Influence of HLA-B27 on the Ankylosing Spondylitis phenotype: results from the REGISPONSER database

Influence of HLA-B27 on the Ankylosing Spondylitis phenotype: results from the REGISPONSER database Objective: To assess HLA-B27 influence on the clinical phenotype of Ankylosing Spondylitis (AS) patients. Method: An observational, cross-sectional and descriptive study of AS patients from the Spanish REGISPONSER database was performed. Demographic, clinical, disease activity (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP)), and radiographic data (Bath Ankylosing Spondylitis Radiology Index (BASRI) score) were compared regarding HLA-B27 status. A univariate and multivariate analysis was performed to identify variables independently related to the presence of HLA-B27. Results: Data from 1235 patients (74.8% male) were analyzed; 1029 were HLA-B27 positive (83%). HLA-B27-positive patients showed higher family aggregation and an earlier onset of disease compared with those who were HLA-B27 negative. HLA-B27-negative patients presented statistically higher BASDAI and BASFI scores and higher prevalence of arthritis, dactylitis, and extra-articular manifestations (psoriasis and inflammatory bowel disease (IBD)) but not anytime uveitis compared with those who were HLA-B27 positive. In the multivariate analysis, family history (odds ratio (OR) 2.10, 95% confidence interval (CI) 1.27–3.49), younger age at diagnosis (OR 0.97, 95% CI 0.96–0.98), presence of peripheral arthritis (OR 0.53, 95% CI 0.32–0.89), dactylitis (OR 0.16, 95% CI 0.05–0.56), psoriasis (OR 0.45, 95% CI 0.26–0.78), and IBD (OR 0.22, 95% CI 0.12–0.40) were the main variables independently related to the presence or not of HLA-B27. Conclusion: In Caucasian AS patients, the presence of HLA-B27 is related to an earlier disease onset and higher family aggregation. Absence of HLA-B27 is related to a higher frequency of peripheral arthritis, dactylitis, and extra-articular manifestations. Being HLAB27 positive is not related to a higher burden of disease or anytime uveitis. Keywords: Ankylosing Spondylitis, HLA-B27, Structural damage, Phenotype, Uveitis Background sites such as peripheral arthritis, enthesitis, dactylitis, Axial Spondyloarthritis (AxSpA) includes an heteroge- and extra-articular manifestations as uveitis, psoriasis, neous group of rheumatisms characterized by their and inflammatory bowel disease (IBD). Frequently, dis- strong association with HLA-B27 and axial skeleton in- ease onset occurs in patients 20–30 years of age and, if volvement. Ankylosing Spondylitis (AS) is the main dis- no effective treatment is given, it can lead to severe dis- ease of this group and is clinically defined by ability in nearly a third of individuals [1]. Its prevalence inflammatory back pain, but it can also involve other is around 0.2–0.3% depending on the geographical dis- tribution of HLA-B27 [2, 3]. HLA-B27, since its discov- ery in 1973 [4], constitutes the main genetic factor * Correspondence: jgratacosmas@gmail.com related to disease etiopathogenesis. However, nearly 10– Rheumatology Department, Consorci Corporació Sanitària Parc Taulí, Institut 20% of patients with defined AS do not carry HLA-B27, d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí s/n, 08208 Sabadell, Barcelona, Spain which increases to 40% when analyzing nonradiographic Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Arévalo et al. Arthritis Research & Therapy (2018) 20:221 Page 2 of 6 axial spondyloarthritis (nrAxSpA) [5]. Previous studies having HLA-B27 typing available, and finally 1235 of suggest a relationship between HLA-B27 and axial mani- these having no data of interest missing (Fig. 1). Recruit- festations including structural progression in early ment of patients started in March 2004 and finished in AxSpA [5]. Moreover, a younger age of onset, more fam- March 2007. All patients included signed an informed ily history [5, 6], and less prevalence of psoriasis and consent form, and the project was approved by the eth- IBD [5] have also been reported. Nevertheless, there are ical committee of all participant hospitals. More infor- few studies evaluating the role of HLA-B27 in defined mation about the methodology and data inclusion are AS patients [7–9], with some of them focused on radio- detailed in a previous publication by Collantes et al. [14]. graphic progression [10–12] and reporting controversial The study included the following clinical and bio- results [13]. The main objective of the present study was logical variables: age (in years), gender, the presence of to evaluate the HLA-B27 influence on the clinical ex- HLA-B27, age at disease onset (in years), disease pression of defined AS patients. For this purpose, we duration (in years), diagnosis delay (in years), axial reviewed data from the REGISPONSER database [14] symptoms, peripheral involvement (peripheral arthritis, which includes more than 1000 AS patients, of whom coxitis, enthesitis, and dactylitis), extra-articular about 20% are HLA-B27 negative. manifestations confirmed by a specialist (uveitis, IBD, psoriasis, palmoplantar pustulosis, balanitis, prostatitis), Material and methods clinical disease activity (Bath Ankylosing Spondylitis Dis- This is a comparative, cross-sectional study including all ease Activity Index (BASDAI), 0–10 cm), clinical disabil- patients fulfilling AS New York modified criteria from ity (Bath Ankylosing Spondylitis Functional Index the REGISPONSER. REGISPONSER is a Spanish registry (BASFI), 0–10 cm), biological disease activity (erythro- that includes 2367 patients who fulfilled European Spon- cyte sedimentation rate (ESR) and C-reactive protein dyloarthropathy Study Group (ESSG) criteria for spon- (CRP)), and structural damage (Bath Ankylosing Spon- dyloarthritis. Of these, 1422 had radiographic sacroiliitis dylitis Radiology Index (BASRI)) assessed by a local radi- as per New York modified criteria, with 1270 of these ologist and confirmed by an experienced rheumatologist. Fig. 1 Flow chart of patients included in the study from the REGISPONSER database. AS Ankylosing Spondylitis, ESSG European Spondyloarthropathy Study Group, nrAxSpA nonradiographic axial spondyloarthritis, NYm New York modified, PsA psoriatic arthritis, ReA reactive arthritis, USpA undifferentiated spondyloarthritis Arévalo et al. Arthritis Research & Therapy (2018) 20:221 Page 3 of 6 Statistical analysis extra-articular manifestations, especially psoriasis (5.9% vs A descriptive analysis of the variables was performed 14.6%; p < 0.001) and IBD (3.6% vs 11.7%; p <0.001) com- using absolute and relative frequencies for qualitative pared with HLA-B27-positive patients. On the other hand, variables and mean with standard deviation for the this study did not find any statistical differences regarding quantitative variables. A 95% confidence interval (CI) axial clinical disease expression (neck pain, low back pain, was calculated. For bivariate analysis the Chi-squared and sacroiliac