Abstract
Objectives
A positive family history (PFH) of spondyloarthritis, in particular a PFH of AS or acute anterior uveitis, is associated with HLA-B27 carriership in chronic back pain patients. As it is unknown, the study aimed to investigate if a PFH contributes to diagnosing axial spondyloarthritis (axSpA) once HLA-B27 status is known.
Methods
In axSpA-suspected patients from the Assessment of SpondyloArthritis international Society (ASAS), DEvenir des Spondyloarthropathies Indifférenciéés Récentes (DESIR) and SPondyloArthritis Caught Early (SPACE) cohorts, logistic regression analyses were performed with HLA-B27 status and PFH according to the ASAS definition (ASAS-PFH) as determinants and clinical axSpA diagnosis as outcome at baseline. Analyses were repeated with a PFH of AS or acute anterior uveitis.
Results
In total, 1818 patients suspected of axSpA were analysed (ASAS n = 594, DESIR n = 647, and SPACE n = 577). In patients from the ASAS, DESIR and SPACE cohorts, respectively 23%, 39% and 38% had an ASAS-PFH, 52%, 58% and 43% were HLA-B27 positive, and 62%, 47% and 54% were diagnosed with axSpA. HLA-B27 was independently associated with an axSpA diagnosis in each cohort but an ASAS-PFH was not [ASAS cohort: HLA-B27 odds ratio (OR): 6.9 (95% CI: 4.7, 10.2), ASAS-PFH OR: 0.9 (95% CI: 0.6, 1.4); DESIR: HLA-B27 OR: 2.1 (95% CI: 1.5, 2.9), ASAS-PFH OR: 1.0 (95% CI 0.7, 1.3); SPACE: HLA-B27 OR: 10.4 (95% CI: 6.9, 15.7), ASAS-PFH OR: 1.0 (95% CI: 0.7, 1.5)]. Similar negative results were found for PFH of AS and acute anterior uveitis.
Conclusion
In three independent cohorts with different ethnical backgrounds, ASAS, DESIR and SPACE, a PFH was not associated independently of HLA-B27 with a diagnosis of axSpA. This indicates that in the vast majority of patients presenting with back pain, a PFH does not contribute to the likelihood of an axSpA diagnosis if HLA-B27 status is known.
Keywords: family history, axial spondyloarthritis, diagnosis
Rheumatology key messages
One-third of patients who are suspected of axial spondyloarthritis have a positive family history.
Positive family history was not associated with an axial spondyloarthritis diagnosis independently of HLA-B27.
These results may have implications for diagnosis and classification of axial spondyloarthritis.
Introduction
Susceptibility for axial spondyloarthritis (axSpA) is thought to be largely genetically determined with HLA-B27 as the strongest known risk factor for axSpA [1, 2]. With several studies showing an increased prevalence of this disease in relatives of axSpA patients, a positive family history (PFH) of spondyloarthritis (SpA) is thought to be a risk factor for axSpA in patients with chronic back pain [3, 4]. Currently, a PFH of SpA is defined, based on consensus, by the Assessment of SpondyloArthritis international Society (ASAS) as a PFH of AS, acute anterior uveitis (AAU), ReA, IBD and/or psoriasis in first- or second-degree relatives [5]. A PFH is a SpA feature in the ASAS classification criteria for axSpA and may contribute to classification independently of HLA-B27 status [5, 6].
We found in two European cohorts of chronic back pain patients suspected of axSpA that a PFH of AS and a PFH of AAU were positively associated with HLA-B27 carriership. However, such an association was not found for a PFH of ReA, IBD or psoriasis [7]. Moreover, another study in a worldwide population of patients suspected of axSpA showed that only a PFH of AS had an association with HLA-B27 carriership irrespective of ethnicity or degree of family relationship [8].
Hence, these two studies show that a PFH according to ASAS (ASAS-PFH), but in particular a PFH of AS, clusters with HLA-B27 positivity in chronic back pain patients [7, 8]. While a PFH can be useful in identifying chronic back pain patients who are more likely to be HLA-B27 positive and therefore may have an increased risk of axSpA, it is currently unknown if a PFH contributes to diagnosing axSpA when HLA-B27 status is known.
