The clinical utility of human leucocyte antigen B27 in axial spondyloarthritis

The clinical utility of human leucocyte antigen B27 in axial spondyloarthritis 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. Disclosure statement: R.S. has received honoraria from AbbVie, UCB, Pfizer, Novartis and Celgene. All other authors have declared no conflicts of interest. References 1 Dougados M , Linden SVD , Juhlin R et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy . Arthritis Rheum 1991 ; 34 : 1218 – 27 . Google Scholar CrossRef Search ADS PubMed 2 van Tubergen A , Weber U. Diagnosis and classification in spondyloarthritis: identifying a chameleon . Nat Rev Rheumatol 2012 ; 8 : 253 – 61 . Google Scholar CrossRef Search ADS PubMed 3 Rudwaleit M , Landewé R , van der Heijde D et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part I): classification of paper patients by expert opinion including uncertainty appraisal . Ann Rheum Dis 2009 ; 68 : 770 – 6 . Google Scholar CrossRef Search ADS PubMed 4 Rudwaleit M , van der Heijde D , Landewé R et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection . Ann Rheum Dis 2009 ; 68 : 777 – 83 . Google Scholar CrossRef Search ADS PubMed 5 Sieper J , Rudwaleit M , Khan MA , Braun J. Concepts and epidemiology of spondyloarthritis . Best Pract Res Clin Rheumatol 2006 ; 20 : 401 – 17 . Google Scholar CrossRef Search ADS PubMed 6 Rudwaleit M , Sieper J. Referral strategies for early diagnosis of axial spondyloarthritis . Nat Rev Rheumatol 2012 ; 8 : 262 – 8 . Google Scholar CrossRef Search ADS PubMed 7 Wallis D , Haroon N , Ayearst R , Carty A , Inman RD. Ankylosing spondylitis and nonradiographic axial spondyloarthritis: part of a common spectrum or distinct diseases? J Rheumatol 2013 ; 40 : 2038 – 41 . Google Scholar CrossRef Search ADS PubMed 8 Slobodin G , Eshed I. Non-radiographic axial spondyloarthritis . Isr Med Assoc J 2015 ; 17 : 770 – 6 . Google Scholar PubMed 9 Robinson PC , Brown MA. Genetics of ankylosing spondylitis . Mol Immunol 2014 ; 57 : 2 – 11 . Google Scholar CrossRef Search ADS PubMed 10 Brown MA. Human leucocyte antigen-B27 and ankylosing spondylitis . Intern Med J 2007 ; 37 : 739 – 40 . Google Scholar CrossRef Search ADS PubMed 11 Brown MA , Kenna T , Wordsworth BP. Genetics of ankylosing spondylitis—insights into pathogenesis . Nat Rev Rheumatol 2016 ; 12 : 81 – 91 . Google Scholar CrossRef Search ADS PubMed 12 Sheehan NJ. HLA-B27: what’s new? Rheumatology 2010 ; 49 : 621 – 31 . Google Scholar CrossRef Search ADS PubMed 13 Khan MA. HLA-B27 and its subtypes in world populations . Curr Opin Rheumatol 1995 ; 7 : 263 – 9 . Google Scholar CrossRef Search ADS PubMed 14 Gonzalez-Roces S , Alvarez MV , Gonzalez S et al. HLA-B27 polymorphism and worldwide susceptibility to ankylosing spondylitis . Tissue Antigens 1997 ; 49 : 116 – 23 . Google Scholar CrossRef Search ADS PubMed 15 Bakland G , Nossent HC. Epidemiology of spondyloarthritis: a review . Curr Rheumatol Rep 2013 ; 15 : 351 . Google Scholar CrossRef Search ADS PubMed 16 Reveille JD , Weisman MH. The epidemiology of back pain, axial spondyloarthritis and HLA-B27 in the United States . Am J Med Sci 2013 ; 345 : 431 – 6 . Google Scholar CrossRef Search ADS PubMed 17 Khan MA. Epidemiology of HLA-B27 and arthritis . Clin Rheumatol 1996 ; 15(Suppl 1) : 10 – 2 . Google Scholar CrossRef Search ADS PubMed 18 Stolwijk C , Boonen A , van Tubergen A , Reveille JD. Epidemiology of spondyloarthritis . Rheum Dis Clin North Am 2012 ; 38 : 441 – 76 . Google Scholar CrossRef Search ADS PubMed 19 Dean LE , Jones GT , MacDonald AG et al. Global prevalence of ankylosing spondylitis . Rheumatology 2014 ; 53 : 650 – 7 . Google Scholar CrossRef Search ADS PubMed 20 Hamilton L , Macgregor A , Toms A et al. The prevalence of axial spondyloarthritis in the UK: a cross-sectional cohort study . BMC Musculoskelet Disord 2015 ; 16 : 392 . Google Scholar CrossRef Search ADS PubMed 21 Brown M , Laval S , Brophy S , Calin A. Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis . Ann Rheum Dis 2000 ; 59 : 883 – 6 . Google Scholar CrossRef Search ADS PubMed 22 van der Linden SM , Valkenburg HA , de Jongh BM , Cats A. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals. A comparison of relatives of spondylitis patients with the general population . Arthritis Rheum 1984 ; 27 : 241 – 9 . Google Scholar CrossRef Search ADS PubMed 23 van der Linden S , Valkenburg H , Cats A. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals: a family and population study . Br J Rheumatol 1983 ; 22(4 Suppl 2) : 18 – 9 . Google Scholar CrossRef Search ADS 24 Brewerton DA , Hart FD , Nicholls A et al. Ankylosing spondylitis and HL-A 27 . Lancet 1973 ; 1 : 904 – 7 . Google Scholar CrossRef Search ADS PubMed 25 Schlosstein L , Terasaki PI , Bluestone R , Pearson CM. High association of an HL-A antigen, W27, with ankylosing spondylitis . N Engl J Med 1973 ; 288 : 704 – 6 . Google Scholar CrossRef Search ADS PubMed 26 Reveille JD. Genetics of spondyloarthritis–beyond the MHC . Nat Rev Rheumatol 2012 ; 8 : 296 – 304 . Google Scholar CrossRef Search ADS PubMed 27 Sheehan NJ. The ramifications of HLA-B27 . J R Soc Med 2004 ; 97 : 10 – 4 . Google Scholar CrossRef Search ADS PubMed 28 Brown MA , Kennedy LG , MacGregor AJ et al. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment . Arthritis Rheum 1997 ; 40 : 1823 – 8 . Google Scholar CrossRef Search ADS PubMed 29 Thomas GP , Brown MA. Genetics and genomics of ankylosing spondylitis . Immunol Rev 2010 ; 233 : 162 – 80 . Google Scholar CrossRef Search ADS PubMed 30 Chandran V , Rahman P. Update on the genetics of spondyloarthritis – ankylosing spondylitis and psoriatic arthritis . Best Pract Res Clin Rheumatol 2010 ; 24 : 579 – 88 . Google Scholar CrossRef Search ADS PubMed 31 Chung H , Yin Machado P , van der Désirée et al. HLA-B27 positive patients differ from HLA-B27 negative patients in clinical presentation and imaging: results from the DESIR cohort of patients with recent onset axial spondyloarthritis . Ann Rheum Dis 2011 ; 70 : 1930 . Google Scholar CrossRef Search ADS PubMed 32 Feldtkeller E , Khan MA , van der Heijde D , van der Linden S , Braun J. Age at disease onset and diagnosis delay in HLA-B27 negative vs. positive patients with ankylosing spondylitis . Rheumatol Int 2003 ; 23 : 61 – 6 . Google Scholar PubMed 33 Baraliakos X , Braun J. Non-radiographic axial spondyloarthritis and ankylosing spondylitis: what