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Recognizing axial spondyloarthritis
de Boer, J.J.H.
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2018
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de Boer, J. J. H. (2018). Recognizing axial spondyloarthritis.
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Clinical and imaging signs of spondyloarthritis
in first-degree relatives of HLA-B27 positive ankylosing
spondylitis patients:
the pre-spondyloarthritis (Pre-SpA) cohort
Janneke J. de Winter1*, Maureen C. Turina 1*, Jaqueline E. Paramarta1, Mihaela Gamala1, Nataliya Yeremenko1,2, Marita N. Nabibux3, Robert Landewé1, Dominique L. Baeten1,2
1Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and
immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands; 2Department of Experimental Immunology, Academic Medical Center/
University of Amsterdam, Amsterdam, The Netherlands; 3Department of Rheumatology,
Tergooi Hospital, Hilversum, The Netherlands
Janneke J de Winter and Maureen C Turina contributed equally to this work Arthritis Rheumatol. 2016 Oct;68(10):2444-55
ABSTRACT
Objective
To investigate whether seemingly healthy first-degree relatives of patients with ankylosing spondylitis (AS) have clinical, laboratory, or imaging features of spondyloarthritis (SpA).
Methods
First-degree relatives (ages 18–40 years) of HLA–B27–positive AS patients were included in the pre-spondyloarthritis (Pre-SpA) cohort, a prospective inception cohort study. Clinical, biologic, and imaging features were recorded. First-degree relatives were classified according to several sets of SpA classification criteria.
Results
We report baseline features of 51 first-degree relatives included in this study. Twenty-nine (57%) had back pain, 2 (4%) had psoriasis, 1 (2%) had inflammatory bowel disease, and 1 (2%) had uveitis. Three (6%) had low-grade sacroiliitis, 1 (2%) had cervical syndesmophytes on radiography, and 10 (20%) had bone marrow edema on magnetic resonance imaging of the sacroiliiac joints. Seventeen of 51 first-degree relatives (33%) fulfilled SpA classification criteria: 7 (14%) fulfilled both Assessment of SpondyloArthritis international Society (ASAS) axial SpA and European Spondylarthropathy Study Group (ESSG) classification criteria, 6 (12%) fulfilled only ASAS axial SpA classification criteria, and 4 (8%) fulfilled only ESSG classification criteria; 3 (6%) also fulfilled the Amor criteria. None fulfilled other SpA classification criteria. First-degree relatives fulfilling the ASAS axial SpA and/ or ESSG classification criteria had more frequent inflammatory back pain, had a higher level of disease activity, and had more psoriasis. No differences were found in parameters of inflammation, peripheral and extra-articular disease other than psoriasis, and HLA–B27 positivity between those who did and those who did not fulfill the ASAS axial SpA and/or ESSG classification criteria. Four first-degree relatives (12%) who did not fulfill the ASAS axial SpA and/or ESSG classification criteria had imaging abnormalities suggestive of SpA.
Conclusion
A substantial proportion of seemingly healthy first-degree relatives of HLA–B27– positive AS patients have clinical and/or imaging abnormalities suggestive of SpA. Thirty-three percent could be classified as having SpA. Further follow-up will show which first-degree relatives will develop clinically manifest SpA.
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INTRODUCTION
A major feature of spondyloarthritis (SpA) is its insidious onset and slow progression of signs, symptoms, and structural damage (1). This leads to a significant diagnostic delay of 5–10 years (2–4). More recently, the development of referral strategies for early inflammatory back pain (IBP) (5–7) and the use of magnetic resonance imaging (MRI) to visualize active sacroiliitis have probably decreased this diagnostic delay. However, detecting the earliest phases of the disease remains challenging, which has 3 potentially important implications. First, the absence of an early diagnosis delays adequate treatment of signs and symptoms of inflammation for several months to years. Second, uncontrolled early disease may initiate osteoproliferation, a process seemingly resistant to treatment in the later phases (8–10). Third, when the earliest phase of the disease is ignored, a comprehensive chronological and hierarchical mapping of all cellular and molecular mechanisms that drive SpA is elusive (11,12). Similar to rheumatoid arthritis, SpA might have a subclinical phase of disease preceding the clinical established phase, in which abnormalities are present but clinical symptoms are lacking. A systematic screening and meticulous follow-up of those who are at high risk of developing SpA may help to address such challenges. Models explaining the genetic susceptibility to ankylosing spondylitis (AS), the prototypical axial form of SpA, suggest an 8% risk of AS in first-degree relatives of AS patients (13). The comparison of familial and sporadic cases of AS suggests a higher familial aggregation of AS in patients who are positive for HLA–B27 (14). Accordingly, several studies have suggested a 10–12% risk of AS (as defined by the presence of radiographic sacroiliitis) in first-degree relatives of AS patients, with a 2-fold higher risk in HLA–B27–positive individuals (15–18). Other SpA subtypes were also frequently observed in first-degree relatives of probands with AS or SpA (18,19). Because all these cross-sectional studies consistently show that first-degree relatives of HLA–B27– positive AS patients have a strongly increased risk of developing SpA, prospective analysis of such first- degree relatives at risk opens the way to systematic and detailed characterization of the earliest phases of SpA. In order to better detect, understand, and eventually treat the earliest phases of disease, the purpose of the present inception cohort study was to prospectively study the appearance and development of clinical, biologic, and imaging (radiographic and MRI) features of SpA in seemingly healthy first-degree relatives of AS patients. Herein we report the baseline analysis of clinical and imaging features in 51 first-degree relatives included in the study.
PATIENTS AND METHODS Study design
Pre-spondyloarthritis (Pre-SpA) is an ongoing, prospective 5-year inception cohort study. First-degree relatives of HLA–B27–positive AS patients were included;
subjects were ages 18–40 years, since new onset of SpA after age 45 years is rare and since the major objective was to study development rather than incidence of SpA. We included all seemingly healthy degree relatives, indicating that first-degree relatives 1) were not diagnosed as having SpA at the time of the baseline visit, 2) were not treated for musculoskeletal symptoms by a physician, and 3) may or may not have had musculoskeletal symptoms at the time of the baseline visit when actively questioned about those symptoms. We selected HLA–B27–positive probands with established AS rather than SpA as a whole spectrum for 3 reasons. First, we aimed for a high entry threshold by only including HLA–B27–positive AS patients, thereby avoiding as many misdiagnosed probands as possible. Second, genetic risk factors other than HLA–B27 have largely only been established in AS and not in other SpA subtypes (20). Finally, HLA–B27–positive patients tend to have more ankylosis than HLA–B27–negative patients (21), thereby possibly favoring the presence and detection of structural radiographic changes in their first-degree relatives.