joint symptoms), the presence of enthesitis test was used, and the Student t test was used for inde- (present in 6.1% of subjects) or uveitis (22.4% in pendent data. Finally, a multiple logistic regression HLA-B27-positive and 19.4% in HLA-B27-negative pa- model was performed including the following variables: tients; not significant). gender, age, age at onset, disease duration, signs and In the multivariate analysis, family history (OR 2.10, symptoms at onset and during follow-up, peripheral and 95% CI 1.27–3.49; p = 0.004), younger age at diagnosis extra-articular manifestations, BASDAI, BASFI, BASRI, (OR 0.97, 95% CI 0.96–0.98; p < 0.001), and the presence ESR, and CRP. The degree of association was expressed of peripheral arthritis (OR 0.53, 95% CI 0.32–0.89; p = as the odds ratio (OR) and Cornfield confidence interval 0.016), dactylitis (OR 0.16, 95% CI 0.05–0.56; p = 0.004), was established at 95% using Wald statistics. Variables psoriasis (OR 0.45, 95% CI 0.26–0.78; p = 0.005), and with p ≥ 0.15 were suppressed from the model one by IBD (OR 0.22, 95% CI 0.12–0.40; p < 0.001) were the one (backward stepwise procedure). Comparison be- main variables independently related to the presence or tween the reduced model and the one including sup- not of HLA-B27. All results are shown in Table 1. pressed variables was made using the likelihood ratio test (G statistic). A scale of continuous variables was Discussion evaluated with the Bow Tidwell test. Possible interac- This is the most extensive study performed comparing tions between variables were studied as possible con- clinical characteristics of Caucasian AS patients regard- founding factors, considering them if the percentage ing HLA-B27. The study confirms the association of change of coefficients was higher than 20%. The Hosmer HLA-B27 with earlier disease onset and family aggrega- Lemeshow statistic was performed to assess the good- tion. Moreover, the study proves that the absence of ness of fit. All contrasts were bilateral and considered HLA-B27 in AS patients is related to a higher frequency significant when p < 0.05. Data were collected, proc- of peripheral arthritis, psoriasis, and IBD. Finally, our essed, and analyzed using SPSS v.17. data do not support the relationship between HLA-B27 and the severity of axial structural damage in AS Results patients. Data from 1235 patients were collected, with 1029 (83.3%) The prevalence of HLA-B27 in our study reaches 83%, patients being HLA-B27 positive and 206 (17.7%) patients similar to that previously reported in AS patients [2]. being HLA-B27 negative. Male gender was observed in We observed a male:female ratio of 3:1, comparable with 924 (74.8%) patients with no differences between both that shown in previous studies in AS patients regardless groups (74.7% of males in the HLA-B27-positive group vs. of the presence of HLA-B27 [15], but clearly different 75.2% in the HLA-B27-negative group; not significant). from the previously reported gender ratio in nrAxSpA HLA-B27-positive patients showed a higher family aggre- patients where there is not a male predominance [5, 6]. gation (22.1% vs 12%; p = 0.002), younger age (47.9 vs 50.4 Our results are also not in accordance with those previ- years; p = 0.012), and younger age at symptom onset (26.2 ously published by Yang et al. who reported a clear male vs 30.6 years; p < 0.001) and at diagnosis (33.9 vs 39 years; predominance in AS patients associated with the pres- p < 0.001) compared with HLA-B27-negative patients. ence of HLA-B27 [9]. However, that study was per- However, the absence of HLA-B27 did not lead to a formed in an Asian population, and race differences greater diagnosis delay (7.8 vs. 8.5 years; not significant). need to be considered. Analyzing disease activity, HLA-B27-negative patients Our study, using the BASRI score, did not show statis- expressed a higher disease activity measured by BASDAI tical differences regarding axial structural damage in (4.1 ± 2.3 vs 4.4 ± 2.4; p = 0.047) and higher clinical disabil- HLA-B27-positive AS patients compared with HLA-B27 ity measured by BASFI (3.8 ± 2.7 vs 4.3 ± 2.9; p =0.005) -negative patients. In this sense, our data are in accord- compared with HLA-B27-positive patients. However, no ance with those reported in the GESPIC cohort [6]. Pre- differences were observed between groups regarding the vious data regarding the influence of HLA-B27 on the biological markers analyzed (ESR and CRP), nor in struc- progression and extent of radiographic axial damage in tural damage expressed by BASRI (7.2 vs 7.4; not signifi- AS patients are controversial due to heterogeneity in cant). Moreover, HLA-B27-negative patients showed a published series and the methods used when measuring higher prevalence of peripheral arthritis (15.4% vs 21.8%; structural damage [9–13]. In the DESIR cohort, the p = 0.023), dactylitis (0.8% vs 3.9%; p = 0.001), and authors observed higher radiographic damage in early Arévalo et al. Arthritis Research & Therapy (2018) 20:221 Page 4 of 6 Table 1 Univariate and multivariate analysis between the HLA-B27-positive and HLA-B27-negative groups B27 negative B27 postive Univariate analysis Multivariate analysis a a n (= 206) Mean ± SD or % n (= 1029) Mean ± SD or % p OR 95% CI p Men 155 75.2 769 74.7 NS Family history 22 12 216 22.1 0.002 2.1 1.27–3.49 0.004 Age (years), mean ± SD 206 50,4 ± 12,9 1025 47,9 ± 13 0,012 Age at onset (years), mean ± SD 204 30.6 ± 12.3 1010 26.2 ± 9.9 < 0.001 Age at diagnosis (years), mean ± SD 199 39 ± 12.3 1002 33.9 ± 11.5 < 0.001 0.97 0.96–0.98 < 0.001 Disease duration since first symptom 204 19.8 ± 12.8 1013 21.9 ± 13.1 0.038 (years), mean ± SD Diagnosis delay (years), mean ± SD 198 8.5 ± 9.6 993 7.8 ± 9.2 NS Disease duration since diagnosis (years), 199 11.3 ± 9.3 1004 14 ± 10.6 0.001 mean ± SD Axial manifestations Cervicalgia 28 13.6 103 10 NS Lumbalgia 148 71.8 741 72 NS Sacroiliac syndrome 85 41.3 435 42.3 NS Peripheral manifestations Peripheral arthritis 45 21.8 158 15.4 0.023 0.53 0.32–0.89 0.016 Coxitis 6 2.9 32 3.1 NS Enthesitis 10 4.9 65 6.3 NS Dactylitis 8 3.9 8 0.8 0.001 0.16 0.05–0.56 0.004 Extra-articular manifestations Psoriasis 30 14.6 61 5.9 < 0.001 0.45 0.26–0.78 0.005 Inflammatory bowel disease 24 11.7 37 3.6 < 0.001 0.22 0.12–0.4 < 0.001 Urethritis, cervicitis, diarrhea 4 1.9 7 0.7 NS Anterior uveitis 40 19.4 230 22.4 NS Palmoplantar pustulosis 6 2.9 4 0.4 0.002 0.12 0.02–0.64 0.013 Balanitis 4 1.9 4 0.4 0.022 Prostatitis 1 0.5 7 0.7 NS BASRI score, mean ± SD 194 7.4 ± 4.1 974 7.2 ± 3.9 NS BASDAI score, mean ± SD 206 4.4 ± 2.4 1029 4.1 ± 2.3 0.047 BASFI score, mean ± SD 206 4.3 ± 2.9 1028 3.8 ± 2.7 0.005 0.94 0.88–1 0.037 ESR (mm/1 h), mean ± SD 174 19 ± 15.98 977 18.3 ± 16.3 NS CRP (mg/L), mean ± SD 174 10.2 ± 17.7 975 9.2 ± 13.7 NS BASDAI Bath Ankylosing Spondylitis Disease Activity Index, BASFI Bath Ankylosing Spondylitis Functional Index, BASRI Bath Ankylosing Spondylitis Radiology Index, CRP C-reactive protein, ESR