are the similarities and differences? RMD Open [Internet] 2015 ; 1(Suppl 1) : e000053 . Google Scholar CrossRef Search ADS 34 Rudwaleit M , Haibel H , Baraliakos X et al. The early disease stage in axial spondylarthritis: results from the German Spondyloarthritis Inception Cohort . Arthritis Rheum 2009 ; 60 : 717 – 27 . Google Scholar CrossRef Search ADS PubMed 35 de Winter JJ , van Mens LJ , van der Heijde D , Landewé R , Baeten DL. Prevalence of peripheral and extra-articular disease in ankylosing spondylitis versus non-radiographic axial spondyloarthritis: a meta-analysis . Arthritis Res Ther 2016 ; 18 : 196 . Google Scholar CrossRef Search ADS PubMed 36 Stolwijk C , van Tubergen A , Castillo-Ortiz JD , Boonen A. Prevalence of extra-articular manifestations in patients with ankylosing spondylitis: a systematic review and meta-analysis . Ann Rheum Dis 2015 ; 74 : 65 – 73 . Google Scholar CrossRef Search ADS PubMed 37 Stolwijk C , Essers I , van Tubergen A et al. The epidemiology of extra-articular manifestations in ankylosing spondylitis: a population-based matched cohort study . Ann Rheum Dis 2015 ; 74 : 1373 – 8 . Google Scholar CrossRef Search ADS PubMed 38 El Maghraoui A. Extra-articular manifestations of ankylosing spondylitis: prevalence, characteristics and therapeutic implications . Eur J Intern Med 2011 ; 22 : 554 – 60 . Google Scholar CrossRef Search ADS PubMed 39 Rudwaleit M , Feldtkeller E , Sieper J. Easy assessment of axial spondyloarthritis (early ankylosing spondylitis) at the bedside . Ann Rheum Dis 2006 ; 65 : 1251 – 2 . Google Scholar CrossRef Search ADS PubMed 40 Rudwaleit M , Khan MA , Sieper J. The challenge of diagnosis and classification in early ankylosing spondylitis: do we need new criteria? . Arthritis Rheum 2005 ; 52 : 1000 – 8 . Google Scholar CrossRef Search ADS PubMed 41 Derhaag PJ , Linssen A , Broekema N , de Waal LP , Feltkamp TE. A familial study of the inheritance of HLA-B27-positive acute anterior uveitis . Am J Ophthalmol 1988 ; 105 : 603 – 6 . Google Scholar CrossRef Search ADS PubMed 42 Haroon M , O’Rourke M , Ramasamy P , Murphy CC , FitzGerald O. A novel evidence-based detection of undiagnosed spondyloarthritis in patients presenting with acute anterior uveitis: the DUET (Dublin Uveitis Evaluation Tool) . Ann Rheum Dis 2015 ; 74 : 1990 – 5 . Google Scholar CrossRef Search ADS PubMed 43 Zeboulon N , Dougados M , Gossec L. Prevalence and characteristics of uveitis in the spondyloarthropathies: a systematic literature review . Ann Rheum Dis 2008 ; 67 : 955 – 9 . Google Scholar CrossRef Search ADS PubMed 44 Wendling D , Prati C , Demattei C et al. Impact of uveitis on the phenotype of patients with recent inflammatory back pain: data from a prospective multicenter French cohort . Arthritis Care Res 2012 ; 64 : 1089 . Google Scholar CrossRef Search ADS 45 Canouï-Poitrine F , Lekpa FK , Farrenq V et al. Prevalence and factors associated with uveitis in spondylarthritis patients in France: results from an observational survey . Arthritis Care Res 2012 ; 64 : 919 . Google Scholar CrossRef Search ADS 46 Accorinti M , Iannetti L , Liverani M , Caggiano C , Gilardi M. Clinical features and prognosis of HLA B27-associated acute anterior uveitis in an Italian patient population . Ocul Immunol Inflamm 2010 ; 18 : 91 . Google Scholar CrossRef Search ADS PubMed 47 Juanola X , Loza Santamaría E , Cordero-Coma M. Description and prevalence of spondyloarthritis in patients with anterior uveitis: the SENTINEL Interdisciplinary Collaborative Project . Ophthalmology 2016 ; 123 : 1632 – 6 . Google Scholar CrossRef Search ADS PubMed 48 Rudwaleit M , Baeten D. Ankylosing spondylitis and bowel disease . Best Pract Res Clin Rheumatol 2006 ; 20 : 451 – 71 . Google Scholar CrossRef Search ADS PubMed 49 Meuwissen SG , Dekker-Saeys BJ , Agenant D , Tytgat GN. Ankylosing spondylitis and inflammatory bowel disease. I. Prevalence of inflammatory bowel disease in patients suffering from ankylosing spondylitis . Ann Rheum Dis 1978 ; 37 : 30 – 2 . Google Scholar CrossRef Search ADS PubMed 50 Brophy S , Pavy S , Lewis P et al. Inflammatory eye, skin, and bowel disease in spondyloarthritis: genetic, phenotypic, and environmental factors . J Rheumatol 2001 ; 28 : 2667 – 73 . Google Scholar PubMed 51 Dekker-Saeys BJ , Meuwissen SG , Van Den Berg-Loonen EM et al. Ankylosing spondylitis and inflammatory bowel disease. II. Prevalence of peripheral arthritis, sacroiliitis, and ankylosing spondylitis in patients suffering from inflammatory bowel disease . Ann Rheum Dis 1978 ; 37 : 33 – 5 . Google Scholar CrossRef Search ADS PubMed 52 Mielants H , Veys EM, D , Vos M , Cuvelier C et al. The evolution of spondyloarthropathies in relation to gut histology. I. Clinical aspects . J Rheumatol 1995 ; 22 : 2266 – 72 . Google Scholar PubMed 53 Mielants H , Veys EM , Cuvelier C et al. The evolution of spondyloarthropathies in relation to gut histology. II. Histological aspects . J Rheumatol 1995 ; 22 : 2273 – 8 . Google Scholar PubMed 54 De F , Elewaut D , De M et al. Bowel inflammation and the spondyloarthropathies . Rheum Dis Clin N Am 1998 ; 24 : 785 – 813 . Google Scholar CrossRef Search ADS 55 Leirisalo-Repo M , Turunen U , Stenman S , Helenius P , Seppälä K. High frequency of silent inflammatory bowel disease in spondylarthropathy . Arthritis Rheum 1994 ; 37 : 23 – 31 . Google Scholar CrossRef Search ADS PubMed 56 Vos MD , Cuvelier C , Mielants H et al. Ileocolonoscopy in seronegative spondylarthropathy . Gastroenterology 1989 ; 96 : 339 – 44 . Google Scholar CrossRef Search ADS PubMed 57 Mielants H , Veys EM , Cuvelier C , De Vos M , Botelberghe L. HLA-B27 related arthritis and bowel inflammation. Part 2. Ileocolonoscopy and bowel histology in patients with HLA-B27 related arthritis . J Rheumatol 1985 ; 12 : 294 – 8 . Google Scholar PubMed 58 Cuvelier C , Barbatis C , Mielants H et al. Histopathology of intestinal inflammation related to reactive arthritis . Gut 1987 ; 28 : 394 – 401 . Google Scholar CrossRef Search ADS PubMed 59 Salvarani C , Fries W. Clinical features and epidemiology of spondyloarthritides associated with inflammatory bowel disease . World J Gastroenterol 2009 ; 15 : 2449 – 55 . Google Scholar CrossRef Search ADS PubMed 60 Rodríguez-Reyna TS , Martínez-Reyes C , Yamamoto-Furusho JK. Rheumatic manifestations of inflammatory bowel disease . World J Gastroenterol 2009 ; 15 : 5517 – 24 . Google Scholar CrossRef Search ADS PubMed 61 