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/lp/ou_press/the-clinical-utility-of-human-leucocyte-antigen-b27-in-axial-I9z2gaPJhu
- Publisher
- Oxford University Press
- Copyright
- © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
- ISSN
- 1462-0324
- eISSN
- 1462-0332
- DOI
- 10.1093/rheumatology/kex345
- pmid
- 29029331
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- See Article on Publisher Site
Abstract
Abstract The association between HLA-B27 and AS was first established in the early 1970s. Since then, our understanding of this disease has changed, such that we now recognize AS to be the extreme of the clinical phenotype within a disease spectrum known as axial SpA (axSpA). Recent advances in therapeutic options have driven the need for earlier diagnosis and many screening strategies have been proposed to facilitate this. In parallel, our understanding of axSpA genetics, and especially the contribution of HLA-B27, has expanded. In this article we will present and discuss the evidence supporting the use of HLA-B27 in clinical practice. We will briefly summarize the evolution of the concept of axSpA, the prevalence of HLA-B27 and axSpA and the potential role of HLA-B27 in the aetiopathogenesis of axSpA and focus on the utility of HLA-B27 in everyday clinical practice. clinical utility, HLA-B27, human leucocyte antigen, axial spondyloarthritis, ankylosing spondylitis, spondyloarthropathy, seronegative spondyloarthritis, axSpA, AS Rheumatology key messages HLA-B27 facilitates the diagnosis of axial SpA and plays a pivotal role in referral strategies from primary and secondary care. HLA-B27 is an adjunct to the diagnosis of axial SpA and an obligatory parameter for axial SpA classification. HLA-B27 may be used in combination with other biomarkers to predict treatment response and prognosis. Evolution of the concept of axial SpA SpA traditionally consists of a group of previously defined related forms of inflammatory arthritis that includes AS, PsA, arthritis and spondylitis associated with IBD and ReA, encompassed by the ESSG classification criteria [1, 2]. The spectrum of axial SpA (axSpA), defined by the Assessment of Spondyloarthritis international Society (ASAS) includes non-radiographic axSpA (nr-axSpA) and AS [3, 4]. Patients can be classified as nr-axSpA according to either the imaging or clinical arm of these criteria; with HLA-B27 being a pivotal component of the clinical arm. Recent advances in MRI have enabled earlier diagnosis through the identification of bone marrow oedema prior to the development of structural changes on X-rays. Although a portion of patients with nr-axSpA will develop AS over time, this is not inevitable [5–8]. Prevalence of HLA-B27 and subtypes in AS and axSpA The prevalence of HLA-B27 varies within different continents and ethnic/racial populations. The prevalence of SpA, axSpA and AS generally mirrors the frequency of HLA-B27, with a few notable exceptions, for example, AS is uncommon (nearly absent) in some ethnic groups in West Africa, despite HLA-B27 prevalence rates being similar to those of European populations at 2–9%; however, in African Americans the prevalence of AS is higher than in Africa even though HLA-B27 prevalence rates are similar and only 50% of cases are HLA-B27 positive. This suggests that environmental factors may be contributing to disease aetiopathogenesis. There is also varied prevalences of HLA-B27 in subgroups of SpA (psoriatic spondyloarthritis, IBD-associated spondyloarthritis, ReA and uSpA). The varying prevalence may partly be as a result of different methodologies in individual prevalence studies, the main variance being case definition and sample selection. Even if biases for the methodological approaches are accounted for, the different axSpA prevalence rates observed in different populations continue to suggest different strengths of association with HLA-B27 [5, 9–11]. Different HLA-B27 subtypes have also been described, which may confer an AS causative association (of varying degrees) or AS protection, depending on the population in which the subtypes are present. In most populations, the determination of HLA-B27 subtype is of no importance in an individual, as the most common subtypes (HLA-B-27*02–27*05, 27*07, 27*08 and 27*10) are disease associated in European and Asian populations. However, there are exceptions: AS prevalence is disproportionately low compared with the prevalence of HLA-B27 in Sardinia, Italy and in some Southeast Asian populations, which may be explained by disease non-associated HLA-B27 subtype: HLA-B27*09 in Sardinia and HLA-B27*06 