In the present study, we combined data of the above mentioned three cohorts of patients suspected of axSpA: the worldwide ASAS cohort, the French DEvenir des Spondyloarthropathies Indifférenciéés Récentes (DESIR) and the European SPondyloArthritis Caught Early (SPACE) cohort. The main objective of this study was to investigate if an ASAS-PFH, a PFH of AS, or a PFH of AAU contributed to a diagnosis of axSpA in an ethnically diverse group of patients with known HLA-B27 status.
Methods
The ASAS study is a longitudinal cohort in 29 centres worldwide and has included patients with a suspicion of axSpA (>3 months’ back pain, onset <45 years, with or without peripheral symptoms) or peripheral SpA (current peripheral arthritis and/or dactylitis and/or enthesitis but without current chronic back pain) [5, 9, 10]. Only patients suspected of axSpA were included in the analysis for this study. The DESIR study (NCT01648907, datalock: April 2015) is a longitudinal cohort study in 25 French centres that included patients aged 18–50 years with inflammatory back pain for ⩾3 months and <3 years [11]. The SPACE study is an ongoing inception cohort and includes patients aged ⩾16 years with chronic back pain (⩾3 months, ⩽2 years, onset ⩽45 years) from rheumatology outpatient clinics in the Netherlands, Italy, Norway and Sweden [12]. All three studies were approved by local ethical committees and informed consent was obtained before inclusion from all patients. A detailed description of all cohorts is provided elsewhere [5, 9–12].
All patients underwent a full diagnostic work-up in which clinical, laboratory and imaging data were collected at baseline, including HLA-B27 testing and radiography of the SI joints (X-SI). MRI of the SI (MRI-SI) was performed in all DESIR and SPACE patients, but in the ASAS cohort the MRI-SI was considered obligatory only for the first 20 patients for each centre. For each patient the clinical diagnosis of axSpA was established by the treating rheumatologist based on the information obtained from the full diagnostic work-up.
The ASAS expert definition of PFH is the presence of AS, AAU, psoriasis, IBD, or ReA in first- or second-degree relatives. Father, mother, sister, brother, daughter and son are first-degree relatives and grandmother, grandfather, aunt, uncle, niece and nephew are second-degree relatives in this definition [5]. In the ASAS cohort, information was available concerning which relatives had a SpA-related disease. Therefore, granddaughter, grandson, half-sister and half-brother were also considered to be second-degree relatives in addition to the ASAS definition.
Data analysis
Baseline data of patients suspected of axSpA in the ASAS, DESIR and SPACE cohorts were analysed. Descriptive statistics were used to present demographic and clinical characteristics for each cohort. In each cohort, univariable logistic regression models were performed with HLA-B27 status and ASAS-PFH as determinants and a clinical axSpA diagnosis as outcome. The analyses were repeated in multivariable models with both determinants. All analyses were repeated with a PFH of AS and a PFH of AAU. Interactions were tested between HLA-B27 status and each PFH. Interaction terms with P < 0.10 were considered to be statistically significantly. Age and gender were tested for confounding. Results were stratified for age, gender and ethnicity in order to test whether results differed between subgroups. Data analyses were performed with Stata SE v.14 software (StataCorp, College Station, TX, USA).
Results
In total, 1818 patients suspected of axSpA and with complete data on family history at baseline were analysed (ASAS n = 594, DESIR n = 647, SPACE n = 577) (Table 1). MRI-SI results were available for 424/594 (71%) ASAS patients, 636/647 (98%) DESIR patients and 565/577 (98%) SPACE patients. ASAS, DESIR and SPACE patients, respectively, had a mean (s.d.) symptom duration of 85.7 (108.4), 18.2 (10.5) and 13.3 (7.1) months; 46%, 47% and 38% were male; 59%, 89% and 94% were Caucasian; 52%, 58% and 43% were HLA-B27 positive; 62%, 47% and 54% received a clinical diagnosis of axSpA. An ASAS-PFH was reported in 23% of ASAS patients, 39% of DESIR patients and 38% of SPACE patients. A PFH of AS and a PFH of AAU were reported in 15% and 1% of ASAS patients, 20% and 4% of DESIR patients and 18% and 6% of SPACE patients, respectively.
Table 1.
