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Ankylosing Spondylitis: HLA-B*27-Positive Versus HLA-B*27-Negative Disease

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Abstract

Purpose of review: We review our current knowledge about the clinical features of patients with ankylosing spondylitis (AS) who possess HLA-B*27 versus those who lack this gene. Recent findings: ERAP1 association is present only in HLA-B*27+ patients, but other genetic associations are similar between the two groups. A genetic study supports the existence of an HLA-B27-independent common link between gut inflammation and AS. It is unusual to observe familial occurrence of primary AS among families of northern European extraction that show no segregation of HLA-B*27, psoriasis, or IBD. Although there are many similarities among AS patients possessing HLA-B*27 versus those lacking this gene, the former group has a younger age of onset, a shorter delay in diagnosis, a better clinical response to tumor necrosis factor inhibitors, a greater familial occurrence, a greater risk for occurrence of acute anterior uveitis, and a lower risk for occurrence of psoriasis and IBD. ERAP1 association is present only in HLA-B*27+ patients, but other genetic associations are similar between the two groups. It is unusual to observe occurrence of primary AS among families of northern European extraction that show no segregation of HLA-B*27, IBD, or psoriasis. A recent genetic study supports the existence of an HLA-B*27-independent common link between gut inflammation and AS.
SPONDYLOARTHRITIS (M KHAN, SECTION EDITOR)
Ankylosing Spondylitis: HLA-B*27-Positive
Versus HLA-B*27-Negative Disease
Nurullah Akkoç
1
&Handan Yarkan
2
&Gökçe Kenar
2
&Muhammad A. Khan
3
Published online: 6 April 2017
#Springer Science+Business Media New York 2017
Abstract
Purpose of Review We review our current knowledge about
the clinical features of patients with ankylosing spondylitis
(AS) who possess HLA-B*27 versus those who lack this gene.
Recent Findings ERAP1 association is present only in HLA-
B*27+ patients, but other genetic associations are similar be-
tween the two groups. A genetic study supports the existence
of an HLA-B27-independent common link between gut in-
flammation and AS. It is unusual to observe familial occur-
rence of primary AS among families of northern European
extraction that show no segregation of HLA-B*27, psoriasis,
or IBD.
Summary Although there are many similarities among AS
patients possessing HLA-B*27 versus those lacking this gene,
the former group has a younger age of onset, a shorter delay in
diagnosis, a better clinical response to tumor necrosis factor
inhibitors, a greater familial occurrence, a greater risk for
occurrence of acute anterior uveitis, and a lower risk for oc-
currence of psoriasis and IBD. ERAP1 association is present
only in HLA-B*27+ patients, but other genetic associations
are similar between the two groups. It is unusual to observe
occurrence of primary AS among families of northern
European extraction that show no segregation of HLA-
B*27, IBD, or psoriasis. A recent genetic study supports the
existence of an HLA-B*27-independent common link be-
tween gut inflammation and AS.
Keywords HLA-B27 .HLA-B*27 .Ankylosing
spondylitis .Spondyloarthritis .Clinical features .Uveitis .
Familial occurrence .Psoriasis .Inflammatory bowel disease .
ERAP1 .Genetic susceptibility
Introduction
Ankylosing spondylitis (AS) is the most prominent form of
spondyloarthritis (SpA), with a prevalence that ranges from
0.1 to 1.4% worldwide, and males are affected two to four
times more frequently than females [1], although this ratio is
shrinking in some recent studies [2]. It shows a strong associ-
ation with HLA-B27 (HLA-B*27) [35], first reported in the
journal Nature on March 9, 1973, by Caffrey and James [3]
and later by Schlosstein et al. [4] and Brewerton et al. [5]. In
the British study [3,5], AS was chosen to test the possibility of
links between HLA and human diseases because family stud-
ies had indicated a hereditary component for its occurrence
[5]. HLA-B*27 was found in 72 of 75 (96%) patients with AS
and in three of 75 (4%) matched controls [5]. The same anti-
gen was also present in 31 of 60 (51%) first-degree relatives of
the patients [5,6]. In the American study [4], the actual
targeted disease to show an association with HLA was gout,
and 40 AS patients were serendipitously included to serve as a
This article is part of the Topical Collection on Spondyloarthritis
*Nurullah Akkoç
nurullah.akkoc@gmail.com
Handan Yarkan
drhandanyarkan@gmail.com
Gökçe Kenar
gokcekenar@gmail.com
Muhammad A. Khan
mkhan@metrohealth.org
1
Izmir, Turkey
2
Department of Rheumatology, Faculty of Medicine, Dokuz Eylul
University, Balcova, 35340 Izmir, Turkey
3
MetroHealth Medical Center, Case Western Reserve University,
2500 MetroHealth Drive, Cleveland, OH 44109, USA
Curr Rheumatol Rep (2017) 19: 26
DOI 10.1007/s11926-017-0654-8
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... However, only a minority of HLA-B*27 carriers develop the disease (1-5%) [1] and individuals who lack the HLA-B*27 alleles also develop SpA. In addition, other non-HLA genes have been associated with the risk of SpA [3,4]. The mechanism by which the HLA-B27 is predisposed to spondyloarthritis remains unresolved [4] and arthritogenic peptides have not been defined in humans and are not involved in experimental models of spondyloarthritis [5]. ...