in southeast Asia [9–14]. The worldwide estimated prevalence of HLA-B27 ranges from 0.5 to 50%, SpA prevalence from 0.4 to 1.9% and AS prevalence from 0 to 20% [13, 15–17]. Using the ESSG definition for SpA, the prevalence rate is between 0.01 and 2.5%, whereas according to the Modified New York Criteria (mNYC) definition of AS, it is between 0.007 and 1.7% [18]. A recent systematic literature review estimated AS prevalence rates of 0.24% in Europe, 0.17% in Asia, 0.32% in North America, 0.10% in Latin America and 0.07% in Africa [19]. Hamilton et al. [20] recently estimated the prevalence of axSpA in a UK primary care population as 1.2% (ESSG), 0.3% (ASAS criteria) and 0.15% (mNYC criteria). HLA-B27 and genetics, aetiopathogenesis and pathogenic mechanism in AS and axSpA AS is known to have a heritability of >90%. Aggregated family studies have shown that the recurrent risk ratio (ratio of disease in family members compared with the general population) in first-degree relatives of AS patients is 52–94 times that of unrelated subjects [11, 21]. The recurrent risk (risk that another relative will develop AS) decreases with increasing familial separation; the recurrent risk is 63% in monozygotic twins, decreasing to between 7.9 and 8.2% in first-degree relatives (siblings and parent–child), 1.0% in second-degree relatives and 0.7% in third-degree relatives [21]. In addition, risk calculations have shown that the risk of developing AS is ∼16-fold higher in HLA-B27-positive first-degree relatives compared with HLA-B27 carriers [22, 23]. The discovery of an association between HLA-B27 and AS in the 1970s [24, 25] led to a number of hypotheses about the pathogenic mechanisms of HLA-B27. There are four main hypotheses: (i) The arthritogenic peptide hypothesis suggests that self-peptides are presented by HLA-B27, which then become the target of immune cells (CD8+ T cells), because they look like peptides from bacteria or viruses, resulting in joint inflammation (now thought to be due to aberrant peptide presentation rather than presentation of a pathogenic peptide that might account for the influence of HLA-B27 molecules). (ii) The HLA-B27 homodimers hypothesis suggests that cell surface HLA-B27 can form homodimers, which then bind to the immunoregulatory receptors of other cells, leading to downstream activation that could play a role in the development of AS. (iii) The HLA-B27 misfolding hypothesis suggests that accumulation of misfolded HLA-B27 in the endoplasmic reticulum during protein processing produces an inflammatory response. (iv) The enhanced intracellular microbial survival hypothesis suggests that the ineffective loading of pathogens by HLA-B27 leads to poor elimination of certain bacteria or viruses, causing prolonged abnormal immune system activation, which leads to disease. All of these mechanisms have a role in disease predisposition but no single one can entirely explain the relationship [12, 26, 27]. Recent twin studies have shown that the concordance rate in monozygotic twins (63%) is substantially higher than in dizygotic twins (12.5%), even when dizygotic twins are concordant for HLA-B27 (27%). This suggests that the development of AS is largely genetically determined and that environmental triggers for disease are probably ubiquitous and contribute little to the population variance. It has been estimated the genetic variance is 97%, leaving little role for either dominance genetic or random environmental effects in susceptibility to AS [28]. In family studies, recurrence risk modelling of genetic susceptibility to AS suggests that the AS model is oligogenic, with multiplicative interaction between loci [21]. These findings have encouraged research aimed at identifying the genes involved in AS. Technological improvements in high-throughput genotyping of single nucleotide polymorphisms have paved the way for discoveries in genomewide association studies, which identified multiple further genetic associations such as HLA-B60, IL-23R, ERAP1, ND/2p15 and KIF21B in decreasing order of genetic variance. It has also been suggested that AS, psoriasis and IBD share similar common pathogenic mechanisms of aberrant intracellular antigen processing or elimination of intracellular bacteria and cytokine production, especially in the IL-17/IL-23 pathway [11, 26]. Although AS is highly heritable, HLA-B27 accounts for only ∼25% of the overall contribution to AS heritability [26]. The emerging evidence from genomewide association studies supports the concept that axSpA is a disease with a spectrum of clinical phenotypes. The aetiopathogenesis may be