Brakenhoff LKPM , van de Heijde DM , Hommes DW et al. The joint–gut axis in inflammatory bowel diseases . J Crohns Colitis 2010 ; 4 : 257 – 68 . Google Scholar CrossRef Search ADS PubMed 62 Karreman MC , Luime JJ , Hazes JMW , Weel AEAM. The prevalence and incidence of axial and peripheral spondyloarthritis in inflammatory bowel disease: a systematic review and meta-analysis . J Crohns Colitis 2017 ; 11 : 631 – 42 . Google Scholar PubMed 63 Palm O , Moum B , Ongre A , Gran JT. Prevalence of ankylosing spondylitis and other spondyloarthropathies among patients with inflammatory bowel disease: a population study (the IBSEN study) . J Rheumatol 2002 ; 29 : 511 – 5 . Google Scholar PubMed 64 Steer S , Jones H , Hibbert J et al. Low back pain, sacroiliitis, and the relationship with HLA-B27 in Crohn’s disease . J Rheumatol 2003 ; 30 : 518 – 22 . Google Scholar PubMed 65 Peeters H , Vander Cruyssen B , Laukens D et al. Radiological sacroiliitis, a hallmark of spondylitis, is linked with CARD15 gene polymorphisms in patients with Crohn’s disease . Ann Rheum Dis 2004 ; 63 : 1131 – 4 . Google Scholar CrossRef Search ADS PubMed 66 Podswiadek M , Punzi L , Stramare R et al. [The prevalence of radiographic sacroiliitis in patients affected by inflammatory bowel disease with inflammatory low back pain] . Reumatismo 2004 ; 56 : 110 – 3 . Google Scholar PubMed 67 Purrmann J , Zeidler H , Bertrams J et al. HLA antigens in ankylosing spondylitis associated with Crohn’s disease. Increased frequency of the HLA phenotype B27,B44 . J Rheumatol 1988 ; 15 : 1658 – 61 . Google Scholar PubMed 68 de Vlam K , Mielants H , Cuvelier C et al. Spondyloarthropathy is underestimated in inflammatory bowel disease: prevalence and HLA association . J Rheumatol 2000 ; 27 : 2860 – 5 . Google Scholar PubMed 69 Enlow RW , Bias WB , Arnett FC. The spondylitis of inflammatory bowel disease. Evidence for a non-HLA linked axial arthropathy . Arthritis Rheum 1980 ; 23 : 1359 – 65 . Google Scholar CrossRef Search ADS PubMed 70 Turkcapar N , Toruner M , Soykan I et al. The prevalence of extraintestinal manifestations and HLA association in patients with inflammatory bowel disease . Rheumatol Int 2006 ; 26 : 663 – 8 . Google Scholar CrossRef Search ADS PubMed 71 Cypers H , Varkas G , Beeckman S et al. Elevated calprotectin levels reveal bowel inflammation in spondyloarthritis . Ann Rheum Dis 2016 ; 75 : 1357 – 62 . Google Scholar CrossRef Search ADS PubMed 72 Duran A , Kobak S , Sen N et al. Fecal calprotectin is associated with disease activity in patients with ankylosing spondylitis . Bosn J Basic Med Sci 2016 ; 16 : 71 – 4 . Google Scholar PubMed 73 Matzkies FG , Targan SR , Berel D et al. Markers of intestinal inflammation in patients with ankylosing spondylitis: a pilot study . Arthritis Res Ther 2012 ; 14 : R261 . Google Scholar CrossRef Search ADS PubMed 74 Machado P , Landewé R , Braun J et al. Ankylosing spondylitis patients with and without psoriasis do not differ in disease phenotype . Ann Rheum Dis 2013 ; 72 : 1104 – 7 . Google Scholar CrossRef Search ADS PubMed 75 Richette P , Tubach F , Breban M et al. Psoriasis and phenotype of patients with early inflammatory back pain . Ann Rheum Dis 2013 ; 72 : 566 – 71 . Google Scholar CrossRef Search ADS PubMed 76 Queiro R , Morante I , Cabezas I , Acasuso B. HLA-B27 and psoriatic disease: a modern view of an old relationship . Rheumatology 2016 ; 55 : 221 – 9 . Google Scholar CrossRef Search ADS PubMed 77 Chandran V , Barrett J , Schentag CT , Farewell VT , Gladman DD. Axial psoriatic arthritis: update on a longterm prospective study . J Rheumatol 2009 ; 36 : 2744 – 50 . Google Scholar CrossRef Search ADS PubMed 78 Hanly JG , Russell ML , Gladman DD. Psoriatic spondyloarthropathy: a long term prospective study . Ann Rheum Dis 1988 ; 47 : 386 – 93 . Google Scholar CrossRef Search ADS PubMed 79 Queiro R , Sarasqueta C , Belzunegui J et al. Psoriatic spondyloarthropathy: a comparative study between HLA-B27 positive and HLA-B27 negative disease . Semin Arthritis Rheum 2002 ; 31 : 413 – 8 . Google Scholar CrossRef Search ADS PubMed 80 Chandran V , Tolusso DC , Cook RJ , Gladman DD. Risk factors for axial inflammatory arthritis in patients with psoriatic arthritis . J Rheumatol 2010 ; 37 : 809 – 15 . Google Scholar CrossRef Search ADS PubMed 81 Baraliakos X , Coates LC , Braun J. The involvement of the spine in psoriatic arthritis . Clin Exp Rheumatol 2015 ; 33(5 Suppl 93) : S31 – 5 . 82 Brandt HC , Spiller I , Song I-H et al. Performance of referral recommendations in patients with chronic back pain and suspected axial spondyloarthritis . Ann Rheum Dis 2007 ; 66 : 1479 – 84 . Google Scholar CrossRef Search ADS PubMed 83 Poddubnyy D , Vahldiek J , Spiller I et al. Evaluation of 2 screening strategies for early identification of patients with axial spondyloarthritis in primary care . J Rheumatol 2011 ; 38 : 2452 – 60 . Google Scholar CrossRef Search ADS PubMed 84 Sieper J. How to screen for axial spondyloarthritis in primary care? Curr Opin Rheumatol 2012 ; 24 : 359 . Google Scholar CrossRef Search ADS PubMed 85 Sieper J , Srinivasan S , Zamani O et al. Comparison of two referral strategies for diagnosis of axial spondyloarthritis: the Recognising and Diagnosing Ankylosing Spondylitis Reliably (RADAR) study . Ann Rheum Dis 2013 ; 72 : 1621 – 7 . Google Scholar CrossRef Search ADS PubMed 86 Braun A , Gnann H , Saracbasi E et al. Optimizing the identification of patients with axial spondyloarthritis in primary care—the case for a two-step strategy combining the most relevant clinical items with HLA B27 . Rheumatology 2013 ; 52 : 1418 . Google Scholar CrossRef Search ADS PubMed 87 Braun A , Saracbasi E , Grifka J , Schnitker J , Braun J. Identifying patients with axial spondyloarthritis in primary care: how useful are items indicative of inflammatory back pain? Ann Rheum Dis 2011 ; 70 : 1782 – 7 . Google Scholar CrossRef Search ADS PubMed 88 Sykes M , Hamilton L , Gaffney K. P25. A prospective evaluation of the Dublin Uveitis Evaluation Tool (DUET) in UK clinical practice. Presented at the 10th International Congress on Spondyloarthritides, Gent, Belgium . Clin Exp Rheumatol 2016 ; 34 : 740 . 