erythrocyte sedimentation rate, NS not significant For qualitative variables as percentage (%) and for quantitative variables as mean ± standard deviation (SD) AxSpA patients related to the presence of HLA-B27, but unknown variables related to the genetic and/or environ- only in the sacroiliac joints [5]. No differences in radio- mental factors when comparing different genetic popula- graphic spine damage measured by the modified Stoke tions. Moreover, since male gender seems to be a strong Ankylosing Spondylitis Spine Score (mSASSS) were predictive factor for radiographic damage [6, 16] and the found. When looking at studies including definite AS male ratio in HLA-B27-positive AS patients was clearly patients, our results differ from those reported by Yang higher in the study by Yang et al. compared with our study et al. [9], who found a higher radiographic extent of [9], we need to consider this variable as a potential explan- structural damage in Asian AS patients and also in the ation for the differences observed between both studies. HLA-B27-positive compared to the HLA-B27-negative Finally, it is also interesting to remark that disease dur- patients. We do not have any precise explanation for these ation was significantly higher in HLA-B27-positive AS pa- observed differences, but we cannot exclude some tients than the other group. Given that disease duration is Arévalo et al. Arthritis Research & Therapy (2018) 20:221 Page 5 of 6 one of the main factors related to structural damage, the outcomes must be interpreted with caution. Our study did data reported here do not support a major role of not support a higher percentage of uveitis in the presence HLA-B27 in the extension of the structural damage in de- or not of HLA-B27. However, we only evaluated the fined AS patients. presence or not as a dichotomic measure, and thus we can- Our data appear to confirm previous studies suggesting not exclude a higher frequency of uveitis flares in AS that HLA-B27 is associated with a younger disease onset HLA-B27-positive patients compared with negative pa- and greater family aggregation in AS patients [9, 13]. Simi- tients. The BASRI score was used instead of the mSASSS, lar results were also described in early forms of which is a more sensitive score to evaluate axial structural HLA-B27-positive patients from the DESIR [5] and GES- changes [20]. Moreover, we do not have data on axial mag- PIC [6] cohorts, in such a way that HLA-B27 seems to an- netic resonance imaging (MRI), and thus we could not ticipate the clinical manifestations and disease onset. evaluate the influence of bone marrow edema on the po- Although HLA-B27 is the strongest genetic factor related tential progression of structural damage. We evaluated only to familiar aggregation of the disease, we observed that definite AS patients with a long disease evolution (around 12% of our HLA-B27-negative patients also had a familial 8 years) and thus we cannot exclude a potential influence background. As this is much higher than that observed in on radiographic progression of HLA-B27 in the early stages the general population, these data support the existence of of the disease. In this sense, it is not possible to extrapolate unknown genetic factors other than HLA-B27 that have a these results to nrAxSpA. However, the data observed sug- role in the familial aggregation of the disease. gest that, despite HLA-B27 typing, other genetic or envir- We did not observe differences in axial symptoms regard- onmental factors might play a major role in bone structural less of the presence or not of HLA-B27. However, we damage in AS patients. Finally, given that BASDAI scores observed a significantly higher frequency of peripheral arth- were not recorded separately, the Ankylosing Spondylitis ritis, dactylitis, psoriasis, and IBD in HLA-B27-negative AS Disease Activity score could not be calculated. patients. This association has also been previously de- scribed in early forms of AxSpA [5]inwhich thepropor- Conclusion tion of HLA-B27-negative patients is much higher than in In summary, this is the most extensive study analyzing dif- definite AS patients. Moreover, our data do not support a ferences in Caucasian AS patients regarding their higher clinical burden of disease in AS patients regarding HLA-B27 status. This study confirms the previously re- thepresenceofHLA-B27.Inthis sense, HLA-B27-negative ported association in AS patients between HLA-B27 and AS patients showed significantly higher BASDAI and an earlier disease onset and greater family aggregation. BASFI scores, even though there were no differences in However, and interestingly, we do not support an associ- biologic parameters (ESR and CRP). ation between HLA-B27 and the extent of axial structural Around a fifth of patients included in the analysis had at damage, or a higher clinical burden of the disease. More- least one episode of uveitis, this being the most frequent over, we cannot prove an association between the pres- extra-articular manifestation as has been shown in previ- ence of anytime uveitis and HLA-B27 in definite AS ous studies [17]. Classically, HLA-B27 has been related to patients. On the other hand, the absence of HLA-B27 is the presence of uveitis regardless of the presence or not of related, in AS patients, to a higher frequency of peripheral adefinite AS[18, 19]; thus, in this sense our data are arthritis, dactylitis, and extra-articular manifestations. unexpected. However, the results previously reported ana- Abbreviations lyzing the potential association between HLA-B27 in AS AS: Ankylosing Spondylitis; AxSpA: Axial spondyloarthritis; BASDAI: Bath patients and the presence of uveitis are quite controversial Ankylosing Spondylitis Disease Activity Index; BASFI: Bath Ankylosing [7, 9, 13]. It is important to note that 19.4% of Spondylitis Functional Index; BASRI: Bath Ankylosing Spondylitis Radiology Index; CI: Confidence interval; CRP: C-reactive protein; ESR: Erythrocyte HLA-B27-negative AS patients had at least one episode of sedimentation rate; ESSG: European Spondyloarthropathy Study Group; uveitis. These results, together with the absence of an as- IBD: Inflammatory bowel disease; mSASSS: Modified Stoke Ankylosing sociation between episodes of uveitis and axial inflamma- Spondylitis Spine Score; nrAxSpA: Nonradiographic axial spondyloarthritis; OR: Odds ratio tion in AS patients, suggest the need for further studies to evaluate the etiopathogenesis of uveitis in AS patients. Acknowledgements Finally, we did not observe any differences in the fre- REGISPONSER group - listed below are the principal investigator. quency of coxitis between both groups, in contrast to the HU REINA SOFÍA- Eduardo Collantes Estévez à Main center and ethical committee H BELLVITGE-Xavier Juanola Roura data reported by Yang et al. [9]. However, the prevalence HU JUAN CANALEJO-Jose Luis Fernández Sueiro of coxitis in our study was low (3.1 and 2.9%, respectively) HU GREGORIO MARAÑÓN- Carlos González Fernández which makes it difficult to draw any conclusions on this H. PARC TAULÍ-Jordi Gratacós Masmitjá CLÍNICA PUERTA HIERRO-Juan Mulero Mendoza matter. H. MONTE NARANCO-Juan Carlos Torre Alonso This study has some limitations. This is a cross-sectional H DOCE DE OCTUBRE- Pilar Fernández Dapica study, and the implications between the observed data and H RAMÓN Y CAJAL- Mª Elia Brito Brito Arévalo et al. Arthritis Research & Therapy (2018) 20:221 Page 6 of 6 HU ALICANTE-Enrique Batlle Gualda 4. Caffrey MF, James DC. Human lymphocyte antigen association in H VIRGEN DE LA ARRIXACA- Luis F. Linares Ferrando Ankylosing Spondylitis. Nature. 