due to a background ubiquitous environmental trigger such as gut flora or infection with a common heritable genetic inflammatory pathway common to both psoriasis and IBD. The final clinical phenotype, including severity of disease and progression to ankylosis, may depend on the cumulative additive genetic component (be it inherited or acquired) of an individual. This may well explain HLA-B27-negative disease, radiographic vs non-radiographic disease and radiographic progression in patients with axSpA [9, 26, 29, 30]. The clinical utility of HLA-B27 HLA-B27 is intimately related to the axSpA spectrum. There are many different proposals for the clinical utility of HLA-B27 in AS and axSpA in the literature. We will present and discuss evidence for HLA-B27 use in different clinical settings, including risk assessment, screening, diagnosis, treatment and prognosis. The influence of HLA-B27 on mode of presentation HLA-B27 status predicts similar characteristics in both early and established AS groups. In an early axSpA cohort study that included patients with inflammatory back pain (IBP) who fulfilled any of the axSpA classification criteria (mNYC, ESSG, Amor or ASAS axSpA), HLA-B27 positivity was associated with earlier-onset IBP and shorter delay to diagnosis [31]. In the established AS group, a member survey has shown that HLA-B27-positive AS patients have earlier age of disease onset (24.8 years for B27-positive vs 27.7 years for B27-negative AS; P < 0.01), are diagnosed earlier (33.2 years for B27-positive vs 39.1 years for B27-negative AS; P < 0.001) and have a shorter delay to diagnosis (8.5 years for B27-positive vs 11.4 years for B27-negative AS; P < 0.01) [32]. A Canadian cohort [7], including pooled data from three other cohorts (local, national and worldwide), has shown that the prevalence of HLA-B27 is similar in nr-axSpA and AS: 72.5–86.4% in nr-axSpA and 78.9–89.1% in AS [33]. HLA-B27 positivity determined the age at disease onset regardless of gender in both nr-axSpA and AS. The mean age at onset was significantly lower in HLA-B27-positive AS patients [28.9 (s.d. 9.7) vs 37.4 (s.d. 11.7) years; P < 0.001]. Among patients with nr-axSpA, the mean age at disease onset was significantly lower in HLA-B27-positive patients [31.6 (s.d. 10.0) vs 37.7 (s.d. 10.6 ) years; P < 0.001] [34]. These data indicate that HLA-B27-positive patients have earlier disease onset and are also diagnosed earlier. There is a need to improve axSpA recognition in HLA-B27-negative patients, perhaps through general practitioner education or the development of other diagnostic biomarkers. However, it is important to note that the threshold (physician’s judgement) for diagnosis needs to be raised in patients who are HLA-B27 negative, to reduce the possibility of a false positive axSpA diagnosis (considered further in the ‘Diagnosis and classification’ section). Extra-articular manifestations Extra-articular manifestations (EAMs), including acute anterior uveitis (AAU), IBD and psoriasis, are commonly associated with axSpA, with reported prevalences of 16–26% (AAU), 10–11% (psoriasis) and 4–7% (IBD) [35, 36]. The risk of developing AAU, psoriasis and IBD in patients with AS compared with the general population is increased by 16-fold, 1.5-fold and 3.3-fold, respectively. The risk for AAU remains throughout the course of the disease, whereas the excessive risk for psoriasis and IBD decreases after the first year following diagnosis. Stolwijk et al. [37] showed that EAMs are often present before the diagnosis of AS: 12% had a diagnosis of AAU, 5% psoriasis and 4% IBD at diagnosis, and 20 years later these percentages doubled to 25, 10 and 7.5%, respectively [38]. As the known estimated positive likelihood ratios for each EAM are 7.3 for AAU, 2.5 for psoriasis and 4.0 for IBD, this information together with HLA-B27 status may serve as an adjunct to clinical assessment that may lead to earlier diagnosis [39, 40]. AAU SpA patients who are HLA-B27 positive have 2.6–4.2 times the risk of developing AAU. In population studies, the estimated prevalence of AAU is 1% in HLA-B27-positive individuals [41–45], however, the prevalence of HLA-B27 in patients presenting with AAU is ∼50% [42]. It is known that the prevalence of AAU in axSpA patients is ∼30%. However, in HLA-B27-positive patients this may be as high as 40% [43]. In an AS survey, HLA-B27-positive subjects have an AAU prevalence of 41% vs 26% in HLA-B27-negative subjects (P < 0.01) [32]. Zeboulon et al. [43] also demonstrated a higher prevalence of AAU in HLA-B27-positive subjects: 39.8 vs 13.6% if HLA-B27 negative [odds