HLA–B27–positive probands with AS from our dedicated SpA outpatient clinic were systematically and consecutively asked by their treating rheumatologists to inform their first-degree relatives about this cohort study both verbally and by letter. The research physician actively contacted the proband to determine whether the first-degree relatives were interested. To increase the sample size further, an interview with one of the research physicians was published in a journal of the Dutch AS association. In this interview, we requested AS patients to inform their first-degree relatives. Thereafter, we followed the same procedure as described above. Of note, probands did not participate in the study. All first-degree relatives signed informed consent prior to any study procedures. Major exclusion criteria were the presence of already diagnosed SpA, other rheumatic conditions including fibromyalgia, and back pain due to other known conditions such as intervertebral disc degeneration and back injury. All study procedures were done in compliance with the Helsinki Declaration. The study protocol was approved by the Medical Ethics Committee of the Academic Medical Center/University of Amsterdam.
Clinical evaluation at baseline
Data on demographics (sex, age, and race), medical and family history, and the use of medication were recorded. History specific for SpA-related features included back pain, IBP as defined by the Assessment of SpondyloArthritis international Society (ASAS) criteria (22), peripheral arthritis, enthesitis, dactylitis, psoriasis, inflammatory bowel disease (IBD), and uveitis, all diagnosed by a physician. Disease activity was measured by physician’s global assessment of disease activity and patient’s global assessment of disease activity on a visual analog scale (VAS), patient’s nocturnal pain on a VAS, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (23), and the Ankylosing Spondylitis Disease Activity Score using the C-reactive protein level (ASDAS-CRP) (24). Function was assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI) (25). Clinical
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examination included a 68-joint tender joint count and a 66-joint swollen joint count, an enthesitis score (the Maastricht Ankylosing Spondylitis Enthesitis Score (26)), a dactylitis evaluation, the linear Bath Ankylosing Spondylitis Metrology Index (27), chest expansion, and occiput-to-wall distance (22). Cutoff values of modified Schober test and chest expansion results were set at 4.5 cm and 3.6 cm, respectively (28).
Biological evaluation at baseline
Laboratory assessments included HLA–B27 testing, serum CRP levels, and erythrocyte sedimentation rate (ESR). Levels of calprotectin were determined by enzyme-linked immunosorbent assay in accordance with the instructions of the manufacturer (Hycult) (29,30).
Imaging evaluation at baseline
Radiographs of the lumbar and cervical spine and of the sacroiliac (SI) joints were obtained. Anteroposterior radiographs of the SI joints were scored according to the modified New York criteria for AS (31). Lateral and anteroposterior radiographs of the lumbar and cervical spine were scored according to the modified Stoke Ankylosing Spondylitis Spine Score (32). MRIs were performed on a 3.0T scanner (Philips Medical Systems) with sagittal T1- weighted and STIR sequences with a slice thickness of 4 mm for the spine (sagittal) and SI joints (semicoronal). Radiographs and MRIs were both scored by 1 experienced reader (RL) in a blinded manner for the presence of bone marrow edema according to the ASAS/Outcome Measures in Rheumatology definition of a positive MRI (33). In order to assess the reproducibility of the MRI scoring, we used a test-retest method. One experienced reader (RL) scored the MRIs in a blinded manner at 2 different time points, with a time lag of at least 6 months. The second reading was complemented with 18 control MRIs, 8 from patients without SpA and 10 from patients with active axial SpA (according to a rheumatologist’s opinion as well as according to the ASAS classification criteria for axial SpA (34)). MRIs of participants in the Pre-SpA cohort study were only considered positive when they were scored as positive at both time points. We quantified agreement between the first and second readings with Cohen’s kappa coefficient.
Statistical analysis
Clinical, biologic, and imaging features of SpA were reported descriptively. Data were complete except for imaging data missing for 1 first-degree relative. Symptoms of first-degree relatives were classified according to the ASAS classification criteria for axial SpA (34), the ASAS classification criteria for peripheral SpA (35), the European Spondylarthropathy Study Group (ESSG) preliminary criteria for the classification of SpA (36), the Amor criteria for SpA (37), the Classification of Psoriatic Arthritis (CASPAR) Study Group criteria for psoriatic arthritis (38), and the modified New York criteria for AS (31). A chi-square test was used to compare
the proportion of first-degree relatives fulfilling any of the SpA classification criteria to that of first-degree relatives not fulfilling SpA classification criteria. The Mann-Whitney U test was used for continuous data. Data are presented as numbers and percentages or as the mean±SD. Statistical tests were 2-sided, and P values less than 0.05 were considered significant. A similar analysis was performed for first-degree relatives with imaging signs suggestive of SpA versus first-first-degree relatives without imaging abnormalities.
RESULTS
Clinical and biological features of SpA in FDRs of HLA-B27 positive AS patients
Fifty-one first-degree relatives of 36 probands (comprising 33 parents and 5 siblings) with AS were included in this analysis. Approximately 85% of the approached first-degree relatives were willing to participate in the study. The main reasons for refusing study participation were living abroad, being too busy, and fear of blood collection, and a few first-degree relatives were not interested in participating without clarifying their motivation. Twenty-seven families of the 36 probands (75%) did not have any members with SpA other than the proband. Six of the probands (17%) had 1 sibling diagnosed as having SpA, and 1 proband (3%) had 1 child diagnosed as having SpA. Five probands (14%) had a parent diagnosed as having SpA. Of the first-degree relatives of these 5 probands, 3 families had both 1 sibling (with the exception of 1 proband having 2 siblings) and 1 parent. The mean±SD age of the first-degree relatives at inclusion was 25±5 years; 25 participants (49%) were male, and 26 (51%) were HLA–B27 positive. The baseline characteristics of the study population are summarized in Table 1. Upon being asked, 29 first-degree relatives (57%) reported back pain and 11 (22%) fulfilled criteria for IBP. Of the 51 first-degree relatives, 20 (39%) reported past or present arthralgia and 1 (2%) reported past or present peripheral arthritis. None of the first-degree relatives reported past or present enthesitis or dactylitis. Of all 51 first-degree relatives, 2 (4%) had psoriasis, 1 (2%) reported IBD, none reported past or present urethritis/diarrhea, and 1 (2%) had past or present uveitis. A modified Schober test result of 4.5 cm was found in 11 first-degree relatives (22%), and 2 first- degree relatives (4%) had a chest expansion of 3.6 cm. None of the first-degree relatives had arthritis, but 8 (16%) had at least 1 tender joint. Ten participants (20%) had tenderness of at least 1 entheseal point, but none had dactylitis, nail psoriasis, or skin psoriasis. Laboratory results showed an elevated CRP level, ESR, or calprotectin level in 6 (12%), 4 (8%), and 0 (0%), respectively, of first-degree relatives.
