The early disease stage in axial spondylarthritis: Results from the german spondyloarthritis inception cohort

Authors

  • Martin Rudwaleit,

    1. Charité Medical University Hospital, Campus Benjamin Franklin, and German Rheumatism Research Centre, Berlin, Germany
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    • Dr. Rudwaleit has received consulting fees from Abbott, Centocor, Schering-Plough, and Wyeth (less than $10,000 each), and speaking fees from Abbott, Centocor, Schering-Plough, Pfizer, Wyeth, and Merck, Sharp, and Dohme (less than $10,000 each).

  • Hildrun Haibel,

    1. Charité Medical University Hospital, Campus Benjamin Franklin, and German Rheumatism Research Centre, Berlin, Germany
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    • Dr. Haibel has received consulting fees, speaking fees, and/or honoraria from Abbott and Schering-Plough (less than $10,000 each).

  • Xenofon Baraliakos,

    1. Centre of Rheumatology Herne, Herne, and Ruhr-University Bochum, Bochum, Germany
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  • Joachim Listing,

    1. German Rheumatism Research Centre, Berlin, Germany
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  • Elisabeth Märker-Hermann,

    1. Dr. Horst-Schmidt Hospital, Wiesbaden, Germany
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    • Dr. Märker-Hermann has received speaking fees from Wyeth, Abbott Immunology, and Essex (less than $10,000 each).

  • Henning Zeidler,

    1. Hannover Medical School, Hannover, Germany
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  • Jürgen Braun,

    1. Centre of Rheumatology Herne, Herne, and Ruhr-University Bochum, Bochum, Germany
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  • Joachim Sieper

    Corresponding author
    1. Charité Medical University Hospital, Campus Benjamin Franklin, and German Rheumatism Research Centre, Berlin, Germany
    • Charité Medical University Hospital, Campus Benjamin Franklin, Rheumatology, Medical Department I, Hindenburgdamm 30, 12203 Berlin, Germany
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    • Dr. Sieper has received speaking fees and/or honoraria from Abbott, Schering-Plough, Wyeth, Pfizer, and Roche (less than $10,000 each).


  • The German Spondyloarthritis Inception Cohort is supported by the German Ministry for Education and Research (BMBF) (grant FKZ 01G19946), as part of the German Competence Network in Rheumatology. Amgen, Centocor, Schering-Plough, and Wyeth have provided support equally since 2005, when BMBF funding was reduced as scheduled. Abbott Immunology has provided an equal part of the support since 2006.

Abstract

Objective

Ankylosing spondylitis (AS) is diagnosed late, because radiographs of the sacroiliac joints often do not show definite sacroiliitis at the time of disease onset. The aim of this study was to investigate whether patients without definite radiographically defined sacroiliitis, referred to as nonradiographic axial spondylarthritis (SpA), are different from patients with AS with regard to clinical manifestations and disease activity measures. Moreover, we sought to identify determinants of the development of radiographic sacroiliitis.

Methods

In a cross-sectional analysis of 462 patients, we compared 226 patients with nonradiographic axial SpA (symptom duration ≤5 years) and 236 patients with AS (symptom duration ≤10 years) who are participants in the German Spondyloarthritis Inception Cohort. Radiographs of the sacroiliac joints and the spine were assessed by 2 readers in a blinded manner. Logistic regression analysis was applied to identify parameters associated with structural damage.

Results

The 2 groups did not differ in the frequency of HLA–B27 positivity, inflammatory back pain, arthritis, enthesitis, and uveitis and had similar levels of disease activity, using measures such as the Bath Ankylosing Spondylitis Disease Activity Index. In both groups, HLA–B27 positivity determined the age at disease onset. Male sex (adjusted odds ratio [OR] 2.38, 95% confidence interval [95% CI] 1.19–4.73 [P = 0.014]) and an elevated C-reactive protein (CRP) level (adjusted OR 1.85, 95% CI 0.96–3.56 [P = 0.066]) were associated with radiographic sacroiliitis. In patients with AS, male sex and an elevated CRP level were also associated with the presence of syndesmophytes.

Conclusion

Clinical manifestations and disease activity measures are highly comparable between patients with early nonradiographic axial SpA and those with early AS, suggesting that these 2 entities are part of the same disease. Male sex and an elevated CRP level are associated with structural damage on radiographs, whereas HLA–B27 positivity determines the age at disease onset.