ratio (OR) 4.2 (95% CI 3.3, 5.3); P < 0.001]. A prospective multicentre French cohort with early IBP suggestive of SpA showed that there was a positive association between AAU and HLA-B27 positivity on multivariate analysis [OR 2.63 (95% CI 1.28, 5.39); P = 0.01] [44]. In a cross-sectional observational survey, being HLA-B27 positive was an independent association for AAU [adjusted OR 2.97 (95% CI 1.83, 4.81); P < 0.0001] in patients attending a rheumatologist’s office for routine SpA medical follow-up [45]. In an attempt to address the prevalence of SpA in AAU patients, studies have shown that in AAU patients who are HLA-B27 positive, between 35 and 66% will have SpA. This is compared with between 3.8 and 6% who are HLA-B27 negative [42, 46]. Two recent papers have explored this in detail. Haroon et al. [42] report that in a cohort of patients presenting with AAU to an eye emergency department, the prevalence of newly diagnosed SpA (using ASAS classification criteria) is ∼40% (of which 90.5% are HLA-B27 positive). In a large multicentre observational prospective study of 798 patients, Juanola et al. [47] recently reported that 41% of patients presenting with more than one episode of AAU (separated by at least 3 months) had axSpA according to ASAS criteria. Educating rheumatologists and ophthalmologists on the association between AAU, HLA-B27 and axSpA is important, as recognizing chronic back pain among patients presenting with AAU may shorten the delay to diagnosis and ultimately improve patient outcome. IBD The estimated prevalence of IBD in AS patients ranges from 3 to 10% [35, 36, 48–50], with a corresponding HLA-B27 prevalence of between 25 and 78% [48, 51–53]. The prevalence of subclinical gastrointestinal inflammation (evident from ileocolonscopic and histological studies of patients without overt clinical manifestation) in AS is reported to between 25 and 69% [48, 54–58], with HLA-B27 prevalence of between 35 and 95% [54–58]. However, there is no evidence to indicate an increased risk of developing IBD or subclinical IBD in AS patients who are HLA-B27 positive. On the other hand, the estimated prevalence of AS in IBD ranges from 1 to 25% [48, 59–61]. The pooled prevalence has recently been calculated as 3% (95% CI 2, 4) [62], and between 25 and 100% are HLA-B27 positive [48, 63–70]. Subclinical sacroiliitis is prevalent in IBD patients, ranging from 1 to 45% [48, 59–61], with a recent calculated pool prevalence of 10% (95% CI 8, 12) [62], and between 0 and 52% are HLA-B27 positive [48, 63–65, 68–70]. Data extracted from these studies show that there is an increasing trend of HLA-B27 prevalence, ranging from 9.6% in IBP, to 40% in radiographic sacroiliitis, to 73% in AS [63]. In patients with Crohn’s disease who have chronic back pain, there is a crude OR of 18 (95% CI 2.1, 151) for axSpA (AS or radiographic sacroiliitis) [64]. A Norwegian study showed that the crude OR of having a diagnosis of AS was 21.6 (95% CI 6.5, 71.1) in patients with a 6 year diagnosis of IBD [63], whereas a smaller Belgian study showed a crude OR of 15 (95% CI 2.4, 90.8) for AS in patients with Crohn’s disease if they are HLA-B27 positive [65]. The strong association between AS and HLA-B27 in IBD is not a consistent finding. However, the association with HLA-B27 is higher than in the general population, yet somewhat lower than in AS without associated IBD. This suggests that being HLA-B27 positive can predispose to the development of sacroiliitis or AS in this population [48]. Based on these data, we recommend that HLA-B27 be tested in patients with IBD who report axial symptoms. On the other hand, given the fact that there is no relationship between HLA-B27 and the presence of IBD in AS patients, the possibility of detecting IBD in axSpA patients may warrant alternative approaches, such as the utilization of other biomarkers [71–73] after undertaking a thorough clinical assessment for the presence of gastrointestinal symptoms. Psoriasis The prevalence of HLA-B27 in AS patients with associated psoriasis is ∼80% in established AS [74] and ∼53% [75] in an early SpA cohort. In the cohort with established AS, HLA-B27 positivity had a crude OR of 0.42 (95% CI 0.13, 1.38) for having psoriasis, while in the early SpA cohort the crude OR was 0.78 (95% CI 0.52, 1.16) [74, 75]. In a multivariate analysis of the early SpA cohort, psoriasis was found to be associated negatively with HLA-B27 [OR 0.59 (95% CI 0.39, 0.90); P = 0.01] [31], suggesting that there is a 22–58% reduction in the odds of having psoriasis in HLA-B27-positive axSpA patients. On the other hand, there is a