... In addition, other non-HLA genes have been associated with the risk of SpA [3,4]. The mechanism by which the HLA-B27 is predisposed to spondyloarthritis remains unresolved [4] and arthritogenic peptides have not been defined in humans and are not involved in experimental models of spondyloarthritis [5]. The pathogenesis theories for SpA include, in addition to the biochemical properties of HLA-B27, the production of tumor necrosis factor-α (TNFα), interleukin-17 (IL-17), IL-23 and interferon-γ [5][6][7][8]. ...
... Vitamin D deficiency is a predisposing factor for SpA [4,45], and has been associated with increased activity of axial disease in spondyloarthritis [46,47] and with more prominent symptoms, such as pain inflammation and structural damage due to less bone activity [9,48,49]. Thus, considering the vitamin D sufficiency and the clinical activity of the disease, we investigate if IL17, TNF and VDR polymorphisms were associated to SpA. ...
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HLA-B*27 is an important marker for spondyloarthritis (SpA), however, many SpA patients are HLA-B*27 negative. Thus, the aim of this study was to investigate the influence of IL17, TNF and VDR gene polymorphisms in SpA patients who were HLA-B*27 negative. This case-control study was conducted in 158 patients [102 patients with ankylosing spondylitis (AS) and 56 with psoriatic arthritis (PsA)] and 184 controls. HLA-B*27 genotyping was performed using PCR-SSP and IL17A (rs2275913), IL17F (rs763780), TNF-308 (rs1800629), TNF-238 (rs361525), FokI C>T (rs2228570), TaqI C>T (rs731236), ApaI A>C (rs7975232), and BsmI C>T (rs1544410) using PCR-RFLP. Statistical analyses were performed by Chi-square and logistic regression using OpenEpi and SNPStats software. The IL17F C allele frequency was higher in patients with SpA, AS and PsA compared to controls. The IL17F T/C genotype frequency was higher in SpA patients in an overdominant inheritance model and when men and women were separately analyzed. IL17A_IL17F AC haplotype was significantly associated to the risk for SpA patients. As for VDR, the ApaI a/a was a potential risk factor for SpA in men. In conclusion, IL17F C variant contributed to the risk of SpA in Brazilian patients who were HLA-B*27 negative and could be a potential marker for SpA.
... [2] AS hastalarında HLA-B27'nin kliniğe etkisi üzerine yapılan daha önceki çalışmalarda erken başlangıç, erken tanı, aile öyküsü, artmış akut anterior üveit, kardiyak tutulum, ileri evre sakroiliit sıklığı, hastalık süresinde uzama ve hastalık progresyonu ile ilişkisi olabileceğine dair veriler elde edilmiştir. [4] Bu çalışmada amacımız; HLA-B27 negatif AS hastalarının klinik, laboratuvar verileri, radyolojik özellikleri ve tedavilerinin nasıl olduğunu değerlendirmek ve HLA-B27 pozitif AS hastaları ile karşılaştırmaktı. ...
... Literatürdeki birçok çalışmada, HLA-B27 negatif AS hastaları daha geç tanı yaşı ile ilişkilendirilmiştir. [4,14,15] Çalışmamızda, HLA-B27 negatif hasta grubunda semptomların başlama yaşı daha geç olsa da bu fark istatistiksel olarak anlamlı değildi. Yang ve ark.'nın [12] çalışmasında da, bizim çalışmamızdaki gibi, HLA-B27 pozitif hastalarda daha genç başlangıç yaşı görülse de, bu fark istatistiksel olarak anlamlı değildi. ...