Imaging features of SpA in first-degree relatives of HLA–B27–positive AS patients
Three first-degree relatives (6%) had low-grade sacroiliitis not fulfilling the modified New York criteria (grade I unilaterally or bilaterally, or grade II unilaterally) on SI joint radiography, and 1 (2%) had syndesmophytes on spinal radiography.
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None of the MRIs showed inflammatory lesions of the spine. Regarding MRIs of the SI joints, 8 of 8 negative control MRIs were scored negative for inflammatory lesions, and 4 of 10 MRIs of patients with active axial SpA were scored positive for inflammatory lesions. In the first reading, MRI showed inflammatory lesions of the SI joint (Figure 1) in 11 first-degree relatives (22%). In the second reading, 10 of the 11 MRIs that had scored positive were confirmed, 1 scored negative, and 3 of the 39 MRIs that had scored negative scored positive. Ten MRIs (20%) showed inflammatory lesions of the SI joint in both readings. The strength of agreement between the first and second readings was considered “good” (k 50.78 (95% confidence interval 0.58–0.99)).
Application of SpA classification criteria to first-degree relatives of HLA–B27– positive AS patients Seventeen first-degree relatives (33%) fulfilled any of the
SpA classification criteria at baseline: 7 (14%) fulfilled both the ASAS axial SpA and ESSG criteria, 6 (12%) fulfilled only the ASAS axial SpA criteria, and 4 (8%) fulfilled only the ESSG criteria. Three (6%) also fulfilled the Amor criteria. None fulfilled the ASAS peripheral SpA criteria, the CASPAR Study Group criteria, or the modified New York criteria. When we compared first-degree relatives who did and those who did not fulfill the ASAS axial SpA and/or ESSG classification criteria (Table 1), back pain (17 (100%) versus 12 (35%); P<0.001) and IBP (11 (65%) versus 0 (0%); P<0.001) were more prevalent in the former group. Good response to nonsteroidal anti-inflammatory drugs was also more prevalent in the group of first-degree relatives who fulfilled the ASAS axial SpA and/or ESSG classification criteria (5 (29%) versus 0 (0%); P<0.001). Furthermore, first-degree relatives who fulfilled the ASAS axial SpA and/or ESSG classification criteria had a higher number of tender entheseal points (7 (41%) versus 3 (9%); P=0.007), showed a trend toward having more tender joints (5 (29%) versus 3 (9%); P=0.059), and had more psoriasis (2 (12%) versus 0 (0%); P=0.043) than those who did not. In contrast, there were no differences in peripheral and other extra-articular disease (past or present) between both groups.
The group that fulfilled the ASAS axial SpA and/or ESSG classification criteria had a higher mean±SD physician’s global assessment of disease activity on a VAS (12±3 mm versus 4±9 mm; P<0.001), a higher VAS score for patient’s nocturnal pain (13±22 mm versus 2±3 mm; P=0.003), a higher BASDAI score (2.04±1.42 versus 0.73±1.00; P<0.001), and a higher ASDAS-CRP (0.67±0.59 versus 0.27±0.38; P=0.007), with a trend toward a higher patient’s global assessment of disease activity on a VAS (15±18 mm versus 8±15 mm; P=0.065). The BASFI score was worse in the first-degree relatives who fulfilled the ASAS axial SpA and/or ESSG classification criteria (0.85±1.08 versus 0.22±0.46; P=0.001). First-degree relatives who fulfilled the ASAS axial SpA and/or ESSG classification criteria had low overall disease activity scores: only 3 first-degree relatives had a BASDAI score >4 and/ or an ASDAS-CRP≥1.3. Serum markers of inflammation were not increased in first-degree relatives who fulfilled the ASAS axial SpA and/or ESSG classification
criteria. However, inflammatory lesions on MRI (7 (41%) versus 3 (9%); P=0.007) and radiographic signs of sacroiliitis (3 (18%) versus 0 (0%); P=0.014) were found more often in those who fulfilled the ASAS axial SpA and/or ESSG classification criteria. In conclusion, first-degree relatives who fulfilled the ASAS axial SpA and/ or ESSG classification criteria had more axial, entheseal, and joint pain, which was reflected in higher disease activity and worse function, than those who did not. Except for more frequent bone marrow edema on MRI, however, they did not show objective signs of inflammation such as clinical arthritis or elevated levels of acute-phase reactants.
Figure 1. Image of cervical syndesmophytes on lateral radiograph (left) and representative image of bone marrow edema on magnetic resonance imaging of the sacroiliac joints in the STIR sequences (right).
Comparison of first-degree relatives with and those without imaging abnormalities
Interestingly, 4 of 34 first-degree relatives (12%) who did not fulfill the ASAS axial SpA and/or ESSG classification criteria had imaging abnormalities suggestive of SpA: 1 had syndesmophytes on cervical spine radiography, and 3 had bone marrow edema on MRI of the SI joint (Table 1 and Figure 1). Therefore, we conducted an analysis of all first-degree relatives with imaging abnormalities (the group fulfilling the ASAS axial SpA and/or ESSG classification criteria and the group without symptoms but with imaging abnormalities) versus those without imaging abnormalities. However, there were no differences between these 2 groups in demographics, history of SpA symptoms, family history, disease activity, clinical examination findings, and laboratory test results (Table 2).
Comparison of HLA-B27-positive and HLA-B27-negative first-degree relatives
Previous studies have shown that SpA mainly manifests in HLA-B27- positive first-degree relatives (13,18). Therefore, we performed another analysis comparing HLA-B27-positive degree relatives with HLA-B27-negative
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degree relatives. Nevertheless, we found no differences between these groups in demographics, history of SpA symptoms, disease activity, clinical examination findings, laboratory test results, and imaging abnormalities (Table 3).