trend for increasing prevalence of HLA-B27 in psoriasis, PsA and axial PsA/psoriatic SpA (axPsA/psSpA) at 5, 20 [76] and 23.4–34.3% [77–79], respectively. Although the debate over the definition of psoriatic axial disease and AS with associated psoriasis continues, a recent comprehensive review by Queiro et al. [76] suggested that HLA-B27 is a genetic biomarker of joint disease in psoriasis patients. In addition, the review also reports that HLA-B27 is a marker for disease expression in PsA with a shorter interval between onset of skin disease and musculoskeletal symptoms, increased risk of enthesitis, dactylitis and uveitis and a tendency to develop peripheral and axial joint damage over time [76, 79–81]. The above paragraph and evidence from a later section (‘HLA-B27 and imaging’) suggest that HLA-B27 may also be a marker of more severe radiographic disease and progression in AS patients, making it possible to postulate that HLA-B27 is a marker associated with more severe axial bone-forming phenotypes of the SpA disease spectrum (AS and axPsA/psSpA) rather than a simple association with a distinct disease phenotype (axSpA or PsA). HLA-B27 and referral strategies Primary care referral strategies The first proof-of-concept study (which confirmed that there may be an effective referral strategy for axSpA) showed that 45.4% of patients referred from primary care (50.3% classified as AS according to the mNYC and 49.7% diagnosed as pre-radiographic axSpA) who presented with chronic back pain for >3 months, onset at <45 years old and at least one more referral criteria (HLA-B27, sacroiliitis on imaging, IBP) were diagnosed with definite axSpA [82]. The study also confirmed the superiority of HLA-B27 testing over IBP with regards to the diagnostic yield: 1 in 3.7 for IBP and 1 in 2.1 for HLA-B27 [6]. Any combination of screening criteria with HLA-B27 also increased the number of diagnoses: HLA-B27 and sacroiliitis (84.8%), HLA-B27 and IBP (57.9%), IBP and sacroiliitis (38.5%) [82]. The Multicentre AS Survey Trial to Evaluate and Compare Referral Parameters in Early SpA compared two referral strategies, both of which included HLA-B27. Both strategies showed similar diagnostic rates: Strategy 1 (at least one of the following: IBP, HLA-B27 positivity, sacroiliitis detected by imaging), 41.8% (95% CI 36.5, 47.3) and Strategy 2 (at least two of the following: IBP, HLA-B27 positivity, sacroiliitis detected by imaging, positive family history of AS, good response to NSAIDs), 36.8% (95% CI 31.0, 43.0) diagnosed with definite axSpA. The difference in the proportion of patients with axSpA between Strategies 1 and 2 was 5% (95% CI 3.1, 13.1) [83]. IBP (76.7%) was the most common variable used for referral in both strategies, followed by sacroiliitis on imaging (55.7%) and positive HLA-B27 (44.7%). HLA-B27 (either alone or in combination with other criteria) was the best performing parameter for a final diagnosis of axSpA (57.7%), followed by sacroiliitis on imaging (50.3%) and IBP (41.8%) [6, 84]. In addition, using HLA-B27 alone as a referral criterion was less successful than a multistrategy approach (38% fewer patients diagnosed) [84]. In the Recognising and Diagnosing Ankylosing Spondylitis Reliably study, the positive likelihood ratio (LR) for a definite clinical diagnosis (rheumatologist expert opinion) of axSpA was 3.3 (sensitivity 66.1%) if HLA-B27 positivity was used as a single referral parameter. When using a two-of-two criteria for referral, assuming HLA-B27 is a mandated criterion together with one other criterion (sacroiliitis on imaging, known extra-articular manifestation, response to NSAIDs, IBP), the positive LR was between 4.8 and 67.2, compared with an LR of 3.0–33.7 when HLA-B27 is excluded from the referral strategy. When using a two-of-three criteria, assuming HLA-B27 and sacroiliitis on imaging are mandatory, together with one other criterion (known extra-articular manifestation, family history of axSpA, IBP), the positive LR was between 5.4 and 11.5, compared with an LR of 1.6–2.8 when HLA-B27 and sacroiliitis on imaging are excluded from the referral strategy [84, 85]. Braun et al. [86, 87] investigated consecutive back pain patients presenting to orthopaedics and recorded the presence/absence of four pre-specified criteria: morning stiffness >30 min, improvement by movement not by rest, waking in the second half of the night because of back pain and improvement with NSAIDs within 48 h. Referral to rheumatology was randomly allocated and the diagnosis of axSpA made by a rheumatologist. Data analysis showed that no single clinical item was