... HLA-B27 negatif AS hastalarında tanı gecikmesinin daha uzun olduğu çalışmalar mevcuttur. [4,11,14,17] Ancak bizim gibi tanıda gecikme süresi ile HLA-B27 arasında ilişki saptayamamış başka çalışmalar da bulunmaktadır. [8,14,16] HLA-B27 pozitif bireylerde aile öyküsü daha sık Çalışmamızda, literatürde yer alan çalışmalara benzer şekilde üveit insidansı belirgin olarak HLA-B27 pozitif grupta fazlaydı. ...
... Ankylosing spondylitis (AS) is an immune-mediated chronic inflammatory condition grouped under spondyloarthritis (SpA) with a prevalence of 0.1% to 1.4% worldwide, and males are affected more frequently than females [1,2]. Spondyloarthritis (SpA) is an umbrella term for a group of interrelated inflammatory rheumatic conditions that include sacroiliitis, spondylitis, peripheral arthritis, enthesitis, dactylitis, acute anterior uveitis, associated psoriasis or inflammatory bowel disease, presence of HLA-B27, and no association with rheumatoid factor [3]. ...
... HLA is strongly associated with the disease, and >80% of patients with AS are positive for HLA B27. Routine HLA testing is not clinically helpful because AS can occur in the absence of the HLA B27, as in the present case [2,33,34]. Further, only 1-5% of HLA-B27-positive individuals develop AS. Therefore, it is likely that there exists a combination of mechanisms involved in the disease pathogenesis [35]. ...
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BACKGROUND Ankylosing spondylitis (AS) is an immune-mediated chronic inflammatory condition grouped under spondyloarthritis (SpA), which is an umbrella term for a group of interrelated inflammatory rheumatic conditions with characteristic radiographic findings such as erosions and ankylosis of the sacroiliac joint. Unfortunately, there is an average delay of 8-9 years between the onset of the symptoms and diagnosis due to infrequent consideration of this disease in the differential diagnosis of patients with low back pain and unusual or incomplete presenting clinical symptoms. CASE REPORT We describe the case of a 37-year-old male patient with no significant past medical history and surgical history of bilateral hip arthroplasty secondary to idiopathic aseptic necrosis of the bilateral femoral head and bilateral rotator cuff repaired surgery due to multiple motor vehicle accidents (MVA) with a chief concern of chronic low back pain. In this case of ankylosing spondylitis presenting with low back pain and radicular symptoms, his symptoms were resistant to multiple opioid medications, trigger point injections, and epidural steroid injections. Initiation of adalimumab subsequently relieved the patient's symptoms and restored his ability to perform daily activities. CONCLUSIONS This is an unusual presentation of AS with radiographic evidence of bilateral sacroiliitis. The neurological manifestations in AS are not uncommon, and they can occur during the quiescent stage of the disease. It should be emphasized that early diagnosis is essential to prevent progression of the disease and avoid unnecessary treatment for the patient.
... [28][29][30] In line with a review by Akkoç et al., the ankylosing spondylitis (AS) patients with negative HLA-B*27 showed less correlation with psoriasis and inflammatory bowel disease. 31 Although there are no studies on the association of HLA-C with the severity of SpA, the correlation of HLA-C with SpA-related diseases, especially psoriasis, has been widely discussed. On the other hand, the relation of HLA-K with SpA has never been reported in any studies. ...
Article
Full-text available
Background: Spondyloarthritis (SpA) is a chronic inflammatory disease characterized by enthesitis, sacroiliitis, and axial joint involvement. Although the association of HLA with SpA has been widely reported, there have been no studies of HLA type in the Indonesian population within the last 20 years. This study aims to identify the HLA type in SpA patients at Dr. Soetomo General Hospital, Indonesia. Methods: This study used a cross-sectional analytical design with samples that met the criteria for SpA according to the 2009 ASAS. The clinical scores used in this study were mSASSS, BASFI, ASDAS, and Schober. Genetic identification using PCR was performed followed by sanger sequencing to determine the HLA type in the patient. DNA sequences were aligned with BLAST, and a phylogenetic tree was created using MEGA 11. Descriptive and comparative analyzes were performed using GraphPad Prism 9.
... Molecular mechanisms leading to the classification of gout as an autoinflammatory disease have been described; notably, hyperuricemia alone is not sufficient to induce gout, which suggests that there are more inflammatory and genetic elements that contribute to the disease [16]. One autoimmune and autoinflammatory disease is ankylosing spondylitis (AS), which has a strong genetic predisposition linked to HLA-B*27 [17]. Interestingly, there is clinical evidence where gout and AS coexist at the same time [18][19][20][21], which could suggest the existence of some common mechanism that links them. ...