Table 1. Clinical characteristics, laboratory and imaging results of the FDRs of those fulfilling and not fulfilling the ASAS axSpA and/or ESSG classification criteria
Study
population Fulfilling the ASAS axSpA and/or ESSG criteria Fulfilling vs not fulfilling the ASAS axSpA and/or ESSG criteria
(n= 51) Yes (n=17) No (n=34) p-value
Demographics
Male gender 25 (49) 7 (41) 18 (53) 0.433 Caucasian 50 (98) 16 (94) 34 (100) 0.157 Age, years, mean (SD) 25.2 (5.1) 25.8 (5.2) 24.9 (5) 0.595 BMI, kg/m2, mean (SD) 23.53 (3.16) 23.57 (3.72) 23.51 (2.89) 0.935 HLA-B27 positive 26 (51) 8 (47) 18 (53) 0.695 Current smoker 14 (28) 4 (24) 10 (29) 0.973 Use of DMARD, TNF inhibitor 0 (0) 0 (0) 0 (0) -or c-orticosteroids ever History Axial disease Back pain 29 (56.9) 17 (100) 12 (35) <0.001 Inflammatory back pain 11 (21.6) 11 (65) 0 (0) <0.001 Buttock pain 2 (3.9) 1 (6) 1 (3) 0.614 Good response to NSAIDs 5 (9.8) 5 (29) 0 (0) 0.001 Peripheral disease Arthralgia (past/ present) 20 (40) 9 (53) 11 (32) 0.160 Peripheral arthritis (past/present) 1 (2) 0 (0) 1 (3) 0.480 Enthesitis(past/ present) 0 (0) 0 (0) 0 (0) -Dactylitis (past/ present) 0 (0) 0 (0) 0 (0) -Extra-articular disease Psoriasis (past/ present) 2 (4) 2 (12) 0 (0) 0.043 IBD (past/present) 1 (2) 1 (6) 0 (0) 0.157 Urethritis/diarrhoea (past/present) 0 (0) 0 (0) 0 (0) -Uveitis (past/present) 1 (2) 1 (6) 0 (0) 0.157 Table 1 continues
Study
population Fulfilling the ASAS axSpA and/or ESSG criteria Fulfilling vs not fulfilling the ASAS axSpA and/or ESSG criteria Family history Ankylosing spondylitis 51 (100) 17 (100) 34 (100) -Psoriatic arthritis 2 (4) 2 (12) 0 (0) 0.043 Psoriasis 2 (4) 0 (0) 2 (6) 0.312 Inflammatory bowel disease 6 (12) 3 (18) 3 (9) 0.361 Uveitis 1 (2) 0 (0) 1 (3) 0.480 Disease activity measurements PhGA, 0-100mm VAS, mean (SD) 7 (11) 12 (3) 4 (9) <0.001 PGA, 0-100mmVAS, mean (SD) 11 (16) 15 (18) 8 (15) 0.065 Patient nocturnal pain,
0-100mm VAS, mean (SD) 5 (14) 13 (22) 2 (3) 0.003 BASDAI, 0-10cm, mean (SD) 1.17 (1.30) 2.04 (1.42) 0.73 (1.00) <0.001 BASDAI >4 3 (6) 2 (12) 1 (3) 0.211 ASDAS-CRP, mean (SD) 0.41 (0.49) 0.67 (0.59) 0.27 (0.38) 0.007 ASDAS-CRP ≥1.3 3 (6) 2 (12) 1 (3) 0.211 BASFI, 0-10cm, mean (SD) 0.43 (0.77) 0.85 (1.08) 0.22 (0.46) 0.001 Clinical examination modified Schober, cm, mean (SD) 6.43 (6.21) 5.79 (4.03) 6.62 (7.09) 0.571 modified Schober <4.5cm 11 (22) 5 (29) 6 (18) 0.336 Chest expansion, cm, mean (SD) 6.26 (2.48) 5.97 (2.25) 6.04 (2.61) 0.628 Chest expansion <3.6cm 2 (4) 1 (6) 1 (3) 0.614 BASMI, 0-10, mean (SD) 2.16 (0.76) 2.35 (0.93) 2.06 (0.65) 0.098 TJC > 0, 0-68 joints 8 (16) 5 (29) 3 (9) 0.059 SJC > 0, 0-66 joints 0 (0) 0 (0) 0 (0) -MASES>0 10 (20) 7 (41) 3 (9) 0.007 Dactylitis, presence 0 (0) 0 (0) 0 (0) -Nail psoriasis, presence 0 (0) 0 (0) 0 (0) -Psoriasis, presence 0 (0) 0 (0) 0 (0)
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Study
population Fulfilling the ASAS axSpA and/or ESSG criteria Fulfilling vs not fulfilling the ASAS axSpA and/or ESSG criteria Laboratory CRP, mg/L, mean (SD) 2.37 (3.45) 1.94 (2.71) 2.58 (3.79) 0.704 CRP above 5 mg/L 6 (12) 1 (6) 5 (15) 0.361 ESR, mm/h, mean (SD) 6.72 (7.16) 6.41 (6.16) 6.88 (7.71) 0.874 ESR above 20 mm/h 4 (8) 1 (6) 3 (9) 0.695 Calprotectin, ng/mL, mean (SD) 345.44 (129.85) 310.03 (136.07) 364 (125) 0.169 Calprotectin above 715 ng/ml 0 (0) 0 (0) 0 (0) -Imaging
Low grade sacroiliitis
on X-ray 3 (6) 3 (17.6) 0 (0) 0.014 Syndesmophytes of the
lumbar spine on X-ray 0 (0) 0 (0) 0 (0) -Syndesmophytes of the
cervical spine on X-ray 1 (2) 0 (0) 1 (3) 0.473 Inflammatory lesions of
the SIJ on MRI 10 (20) 7 (41) 3 (9) 0.007 Inflammatory lesions of
the spine on MRI 0 (0) 0 (0) 0 (0)
-ASAS, Assessment of SpondyloArthritis international Society; ASDAS, Ankylosing Spondylitis Disease Activity Score; AxSpA, axial spondyloarthritis; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Functional Index; BASMI, Bath Ankylosing Spondylitis Metrology Index; BMI, body mass index; cm, centimeter; CRP, c-reactive protein; DMARD, disease modifying antirheumatic drugs; ESR, erythrocyte sedimentation rate; ESSG, European Spondyloarthropathy Study Group; IBD, inflammatory bowel disease; HLA-B27, human leukocyte antigen-B27; kg, kilogram; MASES, Maastricht Ankylosing Spondylitis Enthesitis Score; m, meter; mm, millimeter; MRI, magnetic resonance imaging; NSAIDs, non-steroidal anti-inflammatory drugs; PGA patient global assessment of disease activity; PhGA, physician global assessment of disease activity; SD, standard deviation; SIJ, sacroiliac joints; SJC, swollen joint count; SpA, spondyloarthritis; TJC, tender joint count; TNF, tumor necrosis factor; VAS, visual analogue score. Data presented as n (%) unless otherwise specified.