1973;242(5393):121. H. VIRGEN DEL PERPETUO SOCORRO- Enrique Judez Navarro 5. Chung H, Machado P, van der Heijde D, D’Agostino M-A, Dougados M. H.G. SAN JORGE- Carlos Vázquez Galeano HLA-B27 positive patients differ from HLA-B27 negative patients in clinical H. DE PALAMÓS- Teresa Clavaguera Poch presentation and imaging: results from the DESIR cohort of patients with H. MOSTOLES- Mª Cruz Fernández Espartero recent onset axial spondyloarthritis. Ann RheumDis. 2011;70:1930–6. HU CARLOS HAYA- Enrique Calero Secall 6. Rudwaleit M, Haibel H, Baraliakos X, Listing J, Märker-Hermann E, Zeidler H, H. MUTUA DE TERRASSA- Manuel Pujol Busquets et al. The early disease stage in axial spondyloarthritis: results from the H. DOCTOR NEGRÍN- Carlos Rodríguez Lozano German spondyloarthritis inception cohort. Arthritis Rheumatism. 2009;60: H. SANTA MARÍA DEL ROSELL- Manuel J. Moreno Ramos 717–27. HU PRÍNCIPE DE ASTURIAS- Eduardo Cuende Quintana 7. Khan M, Kushner I, Braun W. Comparison of clinical features in HLA-B27 HU DE GUADALAJARA- Manuel Fernández Prada positive and negative patients with Ankylosing Spondylitis. Arthritis HU CENTRAL DE ASTURIAS- Rubén Queiro Silva Rheumatism. 1977;20:909–12. H. SAN RAFAEL- Estefanía Moreno Ruzafa 8. Feldtkeller E, Khan M, van der Heijde D, van der Linden S, Braun J. Age at HU VIRGEN DE LA VEGA- Carlos Montilla Morales disease onset and diagnosis delay in HLA-B27 negative vs. positive patients H. VIRGEN DEL ROCÍO- Alicia García López with Ankylosing Spondylitis. Rheumatol Int. 2002;23:61–6. HU MIGUEL SERVET- Eugenio Giménez Úbeda 9. Yang M, Xu M, Pan X, Hu Z, Li Q, Wei Y, et al. Epidemiological comparison H. FUNDACIÓN SON LLATZER- Antonio Juan Más of clinical manifestations according to HLA-B*27 carrier status of Chinese H. INTERNACIONAL MERIMAR- Cristina Medrano Le Quement Ankylosing Spondylitis patients. Tissue Antigen. 2013;82(5):338–43. HU NAVARRA- Enrique Ornilla 10. Ward MM, Hendrey MR, Malley JD, Learch TJ, Davis JC Jr, Reveille JD, et al. Clinical and immunogenetic prognostic factors for radiographic severity in Ankylosing Spondylitis. Arthritis Rheum. 2009;61(7):859–66. Availability of data and materials 11. Xiong J, Chen J, Tu J, Ye W, Zhang Z, Liu Q, et al. Association of HLA-B27 For information on availability of data included in the REGISPONSER database, status and gender with sacroiliitis in patients with Ankylosing Spondylitis. please contact Dr. Pilar Font. Pak J Med Sci. 2014;30:22–7. 12. Cortes A, Maksymowych WP, Wordsworth BP, Inman RD, Danoy P, Rahman Declarations P, et al. Association study of genes related to bone formation and We confirm that the article has not been published before and is not under resorption and the extent of radiographic change in Ankylosing Spondylitis. consideration for publication elsewhere, and that it is approved by all the Ann Rheum Dis. 2015;74(7):1387–93. authors listed. 13. Akkoç N, Yarkan H, Kenar G, Khan M. Ankylosing Spondylitis: HLA-B*27- positive versus HLA-B*27-negative disease. Curr Rheumatol Rep. 2017;19:26. Authors’ contributions 14. Collantes E, Zarco P, Muñoz E, Juanola X, Mulero J, Fernández-Sueiro JL, MA analyzed the data and wrote the paper; JGM, ML, and MM supervised et al. Disease pattern of spondyloarthropathies in Spain: description of the and directed paper writing, and JC and EC reviewed the paper. CO corrected first registry (REGISPONSER). Rheumatology. 2007;46:1309–15. the paper translation. DR, CC, and PC reviewed the database and contributed 15. Stolwijk C, van Tubergen A, Castillo-Ortiz JD, Boonen A. Prevalence of extra- to the statistical analysis; PF performed the main statistical analysis. All authors articular manifestations in patients with Ankylosing Spondylitis: a systematic read and approved the final manuscript. review and meta-analysis. Ann Rheum Dis. 2015;74(1):65–73. 16. Ramiro S, Stolwijk C, van Tubergen A, van der Heijde D, Dougados M, van Ethics approval and consent to participate den Bosch F, et al. Evolution of radiographic damage in Ankylosing All patients included signed an informed consent to participate in REGISPONSER Spondylitis: a 12 year prospective follow-up of the OASIS study. Ann Rheum and the project was approved by the ethical committee of all participant Dis. 2015;74(1):52-9. hospitals. 17. Winter J, Mens L, Heijde D, Landewé R, Baeten D. Prevalence of peripheral and extra-articular disease in Ankylosing Spondylitis versus non-radiographic Consent for publication axial spondyloarthritis: a meta-analysis. Arthritis Res Ther. 2016;18:196. Not applicable. 18. D'Ambrosio EM, La Cava M, Tortorella P, Gharbiya M, Campanella M, Iannetti L. Clinical features and complications of the HLA-B27-associated acute Competing interests anterior uveitis: a meta-analysis. Semin Ophthalmol. 2016;12:1–13. The authors declare that they have no competing interests. 19. Valls Pascual E, Fontanilla Ortega P, Vicens Bernabeu E, Martínez-Costa L, Blanco Alonso R. Características clínicas, tratamiento y complicaciones oculares de uveítis anterior asociada y no asociada a HLA-B27. Reumatol Publisher’sNote Clin. 2016;12:244–7. Springer Nature remains neutral with regard to jurisdictional claims in published 20. Creemers MC, Franssen MJ, van't Hof MA, Gribnau FW, van de Putte LB, maps and institutional affiliations. van Riel PL. Assessment of outcome in Ankylosing Spondylitis: an extended radiographic scoring system. Ann Rheum Dis. 2005;64:127–9. Author details Rheumatology Department, Consorci Corporació Sanitària Parc Taulí, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí s/n, 08208 Sabadell, Barcelona, Spain. Rheumatology Department, Hospital General Universitario Reina Sofía/IMIBIC/Universidad de Córdoba, Córdoba, Spain. References 1. Castillo-Ortiz R, Landewé v d H, Dougados v d B, et al. Work outcome in patients with Ankylosing Spondylitis: results from a 12-year follow-up of an international study. Arthritis Care Res. 2016;68:544–52. 2. Khan M. HLA-B27 and its subtypes in world populations. Curr Opin Rheumatol. 1995;7:263–9. 3. Stolwijk C, van Onna M, Boonen A, van Tubergen A. Global prevalence of spondyloarthritis: a systematic review and meta-regression analysis. Arthritis Care Res. 2016;68:1320–31. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Arthritis Research & Therapy Springer Journals