Ankylosing spondylitis (AS) is a chronic inflammatory disease with a prevalence of ∼0.5% (1, 2). AS is the most frequent subtype of the group of spondylarthritides (SpA) that also comprises reactive arthritis, arthritis/spondylitis associated with psoriasis or with inflammatory bowel disease (IBD), and undifferentiated SpA (uSpA) (3, 4). These subgroups share clinical manifestations, the genetic association with HLA–B27, and responsiveness to tumor necrosis factor (TNF)–targeted therapies. The high prevalence of AS and other SpA implicates a substantial impact on health and quality of life for individual patients and an economic burden for society (5–8).

Radiographic changes in the sacroiliac (SI) joints of at least grade II bilaterally or grade III or IV unilaterally are usually a requirement for making the diagnosis of AS according to the modified New York criteria (9). Because AS is a slowly progressing disease as far as radiographic changes are concerned, definite sacroiliitis on plain radiographs appears relatively late, which is one reason for the long diagnostic delay of 5–10 years in AS (10, 11). In early disease without definite radiographic changes, active inflammation of the SI joints can be visualized using magnetic resonance imaging (MRI) technology (12). Clinical experience and limited data (13) suggest that in a sizeable proportion of patients who have inflammation of the SI joints on MRI but in whom radiographic findings are normal or suspicious, radiographically defined sacroiliitis will develop later and thus evolve to AS. Therefore, it has been proposed that all cases of SpA with predominantly axial involvement should be considered as belonging to one disease continuum referred to as axial SpA, irrespective of the presence or absence of radiographic changes (14).

Studies in AS have usually involved patients with longstanding disease (15–20). The goal of the German Spondyloarthritis Inception Cohort (GESPIC) is to study prospectively the disease course of patients with early axial SpA and to identify predictors of outcome. In this study, we compared patients with established early AS and patients with early axial SpA without definite radiographically defined sacroiliitis, hereinafter referred to as nonradiographic axial SpA, with respect to clinical manifestations, disease activity, and laboratory findings at the time of inclusion in GESPIC and sought to identify parameters associated with radiographic changes.

PATIENTS AND METHODS

GESPIC is an ongoing, prospective, longitudinal study on the clinical, functional, and structural outcome of SpA of short duration (inception cohort). GESPIC was set up in 2000 as part of the German Competence Network Rheumatology program and, as a national multicenter study, involves university hospitals (n = 4), community hospitals (n = 5), and private practices (n = 4). Although patients with peripheral SpA including reactive arthritis have also been included, the main focus of GESPIC is on patients with axial disease. The data presented herein focus on patients with adult-onset predominantly axial disease who were included between September 2000 and December 2004.

Inclusion and exclusion criteria.

Patients included in GESPIC were required to have a definite clinical diagnosis of axial SpA according to the treating rheumatologist. Patients with axial SpA were further classified by the local rheumatologist based on radiographic findings, and irrespective of the presence of concomitant psoriasis or inflammatory bowel disease (IBD), as having either AS or nonradiographic axial SpA. Patients were classified as having nonradiographic axial SpA if radiographic changes in the SI joints of at least grade II bilaterally or grade III or IV unilaterally were lacking. The classification of AS was based on fulfillment of the modified New York criteria (9), and the duration of AS symptoms (usually back pain) was restricted to ≤10 years at the time of inclusion. The classification of nonradiographic axial SpA was based on fulfillment of the European Spondylarthropathy Study Group (ESSG) criteria (4), and the maximum duration of symptoms was ≤5 years.

The ESSG criteria were applied with minor modifications, e.g., HLA–B27 positivity, acute anterior uveitis, and dactylitis were added to the list of parameters of which at least 1 must be present in addition to the entry criterion of inflammatory back pain (IBP). This modification was made because the additional parameters are typical of SpA, are part of the criteria described by Amor et al (3), and have performed well in the ESSG study but have not been included in the final set of ESSG criteria because of either low frequencies (uveitis, dactylitis) or the intention to facilitate application of the criteria in field studies without the need for HLA–B27 typing (21). Twenty-three percent of the patients with nonradiographic axial SpA who did not fulfill the original ESSG criteria were included in GESPIC as a result of the modification. In contrast, the modification of the ESSG criteria did not result in a relevant change in the frequencies of HLA–B27 positivity, uveitis, and dactylitis (data not shown). The initial classification as AS or nonradiographic axial SpA was finally adjusted in some patients according to the results of blinded reading of radiographs (see below). Regarding IBP, the local rheumatologist was asked to apply the criteria proposed by Calin et al (22).