Baseline characteristics of the patients suspected of axSpA in the ASAS, DESIR and SPACE cohort
| Characteristic | ASAS (n = 594) | DESIR (n = 647) | SPACE (n = 577) |
|---|---|---|---|
| Age at baseline, mean (s.d.), years | 33.7 (11.7) | 33.6 (8.6) | 30.8 (8.1) |
| Male, n (%) | 276 (46) | 305 (47) | 221 (38) |
| Caucasian, n (%) | 348 (59) | 577 (89) | 454/484 (94) |
| Duration of back pain, mean (s.d.), months | 85.7 (108.4)a | 18.2 (10.6)a | 13.3 (7.1) |
| IBP, n (%) | 301/532 (57) | 647 (100)b | 396/576 (69) |
| Good response to NSAIDsc, n (%) | 274 (46) | 515/644 (80) | 263/563 (47) |
| Peripheral arthritis, n (%) | 197 (33) | 363 (56) | 97/575 (17) |
| Enthesitis, n (%) | 241 (41) | 312 (48) | 121 (21) |
| Dactylitis, n (%) | 23 (4) | 83 (13) | 35 (6) |
| AAU, n (%) | 53 (9) | 51 (8) | 47 (8) |
| Psoriasis, n (%) | 22 (4) | 97 (15) | 77 (13) |
| IBD, n (%) | 8 (1) | 23 (4) | 38 (7) |
| Positive family history according to ASAS definition, n (%) | 135 (23) | 249 (39) | 218 (38) |
| A positive family history of | |||
| AS, n (%) | 87 (15) | 127 (20) | 104 (18) |
| AAU, n (%) | 7 (1) | 29 (4) | 34 (6) |
| ReA, n (%) | 8 (1) | 6 (1) | 19/563 (3) |
| IBD, n (%) | 12 (2) | 32 (5) | 32/570 (6) |
| Psoriasis, n (%) | 36 (6) | 129 (20) | 95/571 (17) |
| HLA-B27 positivity, n (%) | 310 (52) | 376/646 (58) | 246 (43) |
| Elevated CRP/ESR, n (%) | 185 (31) | 254 (39) | 188 (33) |
| Radiographic sacroiliitisd, n (%) | 119/593 (20) | 172 (27) | 80/570 (14) |
| Sacroiliitis on MRId, n (%) | 189/424 (45) | 207/636 (33) | 207/565 (37) |
| Clinical diagnosis of axSpAe, n (%) | 368 (62) | 302 (47) | 313 (54) |
<5% missing values.
Inclusion criterion.
Back pain not present anymore or is much better 24–48 h after a full dose of NSAID.
Imaging based on local reading of the SI joints.
Level of confidence regarding the diagnosis is ≥6 in ASAS and SPACE, ≥8 in DESIR. AAU: acute anterior uveitis; ASAS: Assessment of SpondyloArthritis international Society; (ax)SpA: (axial) spondyloarthritis; DESIR: DEvenir des Spondyloarthropathies Indifférenciéés Récentes; IBP: inflammatory back pain; SPACE: SPondyloArthritis Caught Early.
In the univariable analysis, HLA-B27 status was significantly associated with an axSpA diagnosis in all three cohorts (Table 2). An ASAS-PFH (Table 2) and a PFH of AAU (Supplementary Table S2, available at Rheumatology online) were univariately associated with an axSpA diagnosis in the SPACE cohort, but not in ASAS and DESIR cohorts. A PFH of AS was associated with diagnosis of axSpA in the ASAS cohort, but not in the DESIR and SPACE cohorts (Supplementary Table S1, available at Rheumatology online).
Table 2.