89 Poddubnyy D , Tubergen A , van Landewé R , Sieper J , van der Heijde D. Development of an ASAS-endorsed recommendation for the early referral of patients with a suspicion of axial spondyloarthritis . Ann Rheum Dis 2015 ; 77 : 1483 – 7 . Google Scholar CrossRef Search ADS 90 Hawkins BR , Dawkins RL , Christiansen FT , Zilko PJ. Use of the B27 test in the diagnosis of ankylosing spondylitis: a statistical evaluation . Arthritis Rheum 1981 ; 24 : 743 – 6 . Google Scholar CrossRef Search ADS PubMed 91 Gran JT , Husby G. HLA-B27 and spondyloarthropathy: value for early diagnosis? J Med Genet 1995 ; 32 : 497 – 501 . Google Scholar CrossRef Search ADS PubMed 92 Khan MA , Khan MK. Diagnostic value of HLA-B27 testing ankylosing spondylitis and Reiter’s syndrome . Ann Intern Med 1982 ; 96 : 70 – 6 . Google Scholar CrossRef Search ADS PubMed 93 Rudwaleit M , van der Heijde D , Khan M , Braun J , Sieper J. How to diagnose axial spondyloarthritis early . Ann Rheum Dis 2004 ; 63 : 535 – 43 . Google Scholar CrossRef Search ADS PubMed 94 Braun J , Sieper J. Early diagnosis of spondyloarthritis . Nat Clin Pract Rheumatol 2006 ; 2 : 536 – 45 . Google Scholar CrossRef Search ADS PubMed 95 Vossen MHE , den Broeder AA , Hendriks-Roelofs F , van der Heijde DMFM , Reijnierse M. Improvement in deployment of MRI of the sacroiliac joints in patients suspected for spondyloarthritis using a targeted intervention: a case study . Rheumatology 2013 ; 52 : 933 – 8 . Google Scholar CrossRef Search ADS PubMed 96 Moltó A , Paternotte S , van der Heijde D et al. Evaluation of the validity of the different arms of the ASAS set of criteria for axial spondyloarthritis and description of the different imaging abnormalities suggestive of spondyloarthritis: data from the DESIR cohort . Ann Rheum Dis 2015 ; 74 : 746 – 51 . Google Scholar CrossRef Search ADS PubMed 97 Rudwaleit M. New approaches to diagnosis and classification of axial and peripheral spondyloarthritis . Curr Opin Rheumatol 2010 ; 22 : 375 . Google Scholar CrossRef Search ADS PubMed 98 Braun J , Baraliakos X , Kiltz U , Heldmann F , Sieper J. Classification and diagnosis of axial spondyloarthritis—what is the clinically relevant difference? J Rheumatol 2015 ; 42 : 31 – 8 . Google Scholar CrossRef Search ADS PubMed 99 Sepriano A , Landewé R , van der Heijde D et al. Predictive validity of the ASAS classification criteria for axial and peripheral spondyloarthritis after follow-up in the ASAS cohort: a final analysis . Ann Rheum Dis 2016 ; 75 : 1034 – 42 . Google Scholar CrossRef Search ADS PubMed 100 Bennett AN , McGonagle D , O’Connor P et al. Severity of baseline magnetic resonance imaging-evident sacroiliitis and HLA-B27 status in early inflammatory back pain predict radiographically evident ankylosing spondylitis at eight years . Arthritis Rheum 2008 ; 58 : 3413 – 8 . Google Scholar CrossRef Search ADS PubMed 101 Marzo-Ortega H , McGonagle D , O’Connor P et al. Baseline and 1-year magnetic resonance imaging of the sacroiliac joint and lumbar spine in very early inflammatory back pain. Relationship between symptoms, HLA-B27 and disease extent and persistence . Ann Rheum Dis 2009 ; 68 : 1721 – 7 . Google Scholar CrossRef Search ADS PubMed 102 Heuft-Dorenbosch L , Landewé R , Weijers R et al. Performance of various criteria sets in patients with inflammatory back pain of short duration; the Maastricht early spondyloarthritis clinic . Ann Rheum Dis 2007 ; 66 : 92 – 8 . Google Scholar CrossRef Search ADS PubMed 103 van Onna M , Jurik AG , van der Heijde D et al. HLA-B27 and gender independently determine the likelihood of a positive MRI of the sacroiliac joints in patients with early inflammatory back pain: a 2-year MRI follow-up study . Ann Rheum Dis 2011 ; 70 : 1981 – 5 . Google Scholar CrossRef Search ADS PubMed 104 Atagunduz P , Aydin SZ , Bahadir C , Erer B , Direskeneli H . Determinants of early radiographic progression in ankylosing spondylitis . J Rheumatol 2010 ; 37 : 2356 – 61 . Google Scholar CrossRef Search ADS PubMed 105 Ramiro S , Stolwijk C , van Tubergen A et al. Evolution of radiographic damage in ankylosing spondylitis: a 12 year prospective follow-up of the OASIS study . Ann Rheum Dis 2015 ; 74 : 52 – 9 . Google Scholar CrossRef Search ADS PubMed 106 Maneiro JR , Souto A , Salgado E , Mera A , Gomez-Reino JJ. Predictors of response to TNF antagonists in patients with ankylosing spondylitis and psoriatic arthritis: systematic review and meta-analysis . RMD Open 2015 ; 1 : e000017 . Google Scholar CrossRef Search ADS PubMed 107 Vastesaeger N , van der Heijde D , Inman RD et al. Predicting the outcome of ankylosing spondylitis therapy . Ann Rheum Dis 2011 ; 70 : 973 – 81 . Google Scholar CrossRef Search ADS PubMed 108 Rudwaleit M , Claudepierre P , Wordsworth P et al. Effectiveness, safety, and predictors of good clinical response in 1250 patients treated with adalimumab for active ankylosing spondylitis . J Rheumatol 2009 ; 36 : 801 – 8 . Google Scholar CrossRef Search ADS PubMed 109 Coates LC , Cawkwell LS , Ng NWF et al. Real life experience confirms sustained response to long-term biologics and switching in ankylosing spondylitis . Rheumatology 2008 ; 47 : 897 – 900 . Google Scholar CrossRef Search ADS PubMed 110 Bisson-Vaivre A , Alcaix D , Zarnitsky C et al. Efficacy of anti-TNF in patients with spondyloarthritis in absence of any imaging sign . Jt Bone Spine 2013 ; 80 : 280 – 6 . Google Scholar CrossRef Search ADS 111 Arends S , van der Veer E , Kallenberg CGM , Brouwer E , Spoorenberg A. Baseline predictors of response to TNF-α blocking therapy in ankylosing spondylitis . Curr Opin Rheumatol 2012 ; 24 : 290 – 8 . Google Scholar CrossRef Search ADS PubMed 112 Braun J , van der Heijde D , Dougados M et al. Staging of patients with ankylosing spondylitis: a preliminary proposal . Ann Rheum Dis 2002 ; 61(Suppl 3) : iii9 – 23 . Google Scholar PubMed 113 Zochling J , Braun J , van der Heijde D. Assessments in ankylosing spondylitis . Best Pract Res Clin Rheumatol 2006 ; 20 : 521 – 37 . Google Scholar CrossRef Search ADS PubMed 114 Sampaio-Barros PD , Bortoluzzo AB , Conde RA et al. Undifferentiated spondyloarthritis: a longterm followup . J Rheumatol 2010 ; 37 : 1195 – 9 . Google Scholar CrossRef Search ADS PubMed 115 Peters MJ , van der Horst-Bruinsma IE , Dijkmans BA , Nurmohamed MT. Cardiovascular risk profile of patients with spondylarthropathies, particularly ankylosing spondylitis and psoriatic arthritis . Semin Arthritis Rheum 2004 ; 34 : 585 – 92 . Google Scholar CrossRef Search ADS PubMed © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. 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The clinical utility of human leucocyte antigen B27 in axial spondyloarthritis