predictive, however, three or more items proved useful (sensitivity and specificity of 78.8 and 46.4%, respectively). A subsequent study modelling other clinical criterion and HLA-B27 collected when SpA was suspected in primary care showed that a two-step referral strategy using an initial step of at least two-of-three clinical parameters (bilateral buttock pain, improvement by movement, history of psoriasis) followed by HLA-B27 testing for those with less than two positive clinical parameters yielded 80.4% sensitive and 75.4% specificity with a positive LR of 3.27 and a negative LR of 0.26. This approach needs to be validated in prospective studies. Secondary care referral strategies HLA-B27 is often used by ophthalmologists to prompt rheumatology referral in patients with AAU, as it is known to be strongly associated with both AAU and axSpA. Haroon et al. [42] developed an algorithm to direct AAU referrals to rheumatology; they recommended that AAU patients who are HLA-B27 positive and HLA-B27-negative patients (if they have psoriasis or peripheral arthritis) should be referred, reporting high sensitivity (96%) and specificity (97%) with a positive LR of 41.5 and a negative LR of 0.03. However, Sykes et al. [88] externally tested the Dublin Uveitis Evaluation Tool and found a lower sensitivity and specificity (56% and 68%, respectively) in their prospective cohort. HLA-B27 has a pivotal place in any referral strategy for suspected axSpA patients. However, any referral strategy should not rely on HLA-B27 in isolation and should include other clinical features associated with the disease. The authors endorse the guidelines produced by the ASAS [89] in this regard. The place of HLA-B27 in referral strategies used by other secondary care clinicians, including gastroenterologists and dermatologists, requires further evaluation. Diagnosis and classification Previously it was considered that testing for HLA-B27 in an unselected population was unrewarding unless the clinician suspected AS [90]. Using this principle, given that European AS prevalence is 0.24% and HLA-B27 prevalence is 10%, the prevalence of the HLA-B27 antigen is 41 times more than the prevalence of the disease if all cases are HLA-B27 positive. It has also been shown in similar epidemiological statistics calculations that the positive predictive value of HLA-B27 would only be increased from 0.9 to 9.0% even if the background prevalence of axSpA is increased from 0.10 to 1.00% (i.e. up to 91 of 100 random subjects would be positive for HLA-B27 without a diagnosis of AS; too many false positive results) and the diagnostic test sensitivity is assumed to be 90%. When the diagnostic test specificity and negative predictive value are >90%, then HLA-B27 testing is effective to exclude AS in patients with a low pre-test probability of AS, after giving due consideration to the ethnic/geographic origin of the patient [90]. However, Gran et al. [91] rightly highlighted that there is no reason to test HLA-B27 in a randomly selected person, as any test should only be undertaken if the condition is suspected on clinical grounds. The diagnostic utility of HLA-B27 testing depends on the clinician’s pre-test estimate (clinical presentation, clinical judgement and experience). The higher the pre-test probability, the higher the post-test probability of reaching a diagnostic threshold and this utility is less pronounced at the extremes of diagnostic probability testing (if pre-test probability is closer to 0 or 100%) [92]. It has been calculated that for a positive HLA-B27 test to provide an acceptable post-test probability of 95%, the physician must be > 50% certain of the diagnosis before the test is performed [90]. In addition to the clinician’s best guess, the diagnostic sensitivity and specificity of the test can affect the post-test probability. If the pre-test estimate is fixed, the diagnostic sensitivity is related to the prevalence of HLA-B27 in the AS population and specificity is related to the prevalence of HLA-B27 in the non-disease population, which varies between continents and ethnic groups [5]. In 2004, Rudwaleit et al. [93] re-evaluated the diagnostic utility of HLA-B27 using the LR of clinical items (aggregated from then newly published literature) that allowed for the differential weighting of SpA features and enabled a calculated disease probability estimation using a formula derived from Bayes’ theorem. This demonstrated an evidence-based way of expressing a clinician’s diagnostic reasoning, allowing for the development of a diagnostic algorithm. It was suggested that if the