Influence of HLA-B27 on the Ankylosing Spondylitis phenotype: results from the REGISPONSER database

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Abstract

Objective: To assess HLA-B27 influence on the clinical phenotype of Ankylosing Spondylitis (AS) patients. Method: An observational, cross-sectional and descriptive study of AS patients from the Spanish REGISPONSER database was performed. Demographic, clinical, disease activity (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP)), and radiographic data (Bath Ankylosing Spondylitis Radiology Index (BASRI) score) were compared regarding HLA-B27 status. A univariate and multivariate analysis was performed to identify variables independently related to the presence of HLA-B27. Results: Data from 1235 patients (74.8% male) were analyzed; 1029 were HLA-B27 positive (83%). HLA-B27-positive patients showed higher family aggregation and an earlier onset of disease compared with those who were HLA-B27 negative. HLA-B27-negative patients presented statistically higher BASDAI and BASFI scores and higher prevalence of arthritis, dactylitis, and extra-articular manifestations (psoriasis and inflammatory bowel disease (IBD)) but not anytime uveitis compared with those who were HLA-B27 positive. In the multivariate analysis, family history (odds ratio (OR) 2.10, 95% confidence interval (CI) 1.27–3.49), younger age at diagnosis (OR 0.97, 95% CI 0.96–0.98), presence of peripheral arthritis (OR 0.53, 95% CI 0.32–0.89), dactylitis (OR 0.16, 95% CI 0.05–0.56), psoriasis (OR 0.45, 95% CI 0.26–0.78), and IBD (OR 0.22, 95% CI 0.12–0.40) were the main variables independently related to the presence or not of HLA-B27. Conclusion: In Caucasian AS patients, the presence of HLA-B27 is related to an earlier disease onset and higher family aggregation. Absence of HLA-B27 is related to a higher frequency of peripheral arthritis, dactylitis, and extra-articular manifestations. Being HLAB27 positive is not related to a higher burden of disease or anytime uveitis. Keywords: Ankylosing Spondylitis, HLA-B27, Structural damage, Phenotype, Uveitis Background sites such as peripheral arthritis, enthesitis, dactylitis, Axial Spondyloarthritis (AxSpA) includes an heteroge- and extra-articular manifestations as uveitis, psoriasis, neous group of rheumatisms characterized by their and inflammatory bowel disease (IBD). Frequently, dis- strong association with HLA-B27 and axial skeleton in- ease onset occurs in patients 20–30 years of age and, if volvement. Ankylosing Spondylitis (AS) is the main dis- no effective treatment is given, it can lead to severe dis- ease of this group and is clinically defined by ability in nearly a third of individuals [1]. Its prevalence inflammatory back pain, but it can also involve other is around 0.2–0.3% depending on the geographical dis- tribution of HLA-B27 [2, 3]. HLA-B27, since its discov- ery in 1973 [4], constitutes the main genetic factor * Correspondence: jgratacosmas@gmail.com related to disease etiopathogenesis. However, nearly 10– Rheumatology Department, Consorci Corporació Sanitària Parc Taulí, Institut 20% of patients with defined AS do not carry HLA-B27, d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí s/n, 08208 Sabadell, Barcelona, Spain which increases to 40% when analyzing nonradiographic Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Arévalo et al. Arthritis Research & Therapy (2018) 20:221 Page 2 of 6 axial spondyloarthritis (nrAxSpA) [5]. Previous studies having HLA-B27 typing available, and finally 1235 of suggest a relationship between HLA-B27 and axial mani- these having no data of interest missing (Fig. 1). Recruit- festations including structural progression in early ment of patients started in March 2004 and finished in AxSpA [5]. Moreover, a younger age of onset, more fam- March 2007. All patients included signed an informed ily history [5, 6], and less prevalence of psoriasis and consent form, and the project was approved by the eth- IBD [5] have also been reported. Nevertheless, there are ical committee of all participant hospitals. More infor- few studies evaluating the role of HLA-B27 in defined mation about the methodology and data inclusion are AS patients [7–9], with some of them focused on radio- detailed in a previous publication by Collantes et al. [14]. graphic progression [10–12] and reporting controversial The study included the following clinical and bio- results [13]. The main objective of the present study was logical variables: age (in years), gender, the presence of to evaluate the HLA-B27 influence on the clinical ex- HLA-B27, age at disease onset (in years), disease pression of defined AS patients. For this purpose, we duration (in years), diagnosis delay (in years), axial reviewed data from the REGISPONSER database [14] symptoms, peripheral involvement (peripheral arthritis, which includes more than 1000 AS patients, of whom coxitis, enthesitis, and dactylitis), extra-articular about 20% are HLA-B27 negative. manifestations confirmed by a specialist (uveitis, IBD, psoriasis, palmoplantar pustulosis, balanitis, prostatitis), Material and methods clinical disease activity (Bath Ankylosing Spondylitis Dis- This is a comparative, cross-sectional study including all ease Activity Index (BASDAI), 0–10 cm), clinical disabil- patients fulfilling AS New York modified criteria from ity (Bath Ankylosing Spondylitis Functional Index the REGISPONSER. REGISPONSER is a Spanish registry (BASFI), 0–10 cm), biological disease activity (erythro- that includes 2367 patients who fulfilled European Spon- cyte sedimentation rate (ESR) and C-reactive protein dyloarthropathy Study Group (ESSG) criteria for spon- (CRP)), and structural damage (Bath Ankylosing Spon- dyloarthritis. Of these, 1422 had radiographic sacroiliitis dylitis Radiology Index (BASRI)) assessed by a local radi- as per New York modified criteria, with 1270 of these ologist and confirmed by an experienced rheumatologist. Fig. 1 Flow chart of patients included in the study from the REGISPONSER database. AS Ankylosing Spondylitis, ESSG European Spondyloarthropathy Study Group, nrAxSpA nonradiographic axial spondyloarthritis, NYm New York modified, PsA psoriatic arthritis, ReA reactive arthritis, USpA undifferentiated spondyloarthritis Arévalo et al. Arthritis Research & Therapy (2018) 20:221 Page 3 of 6 Statistical analysis extra-articular manifestations, especially psoriasis (5.9% vs A descriptive analysis of the variables was performed 14.6%; p < 0.001) and IBD (3.6% vs 11.7%; p <0.001) com- using absolute and relative frequencies for qualitative pared with HLA-B27-positive patients. On the other hand, variables and mean with standard deviation for the this study did not find any statistical differences regarding quantitative variables. A 95% confidence interval (CI) axial clinical disease expression (neck pain, low back pain, was calculated. For bivariate analysis the Chi-squared and sacroiliac joint symptoms), the presence of enthesitis test was