Except for the maximum duration of symptoms, there were no further inclusion restrictions. Treatment of GESPIC patients has been done according to the local rheumatologist, without any limitations. Of note, GESPIC was initiated before anti-TNF treatment of AS was approved by the European Medicines Agency. Therefore, the great majority of patients had entered GESPIC in the pre–anti-TNF era.

Study design.

Study visits.

Study visits were scheduled every 6 months for 2 years and annually thereafter. At each visit, outcome assessments were performed. These included the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (23), the Bath Ankylosing Spondylitis Disease Functional Index (BASFI) (24), and the patient's global assessment of disease activity. General pain and nocturnal pain levels were measured with a 0–10-point numerical rating scale. The Short Form 12 Health Survey (25) was applied to evaluate quality of life. In addition, the location and character of back pain, peripheral arthritis, enthesitis, uveitis, and spinal mobility as assessed with the Bath Ankylosing Spondylitis Metrology Index (BASMI) (26), chest expansion, and the type of therapy including nonsteroidal antiinflammatory drugs (NSAIDs) were documented. Laboratory tests included the C-reactive protein (CRP) level, the erythrocyte sedimentation rate (ESR), and HLA–B27 status, if unknown.

Radiography.

Radiographs of the SI joints and the lumbar and cervical spine obtained at baseline from all patients were scored by the local investigator for the initial disease classification. Furthermore, radiographs were collected for digitization and central reading from 77% of the patients with AS and 66% of the patients with nonradiographic axial SpA. Some radiographs were missing because of the loss of films at the local center or because films were provided as paper printouts only, with both patients and physicians being reluctant to provide new radiographs. Available radiographs were centrally digitized, blinded, and scored independently by 2 trained readers (HH and XB). Both readers were completely blinded to all clinical data, in particular to the initial classification as AS or nonradiographic axial SpA. Radiographic sacroiliitis was scored from grade 0 (normal) to grade 4 (ankylosis) according to the modified New York criteria (9). The cervical and lumbar spine was scored according to the modified Stoke AS Spine Score (mSASSS) (27, 28).

Disease classification based on radiographic findings.

All patients were initially classified initially by the local rheumatologist as having AS or nonradiographic axial SpA. Because 77% of radiographs from patients with AS and 66% of radiographs from patients with nonradiographic axial SpA were scored again independently by 2 readers in a blinded manner, some of these patients were reclassified based on unequivocal radiographic scoring results in the following 2 situations: 1) patients classified by the local rheumatologist as having AS were reclassified as having nonradiographic axial SpA if both readers scored sacroiliitis as grade 0 or I bilaterally, and if there were no syndesmophytes in the spine; 2) patients classified as having nonradiographic axial SpA were reclassified as having AS if both readers scored sacroiliitis as grade II bilaterally or grade III or IV unilaterally or bilaterally. Following this approach, 11.4% of patients with AS for whom radiographs were available were reclassified as having nonradiographic axial SpA, and 15.5% of patients with nonradiographic axial SpA were reclassified as having AS. Patients for whom radiographs could not be obtained for central reading retained the classification assigned by the local rheumatologist.

Ethics committee approval.

The study protocol was approved by the ethics committee of the principal investigators and thereafter by the regional ethics committees of all participating centers. Written informed consent was obtained from all patients.

Statistical analysis.

Dichotomous parameters were compared between groups using the chi-square test. Continuous parameters were compared using the Mann-Whitney U test. Logistic regression analyses (univariate and multivariate) were used to investigate factors associated with radiographically identified damage. Analysis of variance was used to estimate the effects of HLA–B27 positivity and sex on the age at disease onset. P values less than 0.05 were considered significant.

RESULTS

Demographic and clinical characteristics at baseline.