Table 2. Clinical characteristics, laboratory and imaging results of the FDRs with and without imaging abnormalities on X-ray and/or MRI of the SIJ and spine
Imaging abnormalities
Yes (n= 12) No (n= 38) p-value
Demographics
Male gender 6 (50) 19 (50)
Imaging abnormalities
Yes (n= 12) No (n= 38) p-value
Caucasian 12 (100) 37 (98) 0.574
Age, years, mean (SD) 26.75 (5.88) 25.45 (5.06) 0.480 BMI, kg/m2, mean (SD) 23.92 (3.91) 23.31 (2.90) 0.667
HLA-B27 positive 6 (50) 19 (50)
-Current smoker 3 (25) 11 (29) 0.910
Use of DMARD, TNF inhibitors or
corticosteriods ever 0 (0) 0 (0)
-History Axial disease
Back pain 8 (67) 21 (65) 0.490
Inflammatory back pain 3 (25) 8 (21) 0.776
Buttock pain 0 (0) 2 (5) 0.416
Good response to NSAIDs 3 (25) 2 (5) 0.049
Peripheral disease
Arthralgia (past/present) 5 (42) 15 (40) 0.894 Peripheral arthritis (past/present) 0 (0) 1 (3) 0.574 Enthesitis(past/present) 0 (0) 0 (0) -Dactylitis (past/present) 0 (0) 0 (0) -Extra-articular disease Psoriasis (past/present) 0 (0) 2 (5) 0.422 IBD (past/present) 1 (8) 0 (0) 0.075 Urethritis/diarrhoea (past/present) 0 (0) 0 (0) -Uveitis (past/present) 0 (0) 1 (3) 0.574 Family history Ankylosing spondylitis 12 (100) 38 (100) -Psoriatic arthritis 0 (0) 2 (5) 0.422 Psoriasis 0 (0) 2 (5) 0.422
Inflammatory bowel disease 3 (25) 3 (8) 0.116
Uveitis 0 (0) 1 (3) 0.574
Disease activity measurements
PhGA, 0-100mm VAS, mean (SD) 10 (14) 6 (11) 0.587 PGA, 0-100mm VAS, mean (SD) 15 (19) 9 (16) 0.231 Patient nocturnal pain, 0-100mm
VAS, mean (SD) 9 (25) 4 (8) 0.530 BASDAI, 0-10cm, mean (SD) 1.48 (1.68) 1.18 (1.18) 0.593 BASDAI >4 1 (8) 2 (5) 0.699 ASDAS-CRP, mean (SD) 0.55 (0.67) 0.36 (0.43) 0.376 ASDAS-CRP ≥1.3 2 (16) 1 (3) 0.077 BASFI, 0-10cm, mean (SD) 0.61 (1.27) 0.39 (0.56) 0.563 Clinical examination
Modified Schober, cm, mean (SD) 6.38 (4.64) 6.39 (6.75) 0.716 Modified Schober <4.5cm 2 (17) 8 (21) 0.743 Chest expansion, cm, mean (SD) 7.50 (2.82) 5.93 (2.28) 0.078
SEVEN Imaging abnormalities Yes (n= 12) No (n= 38) p-value Chest expansion <3.6cm 1 (8) 1 (3) 0.384 BASMI, 0-10, mean (SD) 2.25 (0.45) 2.11 (0.83) 0.714 TJC > 0, 0-68 joints 1 (8) 7 (18) 0.411 SJC > 0, 0-66 joints 0 (0) 0 (0) -MASES>0 3 (25) 7 (18) 0.623 Dactylitis, presence 0 (0) 0 (0) -Nail psoriasis, presence 0 (0) 0 (0)
-Psoriasis, presence 0 (0) 0 (0) -Laboratory measurements CRP, mg/L, mean (SD) 3.19 (4.89) 2.10 (2.95) 0.820 CRP above 5 mg/L 2 (16) 4 (11) 0.572 ESR, mm/h, mean (SD) 7.00 (9.72) 6.65 (6.39) 0.639 ESR above 20 mm/h 3 (25) 1 (3) 0.981 Calprotectin, ng/mL, mean (SD) 383.31 (144.57) 337.27 (126.03) 0.307 Calprotectin above 715 ng/ml 0 (0) 0 (0) -Classification criteria ASAS axSpA 6 (16) 7 (58) 0.004
ASAS peripheral SpA 0 (0) 0 (0)
-ESSG 8 (22) 3 (25) 0.776
Amor criteria 1 (8) 2 (5) 0.699
CASPAR 0 (0) 0 (0)
-mNY 0 (0) 0 (0)
-ASAS, Assessment of SpondyloArthritis international Society; ASDAS, Ankylosing Spondylitis Disease Activity Score; axSpA, axial spondyloarthritis; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Functional Index; BASMI, Bath Ankylosing Spondylitis Metrology Index; BMI, body mass index; CASPAR, ClASsification criteria for Psoriatic ARthritis; cm, centimeter; CRP, c-reactive protein; DMARD, disease modifying antirheumatic drugs; ESSG, European Spondyloarthropathy Study Group; ESR, erythrocyte sedimentation rate; IBD, inflammatory bowel disease; HLA-B27, human leukocyte antigen-B27; kg, kilogram; MASES, Maastricht Ankylosing Spondylitis Enthesitis Score; m, meter; mm, millimeter; mNY, modified New York; NSAIDs, non-steroidal anti-inflammatory drugs; PGA patient global assessment of disease activity; PhGA, physician global assessment of disease activity; SD, standard deviation; SJC, swollen joint count; SpA, spondyloarthritis; TJC, tender joint count; TNF, tumor necrosis factor; VAS, visual analogue score. Data presented as n (%) unless otherwise specified.