used, and the Student t test was used for inde- (present in 6.1% of subjects) or uveitis (22.4% in pendent data. Finally, a multiple logistic regression HLA-B27-positive and 19.4% in HLA-B27-negative pa- model was performed including the following variables: tients; not significant). gender, age, age at onset, disease duration, signs and In the multivariate analysis, family history (OR 2.10, symptoms at onset and during follow-up, peripheral and 95% CI 1.27–3.49; p = 0.004), younger age at diagnosis extra-articular manifestations, BASDAI, BASFI, BASRI, (OR 0.97, 95% CI 0.96–0.98; p < 0.001), and the presence ESR, and CRP. The degree of association was expressed of peripheral arthritis (OR 0.53, 95% CI 0.32–0.89; p = as the odds ratio (OR) and Cornfield confidence interval 0.016), dactylitis (OR 0.16, 95% CI 0.05–0.56; p = 0.004), was established at 95% using Wald statistics. Variables psoriasis (OR 0.45, 95% CI 0.26–0.78; p = 0.005), and with p ≥ 0.15 were suppressed from the model one by IBD (OR 0.22, 95% CI 0.12–0.40; p < 0.001) were the one (backward stepwise procedure). Comparison be- main variables independently related to the presence or tween the reduced model and the one including sup- not of HLA-B27. All results are shown in Table 1. pressed variables was made using the likelihood ratio test (G statistic). A scale of continuous variables was Discussion evaluated with the Bow Tidwell test. Possible interac- This is the most extensive study performed comparing tions between variables were studied as possible con- clinical characteristics of Caucasian AS patients regard- founding factors, considering them if the percentage ing HLA-B27. The study confirms the association of change of coefficients was higher than 20%. The Hosmer HLA-B27 with earlier disease onset and family aggrega- Lemeshow statistic was performed to assess the good- tion. Moreover, the study proves that the absence of ness of fit. All contrasts were bilateral and considered HLA-B27 in AS patients is related to a higher frequency significant when p < 0.05. Data were collected, proc- of peripheral arthritis, psoriasis, and IBD. Finally, our essed, and analyzed using SPSS v.17. data do not support the relationship between HLA-B27 and the severity of axial structural damage in AS Results patients. Data from 1235 patients were collected, with 1029 (83.3%) The prevalence of HLA-B27 in our study reaches 83%, patients being HLA-B27 positive and 206 (17.7%) patients similar to that previously reported in AS patients [2]. being HLA-B27 negative. Male gender was observed in We observed a male:female ratio of 3:1, comparable with 924 (74.8%) patients with no differences between both that shown in previous studies in AS patients regardless groups (74.7% of males in the HLA-B27-positive group vs. of the presence of HLA-B27 [15], but clearly different 75.2% in the HLA-B27-negative group; not significant). from the previously reported gender ratio in nrAxSpA HLA-B27-positive patients showed a higher family aggre- patients where there is not a male predominance [5, 6]. gation (22.1% vs 12%; p = 0.002), younger age (47.9 vs 50.4 Our results are also not in accordance with those previ- years; p = 0.012), and younger age at symptom onset (26.2 ously published by Yang et al. who reported a clear male vs 30.6 years; p < 0.001) and at diagnosis (33.9 vs 39 years; predominance in AS patients associated with the pres- p < 0.001) compared with HLA-B27-negative patients. ence of HLA-B27 [9]. However, that study was per- However, the absence of HLA-B27 did not lead to a formed in an Asian population, and race differences greater diagnosis delay (7.8 vs. 8.5 years; not significant). need to be considered. Analyzing disease activity, HLA-B27-negative patients Our study, using the BASRI score, did not show statis- expressed a higher disease activity measured by BASDAI tical differences regarding axial structural damage in (4.1 ± 2.3 vs 4.4 ± 2.4; p = 0.047) and higher clinical disabil- HLA-B27-positive AS patients compared with HLA-B27 ity measured by BASFI (3.8 ± 2.7 vs 4.3 ± 2.9; p =0.005) -negative patients. In this sense, our data are in accord- compared with HLA-B27-positive patients. However, no ance with those reported in the GESPIC cohort [6]. Pre- differences were observed between groups regarding the vious data regarding the influence of HLA-B27 on the biological markers analyzed (ESR and CRP), nor in struc- progression and extent of radiographic axial damage in tural damage expressed by BASRI (7.2 vs 7.4; not signifi- AS patients are controversial due to heterogeneity in cant). Moreover, HLA-B27-negative patients showed a published series and the methods used when measuring higher prevalence of peripheral arthritis (15.4% vs 21.8%; structural damage [9–13]. In the DESIR cohort, the p = 0.023), dactylitis (0.8% vs 3.9%; p = 0.001), and authors observed higher radiographic damage in early Arévalo et al. Arthritis Research & Therapy (2018) 20:221 Page 4 of 6 Table 1 Univariate and multivariate analysis between the HLA-B27-positive and HLA-B27-negative groups B27 negative B27 postive Univariate analysis Multivariate analysis a a n (= 206) Mean ± SD or % n (= 1029) Mean ± SD or % p OR 95% CI p Men 155 75.2 769 74.7 NS Family history 22 12 216 22.1 0.002 2.1 1.27–3.49 0.004 Age (years), mean ± SD 206 50,4 ± 12,9 1025 47,9 ± 13 0,012 Age at onset (years), mean ± SD 204 30.6 ± 12.3 1010 26.2 ± 9.9 < 0.001 Age at diagnosis (years), mean ± SD 199 39 ± 12.3 1002 33.9 ± 11.5 < 0.001 0.97 0.96–0.98 < 0.001 Disease duration since first symptom 204 19.8 ± 12.8 1013 21.9 ± 13.1 0.038 (years), mean ± SD Diagnosis delay (years), mean ± SD 198 8.5 ± 9.6 993 7.8 ± 9.2 NS Disease duration since diagnosis (years), 199 11.3 ± 9.3 1004 14 ± 10.6 0.001 mean ± SD Axial manifestations Cervicalgia 28 13.6 103 10 NS Lumbalgia 148 71.8 741 72 NS Sacroiliac syndrome 85 41.3 435 42.3 NS Peripheral manifestations Peripheral arthritis 45 21.8 158 15.4 0.023 0.53 0.32–0.89 0.016 Coxitis 6 2.9 32 3.1 NS Enthesitis 10 4.9 65 6.3 NS Dactylitis 8 3.9 8 0.8 0.001 0.16 0.05–0.56 0.004 Extra-articular manifestations Psoriasis 30 14.6 61 5.9 < 0.001 0.45 0.26–0.78 0.005 Inflammatory bowel disease 24 11.7 37 3.6 < 0.001 0.22 0.12–0.4 < 0.001 Urethritis, cervicitis, diarrhea 4 1.9 7 0.7 NS Anterior uveitis 40 19.4 230 22.4 NS Palmoplantar pustulosis 6 2.9 4 0.4 0.002 0.12 0.02–0.64 0.013 Balanitis 4 1.9 4 0.4 0.022 Prostatitis 1 0.5 7 0.7 NS BASRI score, mean ± SD 194 7.4 ± 4.1 974 7.2 ± 3.9 NS BASDAI score, mean ± SD 206 4.4 ± 2.4 1029 4.1 ± 2.3 0.047 BASFI score, mean ± SD 206 4.3 ± 2.9 1028 3.8 ± 2.7 0.005 0.94 0.88–1 0.037 ESR (mm/1 h), mean ± SD 174 19 ± 15.98 977 18.3 ± 16.3 NS CRP (mg/L), mean ± SD 174 10.2 ± 17.7 975 9.2 ± 13.7 NS BASDAI Bath Ankylosing Spondylitis Disease Activity Index, BASFI Bath Ankylosing Spondylitis Functional Index, BASRI Bath Ankylosing Spondylitis Radiology Index, CRP C-reactive protein, ESR erythrocyte sedimentation rate, NS not significant For