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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. Disclosure statement: R.S. has received honoraria from AbbVie, UCB, Pfizer, Novartis and Celgene. All other authors have declared no conflicts of interest. References 1 Dougados M , Linden SVD , Juhlin R et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy . Arthritis Rheum 1991 ; 34 : 1218 – 27 . Google Scholar CrossRef Search ADS PubMed 2 van Tubergen A , Weber U. Diagnosis and classification in spondyloarthritis: identifying a chameleon . Nat Rev Rheumatol 2012 ; 8 : 253 – 61 . Google Scholar CrossRef Search ADS PubMed 3 Rudwaleit M , Landewé R , van der Heijde D et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part I): classification of paper patients by expert opinion including uncertainty appraisal . Ann Rheum Dis 2009 ; 68 : 770 – 6 . Google Scholar CrossRef Search ADS PubMed 4 Rudwaleit M , van der Heijde D , Landewé R et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection . Ann Rheum Dis 2009 ; 68 : 777 – 83 . Google Scholar CrossRef Search ADS PubMed 5 Sieper J , Rudwaleit M , Khan MA , Braun J. Concepts and epidemiology of spondyloarthritis . Best Pract Res Clin Rheumatol 2006 ; 20 : 401 – 17 . Google Scholar CrossRef Search ADS PubMed 6 Rudwaleit M , Sieper J. Referral strategies for early diagnosis of axial spondyloarthritis . Nat Rev Rheumatol 2012 ; 8 : 262 – 8 . Google Scholar CrossRef Search ADS PubMed 7 Wallis D , Haroon N , Ayearst R , Carty A , Inman RD. Ankylosing spondylitis and nonradiographic axial spondyloarthritis: part of a common spectrum or distinct diseases? J Rheumatol 2013 ; 40 : 2038 – 41 . Google Scholar CrossRef Search ADS PubMed 8 Slobodin G , Eshed I. Non-radiographic axial spondyloarthritis . Isr Med Assoc J 2015 ; 17 : 770 – 6 . Google Scholar PubMed 9 Robinson PC , Brown MA. Genetics of ankylosing spondylitis . Mol Immunol 2014 ; 57 : 2 – 11 . Google Scholar CrossRef Search ADS PubMed 10 Brown MA. Human leucocyte antigen-B27 and ankylosing spondylitis . Intern Med J 2007 ; 37 : 739 – 40 . Google Scholar CrossRef Search ADS PubMed 11 Brown MA , Kenna T , Wordsworth BP. Genetics of ankylosing spondylitis—insights into pathogenesis . Nat Rev Rheumatol 2016 ; 12 : 81 – 91 . Google Scholar CrossRef Search ADS PubMed 12 Sheehan NJ. HLA-B27: what’s new? Rheumatology 2010 ; 49 : 621 – 31 . Google Scholar CrossRef Search ADS PubMed 13 Khan MA. HLA-B27 and its subtypes in world populations . Curr Opin Rheumatol 1995 ; 7 : 263 – 9 . Google Scholar CrossRef Search ADS PubMed 14 Gonzalez-Roces S , Alvarez MV , Gonzalez S et al. HLA-B27 polymorphism and worldwide susceptibility to ankylosing spondylitis . Tissue Antigens 1997 ; 49 : 116 – 23 . Google Scholar CrossRef Search ADS PubMed 15 Bakland G , Nossent HC. Epidemiology of spondyloarthritis: a review . Curr Rheumatol Rep 2013 ; 15 : 351 . Google Scholar CrossRef Search ADS PubMed 16 Reveille JD , Weisman MH. The epidemiology of back pain, axial spondyloarthritis and HLA-B27 in the United States . Am J Med Sci 2013 ; 345 : 431 – 6 . Google Scholar CrossRef Search ADS PubMed 17 Khan MA. Epidemiology of HLA-B27 and arthritis . Clin Rheumatol 1996 ; 15(Suppl 1) : 10 – 2 . Google Scholar CrossRef Search ADS PubMed 18 Stolwijk C , Boonen A , van Tubergen A , Reveille JD. Epidemiology of spondyloarthritis . Rheum Dis Clin North Am 2012 ; 38 : 441 – 76 . Google Scholar CrossRef Search ADS PubMed 19 Dean LE , Jones GT , MacDonald AG et al. Global prevalence of ankylosing spondylitis . Rheumatology 2014 ; 53 : 650 – 7 . Google Scholar CrossRef Search ADS PubMed 20 Hamilton L , Macgregor A , Toms A et al. The prevalence of axial spondyloarthritis in the UK: a cross-sectional cohort study . BMC Musculoskelet Disord 2015 ; 16 : 392 . Google Scholar CrossRef Search ADS PubMed 21 Brown M , Laval S , Brophy S , Calin A. Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis . Ann Rheum Dis 2000 ; 59 : 883 – 6 . Google Scholar CrossRef Search ADS PubMed 22 van der Linden SM , Valkenburg HA , de Jongh BM , Cats A. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals. A comparison of relatives of spondylitis patients with the general population . Arthritis Rheum 1984 ; 27 : 241 – 9 . Google Scholar CrossRef Search ADS PubMed 23 van der Linden S , Valkenburg H , Cats A. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals: a family and population study . Br J Rheumatol 1983 ; 22(4 Suppl 2) : 18 – 9 . Google Scholar CrossRef Search ADS 24 Brewerton DA , Hart FD , Nicholls A et al. Ankylosing spondylitis and HL-A 27 . Lancet 1973 ; 1 : 904 – 7 . Google Scholar CrossRef Search ADS PubMed 25 Schlosstein L , Terasaki PI , Bluestone R , Pearson CM. High association of an HL-A antigen, W27, with ankylosing spondylitis . N Engl J Med 1973 ; 288 : 704 – 6 . Google Scholar CrossRef Search ADS PubMed 26 Reveille JD. Genetics of spondyloarthritis–beyond the MHC . Nat Rev Rheumatol 2012 ; 8 : 296 – 304 . Google Scholar CrossRef Search ADS PubMed 27 Sheehan NJ. The ramifications of HLA-B27 . J R Soc Med 2004 ; 97 : 10 – 4 . Google Scholar CrossRef Search ADS PubMed 28 Brown MA , Kennedy LG , MacGregor AJ et al. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment . Arthritis Rheum 1997 ; 40 : 1823 – 8 . Google Scholar CrossRef Search ADS PubMed 29 Thomas GP , Brown MA. Genetics and genomics of ankylosing spondylitis . Immunol Rev 2010 ; 233 : 162 – 80 . Google Scholar CrossRef Search ADS PubMed 30 Chandran V , Rahman P. Update on the genetics of spondyloarthritis – ankylosing spondylitis and psoriatic arthritis . Best Pract Res Clin Rheumatol 2010 ; 24 : 579 – 88 . Google Scholar CrossRef Search ADS PubMed 31 Chung H , Yin Machado P , van der Désirée et al. HLA-B27 positive patients differ from HLA-B27 negative patients in clinical presentation and imaging: results from the DESIR cohort of patients with recent onset axial spondyloarthritis . Ann Rheum Dis 2011 ; 70 : 1930 . Google Scholar CrossRef Search ADS PubMed 32 Feldtkeller E , Khan MA , van der Heijde D , van der Linden S , Braun J. Age at disease onset and diagnosis delay in HLA-B27 negative vs. positive patients with ankylosing spondylitis . Rheumatol Int 2003 ; 23 : 61 – 6 . Google Scholar PubMed 33 Baraliakos X , Braun J. Non-radiographic axial spondyloarthritis and ankylosing spondylitis: what are the similarities and differences? RMD Open [Internet] 2015 ; 1(Suppl 