Table 3. Clinical characteristics, laboratory and imaging results of the HLA-B27 positive and HLA-B27 negative FDRs
HLA-B27 positive
(n=26) HLA-B27 negative (n=25) p-value
Demographics
Male gender 15 (58) 10 (40) 0.211
Caucasian 25 (96) 25 (100) 0.327
Age, years, mean (SD) 25.3 (5.5) 26.3 (4.9) 0.396 BMI, kg/m2, mean (SD) 24.1 (3.1) 22.9 (3.2) 0.248
Current smoker 8 (31) 6 (24) 0.753
Use of DMARD, TNF inhibitor 0 (0) 0 (0) -or c-orticosteroids ever
History Axial disease
Back pain 12 (46) 17 (68) 0.119
Inflammatory back pain 6 (23) 5 (20) 0.791
Buttock pain 2 (10) 0 (0) 0.161
Good response to NSAIDs 4 (15) 1 (4) 0.176
Peripheral disease
History of arthralgia 8 (46) 12 (32) 0.305 History of peripheral arthritis 1 (4) 0 (0) 0.327 History of enthesitis 0 (0) 0 (0) 0.327 History of dactylitis 0 (0) 0 (0) -Extra-articular disease History of psoriasis 2 (8) 0 (0) 0.161 History of IBD 0 (0) 1 (4) 0.308 History of urethritis/diarrhoea 0 (0) 0 (0) -History of uveitis 2 (8) 0 (0) 0.161 Family history Ankylosing spondylitis 26 (100) 25 (100) -Psoriatic arthritis 2 (8) 0 (0) 0.161 Psoriasis 1 (4) 1 (4) 0.978
Inflammatory bowel disease 1 (4) 5 (20) 0.076
Uveitis 1 (4) 0 (0) 0.327
Disease activity measurements
PhGA, 0-100mm VAS, mean (SD) 5.88 (8.95) 7.52 (14.16) 0.898 PGA, 0-100mmVAS, mean (SD) 9.65 (13.29) 11.48 (19.00) 0.923 Patient nocturnal pain, 0-100mm VAS,
mean (SD) 4.00 (7.47) 6.64 (18.35) 0.773 BASDAI, 0-10cm, mean (SD) 1.00 (1.05) 1.35 (1,51) 0.322 BASDAI >4 1 (4) 2 (8) 0.533 ASDAS-CRP, mean (SD) 1 (4) 0 (0) 0.947 ASDAS-CRP ≥1.3 6 (23) 7 (28) 0.690 BASFI, 0-10cm, mean (SD) 0.38 (0.60) 0.49 (0.93) 0.702 Table 3 continues
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HLA-B27 positive
(n=26) HLA-B27 negative (n=25) p-value
Clinical examination
modified Schober, cm, mean (SD) 5.85 (4.63) 6.51 (6.71) 0.212 modified Schober <4.5cm 3 (12) 9 (32) 0.079 Chest expansion, cm, mean (SD) 6.24 (2.74) 6.28 (2.23) 0.447 Chest expansion <3.6cm 1 (4) 1 (4) 0.978 BASMI, 0-10, mean (SD) 2.04 (0.77) 2.28 (0.74) 0.294 TJC > 0, 0-68 joints 5 (19) 3 (12) 0.482 SJC > 0, 0-66 joints 0 (0) 0 (0) -MASES, 0-13, mean (SD) 6 (23) 4 (16) 0.529 Dactylitis 0 (0) 0 (0) -Nail psoriasis 0 (0) 0 (0) -Psoriasis 0 (0) 0 (0) -Laboratory CRP, mg/L, mean (SD) 2.37 (3.65) 2.37 (3.32) 0.763 CRP above 5 mg/L 3 (12) 3 (12) 0.960 ESR, mm/h, mean (SD) 6.68 (7.83) 6.76 (6.58) 0.502 ESR above 20 mm/h 2 (8) 2 (8) 1.000 Calprotectin, ng/mL, mean (SD) 309.39 (121.71) 381.50 (130.00) 0.048 Calprotectin above 715 ng/ml 0 (0) 0 (0) -Imaging
Low grade sacroiliitis on X-ray 2 (8) 1 (4) 0.556 SpA abnormalities of the lumbar spine
on X-ray 0 (0) 0 (0)
-Syndesmophytes of the cervical spine
on X-ray 1 (4) 0 (0) 0.997
Inflammatory lesions of the SIJ on MRI 6 (24) 5 (20) 0.735 Inflammatory lesions of the spine on
MRI 0 (0) 0 (0)
-SpA criteria
mNY 0 (0) 0 (0)
-ESSG 6 (23) 4 (16) 0.529
ASAS axSpA 5 (19) 4 (16) 0.765
ASAS peripheral SpA 0 (0) 0 (0)
-CASPAR 0 (0) 0 (0)
-ASAS, Assessment of SpondyloArthritis international Society; ASDAS, Ankylosing Spondylitis Disease Activity Score; axSpA, axial spondyloarthritis; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Functional Index; BASMI, Bath Ankylosing Spondylitis Metrology Index; BMI, body mass index; CASPAR, ClASsification criteria for Psoriatic ARthritis; cm, centimeter; CRP, c-reactive protein; DMARD, disease modifying antirheumatic drugs; ESSG, European Spondyloarthropathy Study Group; ESR, erythrocyte sedimentation rate; FDR, first degree relatives; IBD, inflammatory bowel disease; HLA-B27, human leukocyte antigen-B27; kg, kilogram; MASES, Maastricht Ankylosing Spondylitis Enthesitis Score; m, meter; mm, millimeter;
mNY, modified New York; MRI, magnetic resonance imaging; NSAIDs, non-steroidal anti-inflammatory drugs; PGA patient global assessment of disease activity; PhGA, physician global assessment of disease activity; SD, standard deviation; SIJ, sacroiliiac joints; SJC, swollen joint count; SpA, spondyloarthritis; TJC, tender joint count; TNF, tumor necrosis factor; VAS, visual analogue score. Data presented as n (%) unless otherwise specified.
DISCUSSION
We report here the baseline demographic, clinical, laboratory, and imaging features of 51 individuals included in a prospective inception cohort study of first- degree relatives of HLA–B27–positive AS patients. This study aimed to investigate the earliest, preclinical phases of disease based on the notion that first-degree relatives of HLA–B27–positive AS patients have a significantly increased risk of developing SpA.
A first major conclusion is that at baseline 33% of first-degree relatives have clinical and/or imaging features that allow a classification of SpA according to the ASAS axial SpA and/or ESSG classification criteria. These findings are perfectly consistent with previous cross-sectional studies showing an increased risk of SpA among degree relatives. Remarkably, the prevalence of SpA among first-degree relatives in our study (33%) was even higher than that in reported studies (5–12%), while the mean age in our study was lower (13,18,39).
Several factors may contribute to this higher prevalence. First, first-degree relatives having clinical symptoms could be more willing to participate in our study than those without symptoms, which may lead to channeling bias. Indeed, a substantial percentage of seemingly healthy first-degree relatives reported having back pain when actively questioned about this symptom at baseline. The fact that these first-degree relatives were not investigated for or diagnosed as having axial SpA before inclusion in the study may be related either to the fact that the back pain symptoms were relatively mild or to ignorance of general physicians regarding these alarm symptoms. Second, we have defined SpA in this study using the ASAS axial SpA, ESSG, Amor, CASPAR Study Group, and modified New York criteria, while previous studies mostly used the modified New York criteria. It is now well recognized that AS defined by the modified New York criteria represents only a fraction of the total spectrum of SpA. In support of this explanation, none of the first-degree relatives fulfilled the modified New York criteria. Third, inclusion of MRI may have led to increased classification of first-degree relatives. However, only 2 of 17 first-degree relatives in our study would not have been classified without MRI (40,41).
In our study, we classified first-degree relatives according to their fulfillment of the ASAS axial SpA and/or ESSG classification criteria, and we did not diagnose SpA based on the rheumatologist’s opinion for 2 reasons. First, there are no diagnostic criteria for SpA. Second, a diagnosis based on expert opinion is subjective and has large intra- and interobserver variation and therefore is not
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feasible in this cohort. However, a potential drawback of using SpA classification criteria is that the a priori probability of fulfilling the ASAS axial SpA, ESSG, and/ or Amor criteria is higher in these first-degree relatives than in populations used to develop these criteria (34,40,42), because the study design implies that all participants have a family history of SpA and that half of them are HLA–B27 positive. Nevertheless, the fact that first-degree relatives fulfilling the ASAS axial SpA and/or ESSG classification criteria had significantly higher scores for disease activity than those not fulfilling these criteria adds to the rightness of using these criteria for this particular study design.