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BackgroundHLA and NLRP3 play an important role in the development of various autoimmune and autoinflammatory diseases. Gout is an autoinflammatory disease associated with multiple genetic and environmental factors. The objective of the present study was to evaluate the interaction and association between genetic polymorphisms of HLA-B and the NLRP3 gene in Mexican patients with gout.Methods and resultsEighty-one patients with gout were included and compared with 95 healthy subjects. The polymorphisms rs4349859, rs116488202, rs2734583 and rs3099844 (within the HLA-B region) and rs3806268 and rs10754558 of the NLRP3 gene were genotyped using TaqMan probes in a Rotor-Gene device. The interactions were determined using the multifactorial dimensionality reduction (MDR) method, while the associations were determined through logistic regression models. The MDR analysis revealed significant interactions between the rs116488202 and rs10754558 polymorphisms with an entropy value of 4.31% (p < 0.0001). Significant risk associations were observed with rs4349859 and rs116488202 polymorphisms (p < 0.01); however, no significant associations were observed with the polymorphisms of the NLRP3 gene.Conclusions The results suggest that HLA-B polymorphisms and their interaction with NLRP3 may contribute to the genetic susceptibility of gout.
... Ayrıca aile öyküsünün kadınlarda erkeklere kıyasla anlamlı derecede daha fazla olduğunu raporlamışlardır [8]. İki Avrupa kohortunda yapılan çalışmada, ailede AS öyküsü HLA-B27 ile ilişkilendirilmiştir [18,19]. HLA-B27 ile aile ilişkisi derecesinin incelendiği ASAS kohortunda yapılan bir çalışmada, ailede AS öyküsü, hem beyaz hem Asyalı hastalarda, hem birinci hem de ikinci derece akrabalarda HLA-B27 taşıyıcılığı ile güçlü bir şekilde ilişkilendirilmiştir [20]. ...
... The association of ERPA1 polymorphisms with AS is controversial. Interestingly, it has been described that ERAP1 is only associated in B27 positive patients [16,30], but the studies conducted have been limited mainly to patients with European origins [19,31,32]. Nonetheless, Hemmatzadeh et al., evaluated three polymorphisms of ERAP1 in the Iranian population, and they observed that only the rs2703 showed a significant association in B27 positive patients [33]. ...
Article
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Background Ankylosing spondylitis (AS) is a type of inflammatory arthritis that affects primarily the spine. There is a strong association of the HLA-B*27 allele with AS pathogenesis, but recent studies have demonstrated the participation of ERAP1 gene in the genetic susceptibility. The aim of this study was to determine whether HLA-B tag-single nucleotide polymorphisms (SNPs) and ERAP1-related genetic variations associated with AS have equal or similarly performance in patients´ screening compared to HLA-B*27 standard genotyping in Mexican population. Methods and Results Genomic DNA from patients with AS and population-based controls from Mexico City was analyzed for five single nucleotide polymorphisms (SNPs): rs4349859, rs13202464, rs116488202, tagging HLA-B*27; and rs30187 and rs27044 in ERAP1 gene. TaqMan genotype assay method was used for SNPs genotyping. We found a significant association between AS and the heterozygote genotypes and minor alleles of the HLA-B*27 tag-SNPs, as well as for their haplotypes. With respect to ERAP1 polymorphisms, no significant associations were observed (p > 0.05). The sensitivity and specificity analysis showed values of 0.96 and 1.00 for the rs4349859 SNP, and 0.96 and 0.94 for the rs116488202 SNP, respectively, in detecting HLA-B*27 compared to the B27 test as the gold standard. Conclusions HLA-B*27 tag-SNPs are associated with AS susceptibility; furthermore, the rs4349859 SNP by its own have an outstanding performance in detecting HLA-B*27 and therefore can be proposed as screening marker in the identification of HLA-B*27 in our population.
... Strong evidence supports that it is an independent risk gene for the pathogenesis of AS/SpA and that it is the strongest among all known HLAs [34]. There is evidence to show that HLA-B27 and IBD have a strong correlation, but whether there is a difference between the prevalence of HLA-B27-positive and HLA-B27-negative patients is still unclear [35] [36]. In a large-scale study, in 908 HLA-B27-positive and 90 HLA-B27-negative patients with AS, the relationship between HLA-B27 and IBD in patients with AS was analyzed [37]; 9% and 20% of the patients had IBD. ...