1) : e000053 . Google Scholar CrossRef Search ADS 34 Rudwaleit M , Haibel H , Baraliakos X et al. The early disease stage in axial spondylarthritis: results from the German Spondyloarthritis Inception Cohort . Arthritis Rheum 2009 ; 60 : 717 – 27 . Google Scholar CrossRef Search ADS PubMed 35 de Winter JJ , van Mens LJ , van der Heijde D , Landewé R , Baeten DL. Prevalence of peripheral and extra-articular disease in ankylosing spondylitis versus non-radiographic axial spondyloarthritis: a meta-analysis . Arthritis Res Ther 2016 ; 18 : 196 . Google Scholar CrossRef Search ADS PubMed 36 Stolwijk C , van Tubergen A , Castillo-Ortiz JD , Boonen A. Prevalence of extra-articular manifestations in patients with ankylosing spondylitis: a systematic review and meta-analysis . Ann Rheum Dis 2015 ; 74 : 65 – 73 . Google Scholar CrossRef Search ADS PubMed 37 Stolwijk C , Essers I , van Tubergen A et al. The epidemiology of extra-articular manifestations in ankylosing spondylitis: a population-based matched cohort study . Ann Rheum Dis 2015 ; 74 : 1373 – 8 . Google Scholar CrossRef Search ADS PubMed 38 El Maghraoui A. Extra-articular manifestations of ankylosing spondylitis: prevalence, characteristics and therapeutic implications . Eur J Intern Med 2011 ; 22 : 554 – 60 . Google Scholar CrossRef Search ADS PubMed 39 Rudwaleit M , Feldtkeller E , Sieper J. Easy assessment of axial spondyloarthritis (early ankylosing spondylitis) at the bedside . Ann Rheum Dis 2006 ; 65 : 1251 – 2 . Google Scholar CrossRef Search ADS PubMed 40 Rudwaleit M , Khan MA , Sieper J. The challenge of diagnosis and classification in early ankylosing spondylitis: do we need new criteria? . Arthritis Rheum 2005 ; 52 : 1000 – 8 . Google Scholar CrossRef Search ADS PubMed 41 Derhaag PJ , Linssen A , Broekema N , de Waal LP , Feltkamp TE. A familial study of the inheritance of HLA-B27-positive acute anterior uveitis . Am J Ophthalmol 1988 ; 105 : 603 – 6 . Google Scholar CrossRef Search ADS PubMed 42 Haroon M , O’Rourke M , Ramasamy P , Murphy CC , FitzGerald O. A novel evidence-based detection of undiagnosed spondyloarthritis in patients presenting with acute anterior uveitis: the DUET (Dublin Uveitis Evaluation Tool) . Ann Rheum Dis 2015 ; 74 : 1990 – 5 . Google Scholar CrossRef Search ADS PubMed 43 Zeboulon N , Dougados M , Gossec L. Prevalence and characteristics of uveitis in the spondyloarthropathies: a systematic literature review . Ann Rheum Dis 2008 ; 67 : 955 – 9 . Google Scholar CrossRef Search ADS PubMed 44 Wendling D , Prati C , Demattei C et al. Impact of uveitis on the phenotype of patients with recent inflammatory back pain: data from a prospective multicenter French cohort . Arthritis Care Res 2012 ; 64 : 1089 . Google Scholar CrossRef Search ADS 45 Canouï-Poitrine F , Lekpa FK , Farrenq V et al. Prevalence and factors associated with uveitis in spondylarthritis patients in France: results from an observational survey . Arthritis Care Res 2012 ; 64 : 919 . Google Scholar CrossRef Search ADS 46 Accorinti M , Iannetti L , Liverani M , Caggiano C , Gilardi M. Clinical features and prognosis of HLA B27-associated acute anterior uveitis in an Italian patient population . Ocul Immunol Inflamm 2010 ; 18 : 91 . Google Scholar CrossRef Search ADS PubMed 47 Juanola X , Loza Santamaría E , Cordero-Coma M. Description and prevalence of spondyloarthritis in patients with anterior uveitis: the SENTINEL Interdisciplinary Collaborative Project . Ophthalmology 2016 ; 123 : 1632 – 6 . Google Scholar CrossRef Search ADS PubMed 48 Rudwaleit M , Baeten D. Ankylosing spondylitis and bowel disease . Best Pract Res Clin Rheumatol 2006 ; 20 : 451 – 71 . Google Scholar CrossRef Search ADS PubMed 49 Meuwissen SG , Dekker-Saeys BJ , Agenant D , Tytgat GN. Ankylosing spondylitis and inflammatory bowel disease. I. Prevalence of inflammatory bowel disease in patients suffering from ankylosing spondylitis . Ann Rheum Dis 1978 ; 37 : 30 – 2 . Google Scholar CrossRef Search ADS PubMed 50 Brophy S , Pavy S , Lewis P et al. Inflammatory eye, skin, and bowel disease in spondyloarthritis: genetic, phenotypic, and environmental factors . J Rheumatol 2001 ; 28 : 2667 – 73 . Google Scholar PubMed 51 Dekker-Saeys BJ , Meuwissen SG , Van Den Berg-Loonen EM et al. Ankylosing spondylitis and inflammatory bowel disease. II. Prevalence of peripheral arthritis, sacroiliitis, and ankylosing spondylitis in patients suffering from inflammatory bowel disease . Ann Rheum Dis 1978 ; 37 : 33 – 5 . Google Scholar CrossRef Search ADS PubMed 52 Mielants H , Veys EM, D , Vos M , Cuvelier C et al. The evolution of spondyloarthropathies in relation to gut histology. I. Clinical aspects . J Rheumatol 1995 ; 22 : 2266 – 72 . Google Scholar PubMed 53 Mielants H , Veys EM , Cuvelier C et al. The evolution of spondyloarthropathies in relation to gut histology. II. Histological aspects . J Rheumatol 1995 ; 22 : 2273 – 8 . Google Scholar PubMed 54 De F , Elewaut D , De M et al. Bowel inflammation and the spondyloarthropathies . Rheum Dis Clin N Am 1998 ; 24 : 785 – 813 . Google Scholar CrossRef Search ADS 55 Leirisalo-Repo M , Turunen U , Stenman S , Helenius P , Seppälä K. High frequency of silent inflammatory bowel disease in spondylarthropathy . Arthritis Rheum 1994 ; 37 : 23 – 31 . Google Scholar CrossRef Search ADS PubMed 56 Vos MD , Cuvelier C , Mielants H et al. Ileocolonoscopy in seronegative spondylarthropathy . Gastroenterology 1989 ; 96 : 339 – 44 . Google Scholar CrossRef Search ADS PubMed 57 Mielants H , Veys EM , Cuvelier C , De Vos M , Botelberghe L. HLA-B27 related arthritis and bowel inflammation. Part 2. Ileocolonoscopy and bowel histology in patients with HLA-B27 related arthritis . J Rheumatol 1985 ; 12 : 294 – 8 . Google Scholar PubMed 58 Cuvelier C , Barbatis C , Mielants H et al. Histopathology of intestinal inflammation related to reactive arthritis . Gut 1987 ; 28 : 394 – 401 . Google Scholar CrossRef Search ADS PubMed 59 Salvarani C , Fries W. Clinical features and epidemiology of spondyloarthritides associated with inflammatory bowel disease . World J Gastroenterol 2009 ; 15 : 2449 – 55 . Google Scholar CrossRef Search ADS PubMed 60 Rodríguez-Reyna TS , Martínez-Reyes C , Yamamoto-Furusho JK. Rheumatic manifestations of inflammatory bowel disease . World J Gastroenterol 2009 ; 15 : 5517 – 24 . Google Scholar CrossRef Search ADS PubMed 61 Brakenhoff LKPM , van de Heijde DM , Hommes DW et al. The joint–gut