Results of the contribution of a PFH and HLA-B27 to a clinical diagnosis of axSpA
| Determinant | axSpA+ | axSpA− | OR (95% CI) | P-value |
|---|---|---|---|---|
| ASAS cohort | ||||
| Univariable analysis: HLA-B27 | ||||
| HLA-B27+ | 254 (43%) | 56 (9%) | 6.7 (4.7, 9.8) | <0.001 |
| HLA-B27− | 114 (19%) | 170 (29%) | 1.0 (ref) | (ref) |
| Univariable analysis: ASAS-PFH | ||||
| ASAS-PFH+ | 91 (15%) | 44 (7%) | 1.4 (0.9, 2.0) | 0.138 |
| ASAS-PFH− | 277 (47%) | 182 (31%) | 1.0 (ref) | (ref) |
| Multivariable analysis: HLA-B27 and ASAS-PFH | ||||
| HLA-B27+ | 254 (43%) | 56 (9%) | 6.9 (4.7, 10.2) | <0.001 |
| ASAS-PFH+ | 91 (15%) | 44 (7%) | 0.9 (0.6, 1.4) | 0.561 |
| DESIR cohort | ||||
| Univariable analysis: HLA-B27 | ||||
| HLA-B27+ | 204 (32%) | 172 (27%) | 2.1 (1.5, 2.9) | <0.001 |
| HLA-B27− | 98 (15%) | 172 (27%) | 1.0 (ref) | (ref) |
| Univariable analysis: ASAS-PFH | ||||
| ASAS-PFH+ | 117 (18%) | 132 (20%) | 1.0 (0.7, 1.4) | 0.900 |
| ASAS-PFH− | 185 (29%) | 213 (33%) | 1.0 (ref) | (ref) |
| Multivariable analysis: HLA-B27 and ASAS-PFH | ||||
| HLA-B27+ | 204 (32%) | 172 (27%) | 2.1 (1.5, 2.9) | <0.001 |
| ASAS-PFH+ | 117 (18%) | 132 (20%) | 1.0 (0.7, 1.3) | 0.772 |
| SPACE cohort | ||||
| Univariable analysis: HLA-B27 | ||||
| HLA-B27+ | 205 (36%) | 41 (7%) | 10.3 (6.9, 15.5) | <0.001 |
| HLA-B27− | 108 (19%) | 223 (39%) | 1.0 (ref) | (ref) |
| Univariable analysis: ASAS-PFH | ||||
| ASAS-PFH+ | 132 (23%) | 86 (15%) | 1.5 (1.1, 2.1) | 0.018 |
| ASAS-PFH− | 181 (31%) | 178 (31%) | 1.0 (ref) | (ref) |
| Multivariable analysis: HLA-B27 and ASAS-PFH | ||||
| HLA-B27+ | 205 (36%) | 41 (7%) | 10.4 (6.9, 15.7) | <0.001 |
| ASAS-PFH+ | 132 (23%) | 86 (15%) | 1.0 (0.7, 1.5) | 0.921 |
Statistically significant associations are shown in bold. ASAS: Assessment of SpondyloArthritis international Society; (ax)SpA: (axial) spondyloarthritis; DESIR: DEvenir des Spondyloarthropathies Indifférenciéés Récentes; OR: odds ratio; PFH: positive family history; SPACE: SPondyloArthritis Caught Early.
In the multivariable models, HLA-B27 status was independently and positively associated with a diagnosis of axSpA but such an independent positive association was not found for ASAS-PFH in any cohort [ASAS cohort: HLA B-27 odds ratio (OR): 6.9, 95% CI: 4.7, 10.2; ASAS-PFH OR: 0.9, 95% CI: 0.6, 1.4; DESIR cohort: HLA-B27 OR: 2.1, 95% CI: 1.5, 2.9; ASAS-PFH OR: 1.0, 95% CI: 0.7, 1.3; SPACE cohort: HLA-B27 OR: 10.4, 95% CI: 6.9, 15.7; ASAS-PFH OR: 1.0, 95% CI: 0.7, 1.5] (Table 2). Similar results were found for the multivariable models with a PFH of AS or a PFH of AAU in the ASAS, DESIR and SPACE cohorts (Supplementary Tables S1 and S2, available at Rheumatology online) although in the SPACE cohort only a PFH of AS was negatively associated with an axSpA diagnosis.
Statistical interactions between HLA-B27 status and a PFH were tested for each association. No statistically significant interactions were found, except the interaction between HLA-B27 status and a PFH in the SPACE cohort (P = 0.016). Compared with the HLA-B27 negative/PFH negative subgroup (n = 234) as reference (OR = 1), the HLA-B27 negative/PFH positive (n = 97) subgroup had an OR of 1.4 (95% CI: 0.9, 2.3) on a diagnosis of axSpA, the HLA-B27 positive/PFH negative subgroup (n = 125) had an OR of 16.8 (95% CI: 9.2, 30.9) and the HLA-B27 positive/PFH positive subgroup (n = 121) had an OR of 8.4 (95% CI: 5.0, 14.0). This illustrates that PFH does not contribute to a diagnosis of axSpA, not even in the absence of HLA-B27 positivity.