qualitative variables as percentage (%) and for quantitative variables as mean ± standard deviation (SD) AxSpA patients related to the presence of HLA-B27, but unknown variables related to the genetic and/or environ- only in the sacroiliac joints [5]. No differences in radio- mental factors when comparing different genetic popula- graphic spine damage measured by the modified Stoke tions. Moreover, since male gender seems to be a strong Ankylosing Spondylitis Spine Score (mSASSS) were predictive factor for radiographic damage [6, 16] and the found. When looking at studies including definite AS male ratio in HLA-B27-positive AS patients was clearly patients, our results differ from those reported by Yang higher in the study by Yang et al. compared with our study et al. [9], who found a higher radiographic extent of [9], we need to consider this variable as a potential explan- structural damage in Asian AS patients and also in the ation for the differences observed between both studies. HLA-B27-positive compared to the HLA-B27-negative Finally, it is also interesting to remark that disease dur- patients. We do not have any precise explanation for these ation was significantly higher in HLA-B27-positive AS pa- observed differences, but we cannot exclude some tients than the other group. Given that disease duration is Arévalo et al. Arthritis Research & Therapy (2018) 20:221 Page 5 of 6 one of the main factors related to structural damage, the outcomes must be interpreted with caution. Our study did data reported here do not support a major role of not support a higher percentage of uveitis in the presence HLA-B27 in the extension of the structural damage in de- or not of HLA-B27. However, we only evaluated the fined AS patients. presence or not as a dichotomic measure, and thus we can- Our data appear to confirm previous studies suggesting not exclude a higher frequency of uveitis flares in AS that HLA-B27 is associated with a younger disease onset HLA-B27-positive patients compared with negative pa- and greater family aggregation in AS patients [9, 13]. Simi- tients. The BASRI score was used instead of the mSASSS, lar results were also described in early forms of which is a more sensitive score to evaluate axial structural HLA-B27-positive patients from the DESIR [5] and GES- changes [20]. Moreover, we do not have data on axial mag- PIC [6] cohorts, in such a way that HLA-B27 seems to an- netic resonance imaging (MRI), and thus we could not ticipate the clinical manifestations and disease onset. evaluate the influence of bone marrow edema on the po- Although HLA-B27 is the strongest genetic factor related tential progression of structural damage. We evaluated only to familiar aggregation of the disease, we observed that definite AS patients with a long disease evolution (around 12% of our HLA-B27-negative patients also had a familial 8 years) and thus we cannot exclude a potential influence background. As this is much higher than that observed in on radiographic progression of HLA-B27 in the early stages the general population, these data support the existence of of the disease. In this sense, it is not possible to extrapolate unknown genetic factors other than HLA-B27 that have a these results to nrAxSpA. However, the data observed sug- role in the familial aggregation of the disease. gest that, despite HLA-B27 typing, other genetic or envir- We did not observe differences in axial symptoms regard- onmental factors might play a major role in bone structural less of the presence or not of HLA-B27. However, we damage in AS patients. Finally, given that BASDAI scores observed a significantly higher frequency of peripheral arth- were not recorded separately, the Ankylosing Spondylitis ritis, dactylitis, psoriasis, and IBD in HLA-B27-negative AS Disease Activity score could not be calculated. patients. This association has also been previously de- scribed in early forms of AxSpA [5]inwhich thepropor- Conclusion tion of HLA-B27-negative patients is much higher than in In summary, this is the most extensive study analyzing dif- definite AS patients. Moreover, our data do not support a ferences in Caucasian AS patients regarding their higher clinical burden of disease in AS patients regarding HLA-B27 status. This study confirms the previously re- thepresenceofHLA-B27.Inthis sense, HLA-B27-negative ported association in AS patients between HLA-B27 and AS patients showed significantly higher BASDAI and an earlier disease onset and greater family aggregation. BASFI scores, even though there were no differences in However, and interestingly, we do not support an associ- biologic parameters (ESR and CRP). ation between HLA-B27 and the extent of axial structural Around a fifth of patients included in the analysis had at damage, or a higher clinical burden of the disease. More- least one episode of uveitis, this being the most frequent over, we cannot prove an association between the pres- extra-articular manifestation as has been shown in previ- ence of anytime uveitis and HLA-B27 in definite AS ous studies [17]. Classically, HLA-B27 has been related to patients. On the other hand, the absence of HLA-B27 is the presence of uveitis regardless of the presence or not of related, in AS patients, to a higher frequency of peripheral adefinite AS[18, 19]; thus, in this sense our data are arthritis, dactylitis, and extra-articular manifestations. unexpected. However, the results previously reported ana- Abbreviations lyzing the potential association between HLA-B27 in AS AS: Ankylosing Spondylitis; AxSpA: Axial spondyloarthritis; BASDAI: Bath patients and the presence of uveitis are quite controversial Ankylosing Spondylitis Disease Activity Index; BASFI: Bath Ankylosing [7, 9, 13]. It is important to note that 19.4% of Spondylitis Functional Index; BASRI: Bath Ankylosing Spondylitis Radiology Index; CI: Confidence interval; CRP: C-reactive protein; ESR: Erythrocyte HLA-B27-negative AS patients had at least one episode of sedimentation rate; ESSG: European Spondyloarthropathy Study Group; uveitis. These results, together with the absence of an as- IBD: Inflammatory bowel disease; mSASSS: Modified Stoke Ankylosing sociation between episodes of uveitis and axial inflamma- Spondylitis Spine Score; nrAxSpA: Nonradiographic axial spondyloarthritis; OR: Odds ratio tion in AS patients, suggest the need for further studies to evaluate the etiopathogenesis of uveitis in AS patients. Acknowledgements Finally, we did not observe any differences in the fre- REGISPONSER group - listed below are the principal investigator. quency of coxitis between both groups, in contrast to the HU REINA SOFÍA- Eduardo Collantes Estévez à Main center and ethical committee H BELLVITGE-Xavier Juanola Roura data reported by Yang et al. [9]. However, the prevalence HU JUAN CANALEJO-Jose Luis Fernández Sueiro of coxitis in our study was low (3.1 and 2.9%, respectively) HU GREGORIO MARAÑÓN- Carlos González Fernández which makes it difficult to draw any conclusions on this H. PARC TAULÍ-Jordi Gratacós Masmitjá CLÍNICA PUERTA HIERRO-Juan Mulero Mendoza matter. H. MONTE NARANCO-Juan Carlos Torre Alonso This study has some limitations. This is a cross-sectional H DOCE DE OCTUBRE- Pilar Fernández Dapica study, and the implications between the observed data and H RAMÓN Y CAJAL- Mª Elia Brito Brito Arévalo et al. Arthritis Research & Therapy (2018) 20:221 Page 6 of 6 HU ALICANTE-Enrique Batlle Gualda 4. Caffrey MF, James DC. Human lymphocyte antigen association in H VIRGEN DE LA ARRIXACA- Luis F. Linares Ferrando Ankylosing Spondylitis. Nature. 