ + or IL-17A + cells to CD4 + T cells was measured by flow cytometric analysis of peripheral blood mononuclear cells., Results: The levels of plasma IL-12p40, plasma IL-12p70, and supernatant IL-12p70 were significantly higher in patients with TAK than in HCs, whereas there were no significant differences in the levels of plasma IL-23, supernatant IL-23, or supernatant IL-12p40. The levels of plasma IL-12p70, supernatant IL-12p40, and supernatant IL-12p70 were significantly higher in patients with the risk allele than in those without. The ratio of CD4 + IFN-γ + cells was significantly higher in patients with the risk allele, whereas CD4 + IL-17A + cells showed no differences., Conclusions: The rs6871626 SNP in IL12B may influence the increased expression of IL-12p40 and IL-12p70. These enhanced cytokines might play roles in the pathophysiology of TAK.

Takayasu arteritis (TAK) is an immune-mediated vasculitis affecting large arteries first reported in 1908 from Japan. Case reports of familial onset of TAK from Japan and other countries indicated genetic contribution to TAK onset beyond ethnicity. Genetic studies of TAK have been performed mainly addressing the human leukocyte antigen (HLA) locus. HLA genetic studies of TAK that have previously been reported are reviewed in this manuscript. HLA-B*52:01 is associated with TAK beyond population. Many of the associations other than HLA-B*52:01 can be explained by a haplotype with HLA-B*52:01. HLA-B*67:01 is a novel susceptibility HLA-B allele to TAK confirmed in the Japanese population. Further independent associations are suggested in the HLA locus. Involvement of the 171st and 67th amino acid residues with TAK onset has been indicated. The 67th amino acid may explain the difference in susceptibility effects to TAK and Behçet's disease between HLA-B*52:01 and *51:01. HLA-B*52:01 is associated not only with TAK susceptibility but also with clinical phenotypes. Recent genome-wide association studies of TAK revealed multiple non-HLA susceptibility genes. In particular, the IL12B region seems to have a central role in TAK onset and its progression. Whether TAK and giant cell arteritis (GCA), the other vasculitis affecting large arteries, are the same disease is an interesting question to address in spite of different clinical manifestations between the two diseases. GCA is associated with HLA-DR4, which is not associated with TAK. GCA is not associated with HLA-Bw52. These two diseases seem not to share non-HLA susceptibility loci based on the recent genetic studies.

Objective: Takayasu arteritis (TAK) is a systemic vasculitis affecting large arteries and large branches of the aorta. Ulcerative colitis (UC) is a prevalent autoimmune colitis. Since TAK and UC share HLA-B*52:01 and IL12B as genetic determinants, and since there are case reports of the co-occurrence of these diseases, we hypothesized that UC is a common complication of TAK. We undertook this study to perform a large-scale analysis of TAK, both to evaluate the prevalence of concurrent cases of TAK and UC and to identify and estimate susceptibility genes shared between the 2 diseases., Methods: We analyzed a total of 470 consecutive patients with TAK from 14 institutions. We characterized patients with TAK and UC by analyzing clinical manifestations and genetic components. Genetic overlapping of TAK and UC was evaluated with the use of UC susceptibility single-nucleotide polymorphisms by comparing risk directions and effect sizes between susceptibility to the 2 diseases., Results: Thirty of 470 patients with TAK had UC (6.4% [95% confidence interval 4.3-9.0]). This percentage was strikingly higher than that expected from the prevalence of UC in Japan. Patients with TAK complicated with UC developed TAK at an earlier stage of life (P = 0.0070) and showed significant enrichment of HLA-B*52:01 compared to TAK patients without UC (P = 1.0 × 10(-5) ) (odds ratio 12.14 [95% confidence interval 2.96-107.23]). The 110 non-HLA markers of susceptibility to UC significantly displayed common risk directions with susceptibility to TAK (P = 0.0054) and showed significant departure of permutation P values from expected P values (P < 1.0 × 10(-10) )., Conclusion: UC is a major complication of TAK. These 2 diseases share a significant proportion of their genetic background, and HLA-B*52:01 may play a central role in their co-occurrence., (© 2015, American College of Rheumatology.)