No confounding by age or gender was found and similar results were found when data were stratified for mean age or gender (data not shown). Results were also stratified for Caucasian vs non-Caucasian patients and we found similar results for Caucasian and non-Caucasian patients (data not shown).
Discussion
In all three cohorts with different ethnical backgrounds, HLA-B27 carriership was associated with a clinical diagnosis of axSpA whereas conflicting results were found in the association between a PFH and an axSpA diagnosis in univariable analyses, irrespective of the definitions tested. In multivariable analyses, HLA-B27 was independently associated with an axSpA diagnosis in each cohort but an ASAS-PFH, a PFH of AS and a PFH of AAU were not (positively) associated with an axSpA diagnosis.
In the multivariable analysis, in the SPACE cohort but not in the ASAS or DESIR cohort, a PFH of AS had a negative association with an axSpA diagnosis after adding HLA-B27 positivity. This is likely a spurious finding as only positive associations (statistically significant or not) with an axSpA diagnosis were found in all three cohorts. Moreover, no interaction was found between HLA-B27 status and a PFH of AS in any of the three cohorts.
A PFH had, at best, only a modest association with a clinical diagnosis of axSpA before adjustment of HLA-B27 and only in the SPACE cohort was this association statistically significant. It was previously shown that HLA-B27 and imaging are key elements for making a diagnosis of axSpA, with other SpA features, including a PFH, playing a more modest role [13]. This can explain the modest association between a PFH and the clinical diagnosis, although a PFH is related to HLA-B27 positivity [7, 8].
We have repeatedly demonstrated that a PFH of SpA helps in identifying chronic back pain patients at increased risk of axSpA as a PFH of SpA is positively associated with HLA-B27 carriership [7, 8]. However, the effect of this positive association is apparently entirely taken over by a positive test for HLA-B27. Although in all three cohorts a few patients who were HLA-B27 negative but had a PFH were considered to have axSpA, our data show at group level that when knowledge about HLA-B27 status is available, a positive PFH does not have further influence on a diagnosis in an ethnically diverse group of patients. Thus, this finding casts doubt about the relative weight of PFH in the classification criteria for axSpA, in which PFH and HLA-B27 have independent contributions.
Nevertheless, our findings are in line with previous studies in which a PFH is a feature of HLA-B27 positive but not of HLA-B27 negative axSpA [14, 15]. In literature HLA-B27 negative familial axSpA was found in only a few cases suggesting that HLA-B27 negative familial axSpA may exist. However, these patients were typed using currently obsolete methods with higher risks of mistypings [16, 17].
Given the potential implications for clinical practice it is important to stress several limitations. The DESIR cohort had inflammatory back pain as an inclusion criterion, while the ASAS and SPACE cohorts included patients with chronic back pain. Nevertheless, similar results were found in all three cohorts. Although data of three cohorts were analysed, there was an under-representation of patients with for instance an African or South American ethnicity. The ASAS cohort included predominantly patients with a Caucasian or Asian ethnicity and the DESIR and SPACE cohorts included predominantly Caucasian patients, which corresponds to the two largest populations of axSpA patients worldwide [18]. Another limitation is the self-reported family history by patients and this could have led to an over- or underestimation of the investigated effects. Nevertheless, this is similar in most clinical settings where the physician usually has to depend on patient-reported information about the family history. Further, HLA-B27 status was known for each patient in each cohort, just as in the clinical setting, and thereby a similar amount of bias was present in each case.
It is important to emphasize that the current study investigated only patients with chronic back pain suspected of axSpA. Therefore, the results are not applicable to patients with predominantly peripheral symptoms. In these patients a PFH of other SpA-related diseases, such as psoriasis, could be valuable in diagnosing patients with peripheral SpA [9].
Furthermore, we have investigated the association between a PFH and a diagnosis of axSpA when the HLA-B27 status is known. However, rheumatologists or other clinicians might have limited access to HLA-B27 testing. In this case, we would like to recommend assessing the presence of a PFH, especially a PFH of AS. A PFH of AS is associated with HLA-B27 positivity and could therefore be used to identify patients with an increased risk of axSpA [7, 8].