background probability of diagnosing axSpA was 5% in a person presenting with chronic low back pain, it could increase to 14% if they had IBP (then thought to be the most important symptom). Thereafter, the presence of two to three SpA features was necessary to increase the diagnostic probability of axSpA to 90% (a set threshold for definite diagnosis). HLA-B27 (LR 9.0) was among these SpA features, in addition to MRI sacroiliitis (LR 9.0) and AAU (LR 7.3). The probability of axSpA in patients with IBP with one or two features of SpA is enhanced from 35–70% to 80–90% with a positive HLA-B27 test and reduced to < 10% with a negative HLA-B27 test. On the other hand, the probability of axSpA in HLA-B27-positive patients with IBP and without additional features of SpA is increased from 14 to 59% and reduced to < 2% if HLA-B27 is negative. This suggests that in subjects with a low to moderate suspicion of axSpA, the diagnostic confidence can be increased (or probably excluded) using the HLA-B27 test as an adjunct to clinical assessment [94, 95]. It was also suggested that the bedside assessment of early axSpA can be enhanced by using the concept of LR product (and knowledge of the estimated LR of SpA features) and a simple graph (of LR product to post-test probability) in order to estimate the diagnostic probability of a clinical presentation without the need for a specific diagnostic algorithm [39, 40, 94]. HLA-B27 is utilized as an obligatory parameter for the clinical arm of the ASAS classification criteria. In the developmental phase, the imaging arm had a sensitivity of 66.2% and a specificity of 97.3%; the clinical arm alone has a sensitivity of 85.7% and a specificity of 76.7% (even with IBP set as an obligatory criteria). This led to further exploration of the clinical arm of the criteria by selecting HLA-B27 as an obligatory parameter; this improved the specificity (from 77.2 to 84.9%) at the expense of sensitivity (from 85.5 to 84.6%) [3, 4, 40]. The clinical arm of the ASAS classification was recently externally verified in the Devenir des Spondylarthropathies Indifférenciées Récentes (DESIR) cohort [96]. It was suggested that although the diagnostic performance of the ASAS criteria for axSpA is good in a secondary care rheumatology setting (with 89% probability of axSpA), these criteria should not be misused as diagnostic criteria [97, 98]. In another recent publication, the positive predictive value of the clinical arm of the ASAS criteria to forecast an expert physician diagnosis of axSpA at 5 years was 88% [99]. HLA-B27 and imaging In a prospective, longitudinal, inception cohort of patients with early IBP, the combination of severe sacroiliitis seen on MRI with HLA-B27 positivity was an excellent predictor of future AS (LR 8.0, specificity 92%), while mild or no sacroiliitis, regardless of HLA-B27 status, was a predictor of not developing AS (LR 0.4, specificity 38%) [100]. In addition, HLA-B27 was associated with both the severity and persistence of osteitis on MRI [101]. The DESIR cohort of early axSpA showed that HLA-B27 is associated with axial inflammation (spine and SI joint) and sacroiliac radiographic damage but not MRI structural lesions [31]. Heuft-Dorenbosch et al. [102] showed the close relationship between HLA-B27 and SI joint inflammation in their early SpA clinic cohort. Of the patients with sacroiliac inflammation on MRI, 73% were positive for HLA-B27 compared with only 33% without inflammation. Conversely, among the HLA-B27-positive patients, 52% had inflammation compared with 16% who were HLA-B27 negative. In addition, when HLA-B27 and MRI are positive at baseline, the likelihood of a subsequent positive MRI at the 2 year follow-up is 88%. In contrast, when MRI is positive and HLA-B27 is negative at baseline, the likelihood of a positive MRI is only 50% [103]. HLA-B27 positivity, the presence of uveitis, male gender and the absence of peripheral arthritis have all been shown to be associated with multiple syndesmophytes or fusion of multiple lumbar vertebrae in a cross-sectional study in patients with AS with extensive radiographic changes [104]. A recent 12 year prospective follow-up study showed that long-term radiographic progression in AS is highly variable at an individual patient level, more severe in HLA-B27-positive men and still occurs after decades of disease. At the group level, AS radiographic progression follows a more linear course [105]. The identification of axSpA patients with a poor prognosis is aided by the identification of a patient’s HLA-B27 status. The authors recommend routine testing of HLA-B27 by