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IntroductionThis study aimed to determine the association between extra-articular manifestations (EAMs) and baseline characteristics of patients with ankylosing spondylitis (AS) and identify their potential risk factors in an observational cohort.Methods We analyzed the data of consecutive patients with AS obtained between April 2016 and May 2019 from the ongoing Chinese Ankylosing Spondylitis Prospective Imaging Cohort.ResultsAmong the 1414 patients with AS, 23.1% had experienced EAMs at baseline. The prevalence rates of acute anterior uveitis (AAU), inflammatory bowel disease, and psoriasis among patients with AS were 16.7, 6.9, and 2.6%, respectively, and the prevalence of AAU increased significantly with the disease duration. Patients with comorbidity of AAU and psoriasis had Ankylosing Spondylitis Disease Activity Score (ASDAS) than patients without EAMs (2.16 ± 0.984 vs. 1.99 ± 0.956 [p = 0.025] and 2.36 ± 1.01 vs. 1.99 ± 0.96 [p = 0.025]). Among the 1087 patients with AS without EAMs at baseline, 98 developed EAMs during follow-up. Long disease duration (> 10 years) and high disease activity at baseline (ASDAS > 2.1) were associated with the risk of new-onset EAMs (hazard ratio [HR] [95% confidence interval, CI], 2.150 [1.229–3.762] and 2.896 [1.509–5.561], respectively) and new-onset AAU (HR [95% CI], 2.197 [1.325–3.642] and 3.717 [1.611–8.574], respectively).Conclusions In Chinese patients with AS, patients with comorbidity of AAU and psoriasis had higher disease activity scores than patients without EAMs. Furthermore, the risk of AAU or combined EAMs increases with the duration of AS and appears to be associated with higher cumulative exposure to inflammation.
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Possession of the human leukocyte antigen (HLA) class I molecule B27 is strongly associated with ankylosing spondylitis (AS), but the pathogenic role of HLA-B27 is unknown. Two broad theories most likely explain the role of HLA-B27 in AS pathogenesis. The first is based on the natural immunological function of HLA-B27 of presenting antigenic peptides to cytotoxic T cells. Thus, HLA-B27-restricted immune responses to self-antigens, or arthritogenic peptides, might drive immunopathology. B27 can also "behave badly," misfolding during assembly and leading to endoplasmic reticulum stress and autophagy responses. β2m-free B27 heavy chain structures including homodimers (B272) can also be expressed at the cell surface following endosomal recycling of cell surface heterotrimers. Cell surface free heavy chains and B272 bind to innate immune receptors on T, NK, and myeloid cells with proinflammatory effects. This review describes the natural function of HLA-B27, its disease associations, and the current theories as to its pathogenic role.
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Investigate the role and relation of disease duration of different factors for achieving clinical remission with anti-tumor necrosis factor (TNF) treatment in patients with active ankylosing spondylitis (AS). Data pooled from 4 large (n = 1281) clinical trials were used to compare disease duration subgroups for placebo or sulfasalazine (SSZ) versus etanercept (ETN), which, in turn, were analyzed by age of diagnosis ≤ 40 versus > 40 years, HLA-B27 status, and baseline C-reactive protein (CRP) ≤ upper limit of normal (ULN) versus > ULN using chi-square tests, and ANCOVA. The primary efficacy measure was Assessments of SpondyloArthritis international Society (ASAS) partial remission (PR) after 12 weeks of treatment. Also analyzed were Bath AS Disease Activity Index and Functional Index, AS Disease Activity Scores, and ASAS response rates. Overall, a larger percentage of patients achieved ASAS-PR with ETN versus SSZ or placebo. More patients with ≤ 2-year disease duration treated with ETN experienced partial remission (34%) versus longer disease duration (30%, 27%, and 22% for > 2-5, > 5-10, and > 10 yrs, respectively; all p < 0.05). In the subgroup of patients with both disease duration ≤ 2 years and aged ≤ 40 years at diagnosis, the treatment response was even more pronounced. Similar results were seen in HLA-B27-positive patients in the disease duration ≤ 2-year subgroup. Overall, patients with high CRP at baseline had better treatment responses compared with patients with normal CRP. Treatment response under anti-TNF treatment with ETN at 12 weeks was greatest among patients with disease duration ≤ 2 years and even more pronounced in subgroups of patients ≤ 40 years old or HLA-B27-positive at diagnosis.