Takayasu arteritis (TAK) is a relatively rare systemic vasculitis mainly affecting the aorta and its large branches. While patients with TAK are more frequently observed in Asian countries, we can find patients with TAK all over the world. This limited number of patients has made it difficult to collect large numbers of patients and perform detailed studies. However, recent progresses have led to the identification of susceptibility genes and novel susceptibility human leukocyte antigen (HLA) alleles as well as accumulation of clues for the pathophysiology of TAK. IL12B was shown to be a susceptibility gene beyond ethnicity. MLX and FCGR2A/3A were shown to be associated with TAK in Japanese and Turkish/American populations, respectively. HLA-B*52:01 and *67:01 are susceptibility alleles to TAK, and the 171st and 67th amino acid residues of HLA-B protein are suggested important for TAK susceptibility. HLA-DQB1/DRB1 is recently reported as an independent susceptibility locus. Although there are no standardized serum markers or composite measures for disease activity of TAK, Japanese and Italian groups showed pentraxin 3 as a novel biomarker for detecting and monitoring patients with TAK. Recently, an Indian group proposed a novel scoring system called ITAS to evaluate disease activity of TAK. Standardization of assessing disease activity would lead to clinical studies with high quality. Several groups reported results of treatment for refractory TAK with biological agents targeting tumor necrosis factor or interleukin-6R. The recent accumulation of research data should improve understanding of the basic pathophysiology of TAK and lead to better management of patients with TAK., (© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Takayasu arteritis (TAK) is a systemic vasculitis affecting aorta and its large branches which were firstly reported from Japan. TAK develops mainly in young females and the number of patients with TAK in Japan is estimated about 6,000 to 10,000. This low prevalence has made genetic studies of TAK difficult to elucidate its genetic background. The HLA region, especially HLA-B locus, is the strongest susceptibility locus to TAK. The association between TAK and HLA-B*52:01 has been established beyond ethnicity. Recently, two different Japanese research groups identified HLA-B67:01, a relatively rare allele in East Asian population, as a novel susceptibility allele. At the same time, two amino acid variations, namely, histidine at position 171 and phenylalanine at position 67 were reported as susceptibility and protective variations, respectively. Since these positions of amino acid are in the peptide binding grooves of HLA-B protein, changes of peptide-binding in MHC class I seem to play a critical role on susceptibility to TAK. Furthermore, the importance of these two amino acid variations would explain the lack of susceptibility effect of HLA-B*51:01 to TAK, which shares most of amino acid sequences with HLA-B*52:01 except for two amino acids including the position 67.

Objective: Takayasu arteritis (TAK) is a rare autoimmune arteritis that affects large arteries. Although the association between TAK and HLA-B 52:01 is established, the other susceptibility HLA-B alleles are not fully known. We performed genetic association studies to determine independent HLA-B susceptibility alleles other than HLA-B 52:01 and to identify important amino acids of HLA-B protein in TAK susceptibility., Methods: One hundred patients with TAK and 1000 unrelated healthy controls were genotyped for HLA-B alleles in the first set, followed by a replication set containing 73 patients with TAK and 1000 controls to compare the frequencies of HLA-B alleles. Step-up logistic regression analysis was performed to identify susceptibility amino acids of HLA-B protein., Results: Strong associations of susceptibility to TAK with HLA-B 52:01 and HLA-B 67:01 were observed (P = 1.0 × 10(-16) and 9.5 × 10(-6), respectively). An independent susceptibility effect of HLA-B 67:01 from HLA-B 52:01 was also detected (P = 1.8 × 10(-7)). Amino acid residues of histidine at position 171 and phenylalanine at position 67, both of which are located in antigen binding grooves of the HLA-B protein, were associated with TAK susceptibility (P ≤ 3.8 × 10(-5)) with a significant difference from other amino acid variations (ΔAIC ≥ 9.65)., Conclusion: HLA-B 67:01 is associated with TAK independently from HLA-B 52:01. Two amino acids in HLA-B protein are strongly associated with TAK susceptibility.

Takayasu arteritis (TAK) is an autoimmune systemic vasculitis of unknown etiology. Although previous studies have revealed that HLA-B*52:01 has an effect on TAK susceptibility, no other genetic determinants have been established so far. Here, we performed genome scanning of 167 TAK cases and 663 healthy controls via Illumina Infinium Human Exome BeadChip arrays, followed by a replication study consisting of 212 TAK cases and 1,322 controls. As a result, we found that the IL12B region on chromosome 5 (rs6871626, overall p = 1.7 × 10(-13), OR = 1.75, 95% CI 1.42-2.16) and the MLX region on chromosome 17 (rs665268, overall p = 5.2 × 10(-7), OR = 1.50, 95% CI 1.28-1.76) as well as the HLA-B region (rs9263739, a proxy of HLA-B*52:01, overall p = 2.8 × 10(-21), OR = 2.44, 95% CI 2.03-2.93) exhibited significant associations. A significant synergistic effect of rs6871626 and rs9263739 was found with a relative excess risk of 3.45, attributable proportion of 0.58, and synergy index of 3.24 (p ≤ 0.00028) in addition to a suggestive synergistic effect between rs665268 and rs926379 (p ≤ 0.027). We also found that rs6871626 showed a significant association with clinical manifestations of TAK, including increased risk and severity of aortic regurgitation, a representative severe complication of TAK. Detection of these susceptibility loci will provide new insights to the basic mechanisms of TAK pathogenesis. Our findings indicate that IL12B plays a fundamental role on the pathophysiology of TAK in combination with HLA-B(∗)52:01 and that common autoimmune mechanisms underlie the pathology of TAK and other autoimmune disorders such as psoriasis and inflammatory bowel diseases in which IL12B is involved as a genetic predisposing factor., (Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The article talks about treatment of Takayasu arteritis (TAK) with the help of Ustekinumab therapy. Topics include using Glucocorticoids and immunosuppressants and biological agents like tumour necrosis factor (TNF)-α and interleukin (IL)-6 receptors for treating refractory TAK, evaluating patients by gadolinium-enhanced magnetic resonance imaging (MRI) for disease activity, and 6.4 percent TAK patients having ulcerative colitis shows genetic architecture outside human leucocyte antigen (HLA).