Importantly, some key features of SpA, including the presence of peripheral disease or extra-articular manifestations and increased parameters of inflammation, were only rarely observed in first-degree relatives and also did not differ between those who did and those who did not fulfill the ASAS axial SpA and/ or ESSG classification criteria. Again, we cannot entirely exclude the possibility of a selection bias, since we recruited seemingly healthy first-degree relatives and since axial symptoms may be less frequently recognized by first-degree relatives and physicians than are those of peripheral or extra-articular disease. Alternatively, this observation may suggest that axial disease precedes other SpA manifestations during disease development.
Strikingly, 4 of 34 first-degree relatives (12%) not fulfilling the ASAS axial SpA and/or ESSG classification criteria had imaging abnormalities suggestive of SpA, 1 with syndesmophytes on cervical spine radiography and 3 with bone marrow edema on MRI of the SI joint. Moreover, we did observe abnormalities on MRI of the SI joint, but we did not observe spine abnormalities on MRI. These individuals did not have any other clinical or biologic signs of SpA. These imaging abnormalities might represent the subclinical phase. Future follow-up will determine whether and which of these first-degree relatives will develop clinically established SpA. We will be able to address the relevance of these observations in the near future by 1) increasing the cohort size, which will allow us to replicate the current findings, and 2) following up these first-degree relatives prospectively, focusing especially on those with imaging abnormalities only. A key question is whether these imaging abnormalities predict clinical signs and symptoms of SpA. One possibility is that a positive MRI, even when “highly suggestive of axial SpA,” can be observed more frequently in “normal individuals” than previously thought. Alternatively, some of the MRI abnormalities may indeed be the first subclinical signs of axial SpA. More female than male first-degree relatives fulfilled the ASAS axial SpA and ESSG classification criteria. This observation could be a numerical issue which would be clarified by increasing the sample size. If this sex imbalance is confirmed, however, it might relate to this study’s classification of first-degree relatives as having SpA (including different subtypes) rather than as having AS. Indeed, the male:female ratio in AS is 2–3:1, but in other subtypes, including non-radiographic axial SpA, the number of females was higher (43,44). Alternatively, male sex may be associated with progression to full-blown disease, which is one of the research
questions that we are currently assessing by meticulous follow-up of these first-degree relatives.
Another intriguing finding was that 9 of 17 first-degree relatives (53%) fulfilling SpA classification criteria were HLA–B27 negative, 1 of whom fulfilled both the ASAS axial SpA and ESSG classification criteria, 4 of whom fulfilled the ASAS axial SpA classification criteria, and 4 of whom fulfilled the ESSG classification criteria. This proportion is higher than those previously reported for first-degree relatives (14–43%) with AS and non-radiographic axial SpA (40,41,45), which indicated a lower risk of disease in HLA–B27–negative first-degree relatives. This could be due to the relative size of the current study. However, if this finding is confirmed in a larger sample set, further follow-up of these first- degree relatives will allow us to determine whether those who show signs and symptoms of SpA will develop more active and severe disease, independent of HLA– B27 status, or, alternatively, whether the presence of HLA–B27 promotes exacerbation and persistence of subclinical pathology. Moreover, we could determine whether genetic factors such as single-nucleotide polymorphisms in endoplasmic reticulum aminopeptidase 1 and interleukin-23 receptor contribute more to the development of SpA than previously thought.
In conclusion, the data from this cohort suggest that a substantial proportion of 18–40-year-old first-degree relatives of HLA–B27–positive AS patients do have clinical signs and symptoms and/or imaging abnormalities suggestive of SpA. Indeed, 33% could already be classified as having SpA. Extension of the sample size and follow-up of all subjects will allow us to disentangle the sequence of events that may lead to clinically manifest SpA and will allow us to determine which initial features may predict such a development.
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REFERENCES
1. Dougados M, Baeten D. Spondyloar-thritis. Lancet 2011;377: 2127–37. 2. 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.
3. Salvadorini G, Bandinelli F, Delle Sedie A, Riente L, Candelieri A, Generini S, et al. Ankylosing spondylitis: how diagnostic and therapeutic delay have changed over the last six decades. Clin Exp Rheumatol 2012;30:561–5.
4. Sorensen J, Hetland ML. Decreases in diagnostic delay are supported by sensitivity analyses. Ann Rheum Dis 2014;73:e45.
5. Brandt HC, Spiller I, Song IH, Vahldiek JL, Rudwaleit M, Sieper J. Performance of referral recommendations in patients with chronic back pain and suspected axial spondyloarthritis. Ann Rheum Dis 2007;66:1479–84.
6. Poddubnyy D, Vahldiek J, Spiller I, Buss B, Listing J, Rudwaleit M, et al. Evaluation of 2 screening strategies for early identification of patients with axial spondyloarthritis in primary care. J Rheumatol 2011;38:2452–60.
7. Sieper J, Srinivasan S, Zamani O, Mielants H, Choquette D, Pavelka K, 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. 8. Van der Heijde D, Landew e R,
Baraliakos X, Houben H, van Tubergen A, Williamson P, et al. Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis. Arthritis Rheum 2008;58:3063–70. 9. Van der Heijde D, Landew e R,
Einstein S, Ory P, Vosse D, Ni L, et al. Radiographic progression of ankylosing spondylitis after up to two years of treatment with etanercept. Arthritis Rheum 2008;58:1324–31. 10. Van der Heijde D, Salonen D,
Weissman BN, Landew eR, Maksymowych WP, Kupper H, et al. Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years. Arthritis Res Ther 2009;11:R127. 11. Hreggvidsdottir HS, Noordenbos T,
Baeten DL. Inflammatory pathways in spondyloarthritis. Mol Immunol 2014;57:28–37.
12. Yeremenko N, Paramarta JE, Baeten D. The interleukin-23/ interleukin-17 immune axis as a promising new target in the treatment of spondyloarthritis. Curr Opin Rheumatol 2014;26: 361–70.
13. Brown MA, Laval SH, Brophy S, Calin A. Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis. Ann Rheum Dis 2000;59:883–6.
14. Joshi R, Reveille JD, Brown MA, Weisman MH, Ward MM, Gensler LS, et al. Is there a higher genetic load of susceptibility loci in familial
Care Res (Hoboken) 2012;64:780–4. 15. Moller P, Vinje O, Dale K, Berg
K, Kass E. Family studies in Bechterew’s syndrome (ankylosing spondylitis). II. Prevalences of symptoms and signs in relatives of HLAB27 negative probands. Scand J Rheumatol 1984;13:11–4.