axis in inflammatory bowel diseases . J Crohns Colitis 2010 ; 4 : 257 – 68 . Google Scholar CrossRef Search ADS PubMed 62 Karreman MC , Luime JJ , Hazes JMW , Weel AEAM. The prevalence and incidence of axial and peripheral spondyloarthritis in inflammatory bowel disease: a systematic review and meta-analysis . J Crohns Colitis 2017 ; 11 : 631 – 42 . Google Scholar PubMed 63 Palm O , Moum B , Ongre A , Gran JT. Prevalence of ankylosing spondylitis and other spondyloarthropathies among patients with inflammatory bowel disease: a population study (the IBSEN study) . J Rheumatol 2002 ; 29 : 511 – 5 . Google Scholar PubMed 64 Steer S , Jones H , Hibbert J et al. Low back pain, sacroiliitis, and the relationship with HLA-B27 in Crohn’s disease . J Rheumatol 2003 ; 30 : 518 – 22 . Google Scholar PubMed 65 Peeters H , Vander Cruyssen B , Laukens D et al. Radiological sacroiliitis, a hallmark of spondylitis, is linked with CARD15 gene polymorphisms in patients with Crohn’s disease . Ann Rheum Dis 2004 ; 63 : 1131 – 4 . Google Scholar CrossRef Search ADS PubMed 66 Podswiadek M , Punzi L , Stramare R et al. [The prevalence of radiographic sacroiliitis in patients affected by inflammatory bowel disease with inflammatory low back pain] . Reumatismo 2004 ; 56 : 110 – 3 . Google Scholar PubMed 67 Purrmann J , Zeidler H , Bertrams J et al. HLA antigens in ankylosing spondylitis associated with Crohn’s disease. Increased frequency of the HLA phenotype B27,B44 . J Rheumatol 1988 ; 15 : 1658 – 61 . Google Scholar PubMed 68 de Vlam K , Mielants H , Cuvelier C et al. Spondyloarthropathy is underestimated in inflammatory bowel disease: prevalence and HLA association . J Rheumatol 2000 ; 27 : 2860 – 5 . Google Scholar PubMed 69 Enlow RW , Bias WB , Arnett FC. The spondylitis of inflammatory bowel disease. Evidence for a non-HLA linked axial arthropathy . Arthritis Rheum 1980 ; 23 : 1359 – 65 . Google Scholar CrossRef Search ADS PubMed 70 Turkcapar N , Toruner M , Soykan I et al. The prevalence of extraintestinal manifestations and HLA association in patients with inflammatory bowel disease . Rheumatol Int 2006 ; 26 : 663 – 8 . Google Scholar CrossRef Search ADS PubMed 71 Cypers H , Varkas G , Beeckman S et al. Elevated calprotectin levels reveal bowel inflammation in spondyloarthritis . Ann Rheum Dis 2016 ; 75 : 1357 – 62 . Google Scholar CrossRef Search ADS PubMed 72 Duran A , Kobak S , Sen N et al. Fecal calprotectin is associated with disease activity in patients with ankylosing spondylitis . Bosn J Basic Med Sci 2016 ; 16 : 71 – 4 . Google Scholar PubMed 73 Matzkies FG , Targan SR , Berel D et al. Markers of intestinal inflammation in patients with ankylosing spondylitis: a pilot study . Arthritis Res Ther 2012 ; 14 : R261 . Google Scholar CrossRef Search ADS PubMed 74 Machado P , Landewé R , Braun J et al. Ankylosing spondylitis patients with and without psoriasis do not differ in disease phenotype . Ann Rheum Dis 2013 ; 72 : 1104 – 7 . Google Scholar CrossRef Search ADS PubMed 75 Richette P , Tubach F , Breban M et al. Psoriasis and phenotype of patients with early inflammatory back pain . Ann Rheum Dis 2013 ; 72 : 566 – 71 . Google Scholar CrossRef Search ADS PubMed 76 Queiro R , Morante I , Cabezas I , Acasuso B. HLA-B27 and psoriatic disease: a modern view of an old relationship . Rheumatology 2016 ; 55 : 221 – 9 . Google Scholar CrossRef Search ADS PubMed 77 Chandran V , Barrett J , Schentag CT , Farewell VT , Gladman DD. Axial psoriatic arthritis: update on a longterm prospective study . J Rheumatol 2009 ; 36 : 2744 – 50 . Google Scholar CrossRef Search ADS PubMed 78 Hanly JG , Russell ML , Gladman DD. Psoriatic spondyloarthropathy: a long term prospective study . Ann Rheum Dis 1988 ; 47 : 386 – 93 . Google Scholar CrossRef Search ADS PubMed 79 Queiro R , Sarasqueta C , Belzunegui J et al. Psoriatic spondyloarthropathy: a comparative study between HLA-B27 positive and HLA-B27 negative disease . Semin Arthritis Rheum 2002 ; 31 : 413 – 8 . Google Scholar CrossRef Search ADS PubMed 80 Chandran V , Tolusso DC , Cook RJ , Gladman DD. Risk factors for axial inflammatory arthritis in patients with psoriatic arthritis . J Rheumatol 2010 ; 37 : 809 – 15 . Google Scholar CrossRef Search ADS PubMed 81 Baraliakos X , Coates LC , Braun J. The involvement of the spine in psoriatic arthritis . Clin Exp Rheumatol 2015 ; 33(5 Suppl 93) : S31 – 5 . 82 Brandt HC , Spiller I , Song I-H et al. Performance of referral recommendations in patients with chronic back pain and suspected axial spondyloarthritis . Ann Rheum Dis 2007 ; 66 : 1479 – 84 . Google Scholar CrossRef Search ADS PubMed 83 Poddubnyy D , Vahldiek J , Spiller I et al. Evaluation of 2 screening strategies for early identification of patients with axial spondyloarthritis in primary care . J Rheumatol 2011 ; 38 : 2452 – 60 . Google Scholar CrossRef Search ADS PubMed 84 Sieper J. How to screen for axial spondyloarthritis in primary care? Curr Opin Rheumatol 2012 ; 24 : 359 . Google Scholar CrossRef Search ADS PubMed 85 Sieper J , Srinivasan S , Zamani O et al. Comparison of two referral strategies for diagnosis of axial spondyloarthritis: the Recognising and Diagnosing Ankylosing Spondylitis Reliably (RADAR) study . Ann Rheum Dis 2013 ; 72 : 1621 – 7 . Google Scholar CrossRef Search ADS PubMed 86 Braun A , Gnann H , Saracbasi E et al. Optimizing the identification of patients with axial spondyloarthritis in primary care—the case for a two-step strategy combining the most relevant clinical items with HLA B27 . Rheumatology 2013 ; 52 : 1418 . Google Scholar CrossRef Search ADS PubMed 87 Braun A , Saracbasi E , Grifka J , Schnitker J , Braun J. Identifying patients with axial spondyloarthritis in primary care: how useful are items indicative of inflammatory back pain? Ann Rheum Dis 2011 ; 70 : 1782 – 7 . Google Scholar CrossRef Search ADS PubMed 88 Sykes M , Hamilton L , Gaffney K. P25. A prospective evaluation of the Dublin Uveitis Evaluation Tool (DUET) in UK clinical practice. Presented at the 10th International Congress on Spondyloarthritides, Gent, Belgium . Clin Exp Rheumatol 2016 ; 34 : 740 . 