In conclusion, in three independent cohorts including one worldwide cohort, a PFH was not associated independently of HLA-B27 with a diagnosis of axSpA in patients suspected of axSpA. These results may have implications for diagnosis and classification.
Supplementary Material
Acknowledgements
We thank all the investigators and teams involved in the ASAS, SPACE and DESIR cohort.
Funding: This work has been supported by unrestricted grants from French Society of Rheumatology and Pfizer Ltd France for the DESIR study. The DESIR study is conducted as a Programme Hospitalier de Recherche Clinique (PHRC), which is sponsored by the Assistance Publique–Hôpitaux de Paris.
Disclosure statement: The authors have declared no conflicts of interest.
References
- 1. 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. [DOI] [PubMed] [Google Scholar]
- 2. Sieper J, Poddubnyy D.. Axial spondyloarthritis. Lancet 2017;390:73–84. [DOI] [PubMed] [Google Scholar]
- 3. Bedendo A, Glorioso S, Venturi Pasini C et al. . A family study of ankylosing spondylitis. Rheumatol Int 1984;5:29–32. [DOI] [PubMed] [Google Scholar]
- 4. 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. [DOI] [PubMed] [Google Scholar]
- 5. 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. [DOI] [PubMed] [Google Scholar]
- 6. 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. [DOI] [PubMed] [Google Scholar]
- 7. Ez-Zaitouni Z, Hilkens A, Gossec L et al. . Is the current ASAS expert definition of a positive family history useful in identifying axial spondyloarthritis? Results from the SPACE and DESIR cohorts. Arthritis Res Ther 2017;19:118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. van Lunteren M, Sepriano A, Landewé R et al. . Do ethnicity, degree of family relationship, and spondyloarthritis subtype in affected relatives influence the association between a positive family history for spondyloarthritis and HLA-B27 carriership? Results from the worldwide ASAS cohort. Ann Rheum Dis 2018;77:335–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Rudwaleit M, van der Heijde D, Landewé R et al. . The Assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann Rheum Dis 2011;70:25–31. [DOI] [PubMed] [Google Scholar]
- 10. 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. [DOI] [PubMed] [Google Scholar]
- 11. Dougados M, d’Agostino M-A, Benessiano J et al. . The DESIR cohort: a 10-year follow-up of early inflammatory back pain in France: study design and baseline characteristics of the 708 recruited patients. Joint Bone Spine 2011;78:598–603. [DOI] [PubMed] [Google Scholar]
- 12. van den Berg R, de Hooge M, van Gaalen F et al. . Percentage of patients with spondyloarthritis in patients referred because of chronic back pain and performance of classification criteria: experience from the Spondyloarthritis Caught Early (SPACE) cohort. Rheumatology 2013;52:1492–9. [DOI] [PubMed] [Google Scholar]
- 13. Ez-Zaitouni Z, Bakker PAC, van Lunteren M et al. . Presence of multiple spondyloarthritis (SpA) features is important but not sufficient for a diagnosis of axial spondyloarthritis: data from the SPondyloArthritis Caught Early (SPACE) cohort. Ann Rheum Dis 2017;76:1086–92. [DOI] [PubMed] [Google Scholar]
- 14. Linssen A, Feltkamp TEW.. B27 positive diseases versus B27 negative diseases. Ann Rheum Dis 1988;47:431–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Akkoç N, Yarkan H, Kenar G, Khan MA.. Ankylosing spondylitis: HLA-B*27-positive versus HLA-B*27-negative disease. Curr Rheumatol Rep 2017;19:26. [DOI] [PubMed] [Google Scholar]
- 16. Calin A, Marder A, Becks E, Burns T.. Genetic differences between B27 positive patients with ankylosing spondylitis and B27 positive healthy controls. Arthritis Rheum 1983;26:1460–4. [DOI] [PubMed] [Google Scholar]
- 17. van der Linden S, Valkenburg HA, Cats A.. Evaluation of diagnostic criteria for ankylosing spondylitis. Arthritis Rheum 1984;27:361–8. [DOI] [PubMed] [Google Scholar]
- 18. Dean LE, Jones GT, MacDonald AG et al. . Global prevalence of ankylosing spondylitis. Rheumatology 2014;53:650–7. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.