16. 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. 17. Vinje O, Dale K, Moller P.
Radiographic evaluation of patients with Bechterew’s syndrome (ankylosing spondylitis) and their first-degree relatives. Findings in the spine and sacro-iliac joints and relations to non-radiographic findings. Scand J Rheumatol 1985;14:119–32.
18. Dernis E, Said-Nahal R, D’Agostino MA, Aegerter P, Dougados M, Breban M. Recurrence of spondylarthropathy among first- degree relatives of patients: a systematic cross-sectional study. Ann Rheum Dis 2009;68:502–7. 19. Chou CT, Lin KC, Wei JC, Tsai
WC, Ho HH, Hwang CM, et al. Study of undifferentiated spondyloarthropathy among first-degree relatives of ankylosing spondylitis probands. Rheumatology (Oxford) 2005;44:662–5.
20. Reveille JD. The genetic basis of spondyloarthritis. Ann Rheum Dis 2011;70 Suppl 1:i44–50.
21. Ramiro S, Stolwijk C, van Tubergen A, van der Heijde D, Dougados M,
radiographic
damage in ankylosing spondylitis: a 12 year prospective follow-up of the OASIS study. Ann Rheum Dis 2015;74:52–9.
22. Sieper J, Rudwaleit M, Baraliakos X, Brandt J, Braun J, Burgos-Vargas R, et al. The Assessment of SpondyloArthritis international Society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis 2009;68 Suppl 2:ii1–44. 23. Garrett S, Jenkinson T, Kennedy LG,
Whitelock H, Gaisford P, Calin A. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol 1994;21:2286–91.
24. Lukas C, Landewe R, Sieper J, Dougados M, Davis J, Braun J, et al. Development of an ASAS-endorsed disease activity score (ASDAS) in patients with ankylosing spondylitis. Ann Rheum Dis 2009;68:18–24. 25. Calin A, Garrett S, Whitelock H,
Kennedy LG, O’Hea J, Mallorie P, et al. A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol 1994;21:2281–5.
26. Heuft-Dorenbosch L, Spoorenberg A, van Tubergen A, Landewe R, van der Tempel H, Mielants H, et al. Assessment of enthesitis in ankylosing spondylitis. Ann Rheum Dis 2003;62:127–32.
27. Jenkinson TR, Mallorie PA, Whitelock HC, Kennedy LG, Garrett SL, Calin A. Defining spinal mobility in ankylosing spondylitis (AS): the Bath
SEVEN
1994;21:1694–8.
28. Ramiro S, van Tubergen A, Stolwijk C, van der Heijde D, Royston P, Landewé R. Reference intervals of spinal mobility measures in normal individuals: the MOBILITY study. Ann Rheum Dis 2015;74:1218–24. 29. Turina MC, Sieper J, Yeremenko
N, Conrad K, Haibel H, Rudwaleit M, et al. Calprotectin serum level is an independent marker for radiographic spinal progression in axial spondyloarthritis. Ann Rheum Dis 2014;73:1746–8.
30. Turina MC, Yeremenko N, Paramarta JE, De Rycke L, Baeten D. Calprotectin (S100A8/9) as serum biomarker for clinical response in proof-of-concept trials in axial and peripheral spondyloarthritis. Arthritis Res Ther 2014;16:413.
31. Van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis: a proposal for modification of the New York criteria. Arthritis Rheum 1984;27:361–8.
32. Creemers MC, Franssen MJ, van’t Hof MA, Gribnau FW, van de Putte LB, van Riel PL. Assessment of outcome in ankylosing spondylitis: an extended radiographic scoring system. Ann Rheum Dis 2005;64:127–9.
33. Rudwaleit M, Jurik AG, Hermann KG, Landew e R, van der Heijde D, Baraliakos X, et al. Defining active sacroiliitis on magnetic resonance imaging (MRI) for classification of axial spondyloarthritis: a consensual approach by the ASAS/OMERACT MRI group. Ann Rheum Dis 2009;68:1520–7.
Landew e R, Listing J, Akkoc N, Brandt J, 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.
35. Rudwaleit M, van der Heijde D, Landew e R, Akkoc N, Brandt J, Chou CT, 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.
36. Dougados M, van der Linden S, Juhlin R, Huitfeldt B, Amor B, Calin A, et al, and the European Spondylarthropathy Study Group. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 1991;34:1218–27.
37. Amor B, Dougados M, Mijiyawa M. Crite `res de classification
des spondylarthropathies. Rev Rhum Mal Osteoartic 1990;57: 85–9. 38. Taylor W, Gladman D, Helliwell P,
Marchesoni A, Mease P, Mielants H, and the CASPAR Study Group. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum 2006;54:2665–73. 39. De Blecourt J, Polman A, de
Blecourt-Meindersma. Hereditary factors in rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis 1961;20:215–20.
40. Molto A, Paternotte S, Comet D, Thibout E, Rudwaleit M, Claudepierre
Assessment of SpondyloArthritis International Society axial spondyloarthritis criteria for diagnostic and classification purposes in patients visiting a rheumatologist because of chronic back pain: results from a multicenter, cross-sectional study. Arthritis Care Res (Hoboken) 2013;65:1472–81. 41. Weber U, Hodler J, Jurik AG,
Pfirrmann CW, Rufibach K, Kissling RO, et al. Assessment of active spinal inflammatory changes in patients with axial spondyloarthritis: validation of whole body MRI against conventional MRI. Ann Rheum Dis 2010;69:648–53.
42. Van den Berg R, de Hooge M, van Gaalen F, Reijnierse M, Huizinga T, van der Heijde D. Percentage of patients with spondyloarthritis in patients referred because of chronic back pain and performance of classification criteria: experience from the Spondyloarthritis Caught
(Oxford) 2013;52:1492–9.
43. Paramarta J, De Rycke L, Ambarus C, Tak P, Baeten D. Undifferentiated spondyloarthritis vs ankylosing spondylitis and psoriatic arthritis: a real-life prospective cohort study of clinical presentation and response to treatment. Rheumatology (Oxford) 2013;52:1873–8.
44. Stolwijk C, van Onna M, Boonen A, van Tubergen A. The global prevalence of spondyloarthritis: a systematic review and meta-regression analysis. Arthritis Care Res (Hoboken) 2016;68: 1320–31. 45. Tomero E, Mulero J, de Miguel E,
Fernandez-Espartero C, Gobbo M, Descalzo MA, et al. Performance of the Assessment of Spondyloarthritis International Society criteria for the classification of spondyloarthritis in early spondyloarthritis clinics participating in the ESPERANZA programme. Rheumatology (Oxford) 2014;53: 353–60.