89 Poddubnyy D , Tubergen A , van Landewé R , Sieper J , van der Heijde D. Development of an ASAS-endorsed recommendation for the early referral of patients with a suspicion of axial spondyloarthritis . Ann Rheum Dis 2015 ; 77 : 1483 – 7 . Google Scholar CrossRef Search ADS 90 Hawkins BR , Dawkins RL , Christiansen FT , Zilko PJ. Use of the B27 test in the diagnosis of ankylosing spondylitis: a statistical evaluation . Arthritis Rheum 1981 ; 24 : 743 – 6 . Google Scholar CrossRef Search ADS PubMed 91 Gran JT , Husby G. HLA-B27 and spondyloarthropathy: value for early diagnosis? J Med Genet 1995 ; 32 : 497 – 501 . Google Scholar CrossRef Search ADS PubMed 92 Khan MA , Khan MK. Diagnostic value of HLA-B27 testing ankylosing spondylitis and Reiter’s syndrome . Ann Intern Med 1982 ; 96 : 70 – 6 . Google Scholar CrossRef Search ADS PubMed 93 Rudwaleit M , van der Heijde D , Khan M , Braun J , Sieper J. How to diagnose axial spondyloarthritis early . Ann Rheum Dis 2004 ; 63 : 535 – 43 . Google Scholar CrossRef Search ADS PubMed 94 Braun J , Sieper J. Early diagnosis of spondyloarthritis . Nat Clin Pract Rheumatol 2006 ; 2 : 536 – 45 . Google Scholar CrossRef Search ADS PubMed 95 Vossen MHE , den Broeder AA , Hendriks-Roelofs F , van der Heijde DMFM , Reijnierse M. Improvement in deployment of MRI of the sacroiliac joints in patients suspected for spondyloarthritis using a targeted intervention: a case study . Rheumatology 2013 ; 52 : 933 – 8 . Google Scholar CrossRef Search ADS PubMed 96 Moltó A , Paternotte S , van der Heijde D et al. Evaluation of the validity of the different arms of the ASAS set of criteria for axial spondyloarthritis and description of the different imaging abnormalities suggestive of spondyloarthritis: data from the DESIR cohort . Ann Rheum Dis 2015 ; 74 : 746 – 51 . Google Scholar CrossRef Search ADS PubMed 97 Rudwaleit M. New approaches to diagnosis and classification of axial and peripheral spondyloarthritis . Curr Opin Rheumatol 2010 ; 22 : 375 . Google Scholar CrossRef Search ADS PubMed 98 Braun J , Baraliakos X , Kiltz U , Heldmann F , Sieper J. Classification and diagnosis of axial spondyloarthritis—what is the clinically relevant difference? J Rheumatol 2015 ; 42 : 31 – 8 . Google Scholar CrossRef Search ADS PubMed 99 Sepriano A , Landewé R , van der Heijde D et al. Predictive validity of the ASAS classification criteria for axial and peripheral spondyloarthritis after follow-up in the ASAS cohort: a final analysis . Ann Rheum Dis 2016 ; 75 : 1034 – 42 . Google Scholar CrossRef Search ADS PubMed 100 Bennett AN , McGonagle D , O’Connor P et al. Severity of baseline magnetic resonance imaging-evident sacroiliitis and HLA-B27 status in early inflammatory back pain predict radiographically evident ankylosing spondylitis at eight years . Arthritis Rheum 2008 ; 58 : 3413 – 8 . Google Scholar CrossRef Search ADS PubMed 101 Marzo-Ortega H , McGonagle D , O’Connor P et al. Baseline and 1-year magnetic resonance imaging of the sacroiliac joint and lumbar spine in very early inflammatory back pain. Relationship between symptoms, HLA-B27 and disease extent and persistence . Ann Rheum Dis 2009 ; 68 : 1721 – 7 . Google Scholar CrossRef Search ADS PubMed 102 Heuft-Dorenbosch L , Landewé R , Weijers R et al. Performance of various criteria sets in patients with inflammatory back pain of short duration; the Maastricht early spondyloarthritis clinic . Ann Rheum Dis 2007 ; 66 : 92 – 8 . Google Scholar CrossRef Search ADS PubMed 103 van Onna M , Jurik AG , van der Heijde D et al. HLA-B27 and gender independently determine the likelihood of a positive MRI of the sacroiliac joints in patients with early inflammatory back pain: a 2-year MRI follow-up study . Ann Rheum Dis 2011 ; 70 : 1981 – 5 . Google Scholar CrossRef Search ADS PubMed 104 Atagunduz P , Aydin SZ , Bahadir C , Erer B , Direskeneli H . Determinants of early radiographic progression in ankylosing spondylitis . J Rheumatol 2010 ; 37 : 2356 – 61 . Google Scholar CrossRef Search ADS PubMed 105 Ramiro S , Stolwijk C , van Tubergen A et al. Evolution of radiographic damage in ankylosing spondylitis: a 12 year prospective follow-up of the OASIS study . Ann Rheum Dis 2015 ; 74 : 52 – 9 . Google Scholar CrossRef Search ADS PubMed 106 Maneiro JR , Souto A , Salgado E , Mera A , Gomez-Reino JJ. Predictors of response to TNF antagonists in patients with ankylosing spondylitis and psoriatic arthritis: systematic review and meta-analysis . RMD Open 2015 ; 1 : e000017 . Google Scholar CrossRef Search ADS PubMed 107 Vastesaeger N , van der Heijde D , Inman RD et al. Predicting the outcome of ankylosing spondylitis therapy . Ann Rheum Dis 2011 ; 70 : 973 – 81 . Google Scholar CrossRef Search ADS PubMed 108 Rudwaleit M , Claudepierre P , Wordsworth P et al. Effectiveness, safety, and predictors of good clinical response in 1250 patients treated with adalimumab for active ankylosing spondylitis . J Rheumatol 2009 ; 36 : 801 – 8 . Google Scholar CrossRef Search ADS PubMed 109 Coates LC , Cawkwell LS , Ng NWF et al. Real life experience confirms sustained response to long-term biologics and switching in ankylosing spondylitis . Rheumatology 2008 ; 47 : 897 – 900 . Google Scholar CrossRef Search ADS PubMed 110 Bisson-Vaivre A , Alcaix D , Zarnitsky C et al. Efficacy of anti-TNF in patients with spondyloarthritis in absence of any imaging sign . Jt Bone Spine 2013 ; 80 : 280 – 6 . Google Scholar CrossRef Search ADS 111 Arends S , van der Veer E , Kallenberg CGM , Brouwer E , Spoorenberg A. Baseline predictors of response to TNF-α blocking therapy in ankylosing spondylitis . Curr Opin Rheumatol 2012 ; 24 : 290 – 8 . Google Scholar CrossRef Search ADS PubMed 112 Braun J , van der Heijde D , Dougados M et al. Staging of patients with ankylosing spondylitis: a preliminary proposal . Ann Rheum Dis 2002 ; 61(Suppl 3) : iii9 – 23 . Google Scholar PubMed 113 Zochling J , Braun J , van der Heijde D. Assessments in ankylosing spondylitis . Best Pract Res Clin Rheumatol 2006 ; 20 : 521 – 37 . Google Scholar CrossRef Search ADS PubMed 114 Sampaio-Barros PD , Bortoluzzo AB , Conde RA et al. Undifferentiated spondyloarthritis: a longterm followup . J Rheumatol 2010 ; 37 : 1195 – 9 . Google Scholar CrossRef Search ADS PubMed 115 Peters MJ , van der Horst-Bruinsma IE , Dijkmans BA , Nurmohamed MT. Cardiovascular risk profile of patients with spondylarthropathies, particularly ankylosing spondylitis and psoriatic arthritis . Semin Arthritis Rheum 2004 ; 34 : 585 – 92 . Google Scholar CrossRef Search ADS PubMed © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. 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RheumatologyOxford University Press

Published: Sep 25, 2017

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