rheumatologists who request imaging for the diagnosis of axSpA. The HLA-B27 status can aid the interpretation of imaging findings to diagnose axSpA. In addition, the HLA-B27 status enables the clinician to have a more informed conversation with the patient when defining that individual’s longer-term prognosis. HLA-B27 and treatment response A recent systematic review and meta-analysis of AS clinical trials and observational studies reported that HLA-B27 positivity predicts response to TNF-α inhibitors [106], however, this association is not unanimous [107–109]. Meta-analysis of the relevant articles from the systematic review between HLA-B27 positivity and various outcome measures show that in three studies an OR of 2.81 (95% CI 0.95, 7.16) was reported for achieving a 20% improvement in ASAS criteria, in three other studies an OR of 1.83 (95% CI 1.39, 2.42) was reported for 40% improvement in ASAS criteria and in the final three studies an OR of 1.81 (95% CI 1.35, 2.42) was reported for a 50% improvement in the BASDAI [106]. In addition, a retrospective study showed that in a predominantly axSpA population (ESSG criteria) who failed conventional therapy, HLA-B27-positive patients with positive imaging had a significantly higher response rate to TNF-α inhibitors (65.7%) vs other groups (42–46%) when either parameter was absent (P = 0.03) [110]. HLA-B27 positivity in addition to elevated acute phase reactants, the presence of peripheral arthritis, higher disease activity, higher functional status, younger age and male sex have all been identified as independent predictors for achieving clinical response and/or for continuation of TNF-α inhibitor therapy in multivariate analyses. Using this, Vastesaeger et al. [107] created a model that provides a potential basis for candidate selection for TNF-α inhibitor therapy by predicting future outcomes relative to the current disease profile of individual patients with AS. Arends et al. [111] further suggest that composite predictive models may lead to the development of better instruments to support physicians when choosing TNF-α inhibitors in daily clinical practice, as the predictive value of a single parameter is not powerful enough to predict treatment response in an individual patient. HLA-B27 and prognosis Prognosis in axSpA can be defined by different outcomes, such as activity (symptoms and disease activity), damage (structural, such as radiological progression) and function (relating to physical function, activities of daily living and health-related quality of life) [112, 113]. In the DESIR cohort of early axSpA (IBP <3 years), HLA-B27 is associated with decreased disease activity (ASDAS-CRP and BASDAI) but not with physical function (measured via the BASFI) on multivariate analysis. The negative association of HLA-B27 with disease activity in the study was unexpected, but the authors explained that in this early IBP cohort there was more use of NSAIDs and a decreased delay to diagnosis, thus earlier diagnosis and appropriate treatment may contribute to lower disease activity [31]. A prospective study of a Brazilian cohort of uSpA (ESSG and Amor criteria) found that 24.3% developed AS after 10 years of follow-up, and multivariate logistic regression analysis revealed that being HLA-B27 positive was statistically associated with progression to AS [OR 6.720 (95% CI 11.45, 39.43); P = 0.035] [114]. In addition to effects on disease activity and structural progression, HLA-B27 may contribute to poor cardiovascular outcomes. It has been suggested that HLA-B27 may play a role in increased cardiovascular mortality and morbidity, independent of other traditional factors. Aortic valve insufficiency is also more common in HLA-B27-positive SpA patients and HLA-B27 may play a role in the development of conduction disturbances requiring permanent pacing [115]. Conclusion The role of HLA-B27 in the diagnosis and management of axSpA has evolved since its discovery in the early 1970s. The exact role of HLA-B27 in the aetiopathogenesis of axSpA remains unclear and of considerable research interest. We have described how a positive HLA-B27 result, used in conjunction with other clinical parameters, significantly aids the clinical diagnosis. In addition, HLA-B27 is a useful adjunct in any referral strategy in order to direct referral of appropriate back pain patients. HLA-B27 also helps identify axSpA patients with a poor prognosis and may aid in the optimization of treatment decisions. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. 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Published: Sep 25, 2017