1973;242(5393):121. H. VIRGEN DEL PERPETUO SOCORRO- Enrique Judez Navarro 5. Chung H, Machado P, van der Heijde D, D’Agostino M-A, Dougados M. H.G. SAN JORGE- Carlos Vázquez Galeano HLA-B27 positive patients differ from HLA-B27 negative patients in clinical H. DE PALAMÓS- Teresa Clavaguera Poch presentation and imaging: results from the DESIR cohort of patients with H. MOSTOLES- Mª Cruz Fernández Espartero recent onset axial spondyloarthritis. Ann RheumDis. 2011;70:1930–6. HU CARLOS HAYA- Enrique Calero Secall 6. Rudwaleit M, Haibel H, Baraliakos X, Listing J, Märker-Hermann E, Zeidler H, H. MUTUA DE TERRASSA- Manuel Pujol Busquets et al. The early disease stage in axial spondyloarthritis: results from the H. DOCTOR NEGRÍN- Carlos Rodríguez Lozano German spondyloarthritis inception cohort. Arthritis Rheumatism. 2009;60: H. SANTA MARÍA DEL ROSELL- Manuel J. Moreno Ramos 717–27. HU PRÍNCIPE DE ASTURIAS- Eduardo Cuende Quintana 7. Khan M, Kushner I, Braun W. Comparison of clinical features in HLA-B27 HU DE GUADALAJARA- Manuel Fernández Prada positive and negative patients with Ankylosing Spondylitis. Arthritis HU CENTRAL DE ASTURIAS- Rubén Queiro Silva Rheumatism. 1977;20:909–12. H. SAN RAFAEL- Estefanía Moreno Ruzafa 8. Feldtkeller E, Khan M, van der Heijde D, van der Linden S, Braun J. Age at HU VIRGEN DE LA VEGA- Carlos Montilla Morales disease onset and diagnosis delay in HLA-B27 negative vs. positive patients H. VIRGEN DEL ROCÍO- Alicia García López with Ankylosing Spondylitis. Rheumatol Int. 2002;23:61–6. HU MIGUEL SERVET- Eugenio Giménez Úbeda 9. Yang M, Xu M, Pan X, Hu Z, Li Q, Wei Y, et al. Epidemiological comparison H. FUNDACIÓN SON LLATZER- Antonio Juan Más of clinical manifestations according to HLA-B*27 carrier status of Chinese H. INTERNACIONAL MERIMAR- Cristina Medrano Le Quement Ankylosing Spondylitis patients. Tissue Antigen. 2013;82(5):338–43. HU NAVARRA- Enrique Ornilla 10. Ward MM, Hendrey MR, Malley JD, Learch TJ, Davis JC Jr, Reveille JD, et al. Clinical and immunogenetic prognostic factors for radiographic severity in Ankylosing Spondylitis. Arthritis Rheum. 2009;61(7):859–66. Availability of data and materials 11. Xiong J, Chen J, Tu J, Ye W, Zhang Z, Liu Q, et al. Association of HLA-B27 For information on availability of data included in the REGISPONSER database, status and gender with sacroiliitis in patients with Ankylosing Spondylitis. please contact Dr. Pilar Font. Pak J Med Sci. 2014;30:22–7. 12. Cortes A, Maksymowych WP, Wordsworth BP, Inman RD, Danoy P, Rahman Declarations P, et al. Association study of genes related to bone formation and We confirm that the article has not been published before and is not under resorption and the extent of radiographic change in Ankylosing Spondylitis. consideration for publication elsewhere, and that it is approved by all the Ann Rheum Dis. 2015;74(7):1387–93. authors listed. 13. Akkoç N, Yarkan H, Kenar G, Khan M. Ankylosing Spondylitis: HLA-B*27- positive versus HLA-B*27-negative disease. Curr Rheumatol Rep. 2017;19:26. Authors’ contributions 14. Collantes E, Zarco P, Muñoz E, Juanola X, Mulero J, Fernández-Sueiro JL, MA analyzed the data and wrote the paper; JGM, ML, and MM supervised et al. Disease pattern of spondyloarthropathies in Spain: description of the and directed paper writing, and JC and EC reviewed the paper. CO corrected first registry (REGISPONSER). Rheumatology. 2007;46:1309–15. the paper translation. DR, CC, and PC reviewed the database and contributed 15. Stolwijk C, van Tubergen A, Castillo-Ortiz JD, Boonen A. Prevalence of extra- to the statistical analysis; PF performed the main statistical analysis. All authors articular manifestations in patients with Ankylosing Spondylitis: a systematic read and approved the final manuscript. review and meta-analysis. Ann Rheum Dis. 2015;74(1):65–73. 16. Ramiro S, Stolwijk C, van Tubergen A, van der Heijde D, Dougados M, van Ethics approval and consent to participate den Bosch F, et al. Evolution of radiographic damage in Ankylosing All patients included signed an informed consent to participate in REGISPONSER Spondylitis: a 12 year prospective follow-up of the OASIS study. Ann Rheum and the project was approved by the ethical committee of all participant Dis. 2015;74(1):52-9. hospitals. 17. Winter J, Mens L, Heijde D, Landewé R, Baeten D. Prevalence of peripheral and extra-articular disease in Ankylosing Spondylitis versus non-radiographic Consent for publication axial spondyloarthritis: a meta-analysis. Arthritis Res Ther. 2016;18:196. Not applicable. 18. D'Ambrosio EM, La Cava M, Tortorella P, Gharbiya M, Campanella M, Iannetti L. Clinical features and complications of the HLA-B27-associated acute Competing interests anterior uveitis: a meta-analysis. Semin Ophthalmol. 2016;12:1–13. The authors declare that they have no competing interests. 19. Valls Pascual E, Fontanilla Ortega P, Vicens Bernabeu E, Martínez-Costa L, Blanco Alonso R. Características clínicas, tratamiento y complicaciones oculares de uveítis anterior asociada y no asociada a HLA-B27. Reumatol Publisher’sNote Clin. 2016;12:244–7. Springer Nature remains neutral with regard to jurisdictional claims in published 20. Creemers MC, Franssen MJ, van't Hof MA, Gribnau FW, van de Putte LB, maps and institutional affiliations. van Riel PL. Assessment of outcome in Ankylosing Spondylitis: an extended radiographic scoring system. Ann Rheum Dis. 2005;64:127–9. Author details Rheumatology Department, Consorci Corporació Sanitària Parc Taulí, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Parc Taulí s/n, 08208 Sabadell, Barcelona, Spain. Rheumatology Department, Hospital General Universitario Reina Sofía/IMIBIC/Universidad de Córdoba, Córdoba, Spain. References 1. Castillo-Ortiz R, Landewé v d H, Dougados v d B, et al. Work outcome in patients with Ankylosing Spondylitis: results from a 12-year follow-up of an international study. Arthritis Care Res. 2016;68:544–52. 2. Khan M. HLA-B27 and its subtypes in world populations. Curr Opin Rheumatol. 1995;7:263–9. 3. Stolwijk C, van Onna M, Boonen A, van Tubergen A. Global prevalence of spondyloarthritis: a systematic review and meta-regression analysis. Arthritis Care Res. 2016;68:1320–31.

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Arthritis Research & TherapySpringer Journals

Published: Oct 3, 2018

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