Of the 462 patients analyzed, 322 were included at 4 university hospitals, 85 were included at 5 community hospitals, and 55 were included at 4 private practices. Across these 3 settings, no major differences in the clinical manifestations of the patients were observed (data not shown). The clinical data for the patients at baseline are shown in Table 1. The mean symptom duration of 5.2 years in patients with AS (n = 236) and 2.6 years in patients with nonradiographic axial SpA (n = 226), as well as the short lengths of time since diagnosis of 2.8 and 1.7 years, respectively, reflect the early-disease character of this cohort. Male sex was more frequent among patients with AS than among those with nonradiographic axial SpA (64.0% versus 42.9%; P < 0.001). A positive family history for SpA was reported equally often in patients with AS and those with nonradiographic axial SpA (Table 1).

Table 1. Baseline demographic and clinical characteristics of the patients with AS and the patients with nonradiographic axial SpA*
CharacteristicAll patients with AS (n = 236)Patients with AS >5 years (n = 117)Patients with AS ≤5 years (n = 119)PPatients with nonradiographic axial SpA ≤5 years (n = 226)P
  • *

    Except where indicated otherwise, values are the percent of patients. A positive family history for spondylarthritis (SpA) includes the presence in a first- or second-degree relative of ≥1 of the following: ankylosing spondylitis (AS), psoriasis, Crohn's disease, reactive arthritis, or uveitis. Clinical manifestations were assessed retrospectively by clinical history and/or medical records. NS = not significant; IBP = inflammatory back pain.

  • AS duration >5 years versus ≤5 years.

  • AS symptom duration ≤5 years versus nonradiographic axial SpA.

Age, mean ± SD years35.6 ± 10.235.1 ± 8.936.1 ± 11.4NS36.1 ± 10.6NS
Age at disease onset, mean ± SD years30.4 ± 10.627.7 ± 9.033.2 ± 11.3<0.00133.2 ± 10.5NS
Symptom duration, mean ± SD years5.2 ± 2.77.5 ± 1.53.0 ± 1.6<0.0012.6 ± 1.7NS
Duration since diagnosis, mean ± SD years2.8 ± 2.33.8 ± 2.71.7 ± 1.1<0.0011.7 ± 1.5NS
Male sex64.062.465.5NS42.9<0.001
HLA–B27 positive82.291.573.1<0.00174.7NS
Positive family history for SpA37.235.039.3NS34.5NS
Clinical manifestations, current (last week)      
 IBP, according to rheumatologist81.882.181.5NS87.2NS
 Peripheral arthritis14.410.318.5NS18.2NS
 Enthesitis20.820.521.0NS24.8NS
 Uveitis1.71.71.7NS2.2NS
 Dactylitis2.10.93.4NS3.1NS
 Psoriasis8.19.56.7NS5.3NS
 Inflammatory bowel disease1.70.92.5NS0.9NS
Clinical manifestions, ever      
 IBP ever, according to rheumatologist98.710097.5NS100NS
  IBP during past 6 months, according to rheumatologist94.194.094.1NS97.8NS
  IBP during past 6 months, according to Calin et al criteria (ref. 22)86.791.182.3NS84.6NS
 Peripheral arthritis37.435.039.8NS40.9NS
 Enthesitis39.441.037.8NS43.6NS
 Uveitis20.922.419.3NS12.4NS
 Dactylitis6.34.38.4NS4.0NS
 Psoriasis10.211.29.2NS9.8NS
 Inflammatory bowel disease2.62.62.5NS1.8NS

Among the 236 patients with AS, 50.4% had a symptom duration of ≤5 years. To better compare patients with AS and those with nonradiographic axial SpA, patients with AS were split into 2 groups according to symptom duration (≤5 years versus >5 years). The clinical, laboratory, and radiography data for the various groups are shown in Tables 1–3. There were no significant differences between patients with AS and those with nonradiographic axial SpA regarding current or previous clinical manifestations (Table 1). As expected, IBP was the most frequent clinical symptom across all groups.

Table 2. Baseline clinical characteristics of the patients with AS and the patients with nonradiographic axial SpA*
CharacteristicAll patients with AS (n = 236)Patients with AS >5 years (n = 117)Patients with AS ≤5 years (n = 119)PPatients with nonradiographic axial SpA ≤5 years (n = 226)P
  • *

    Except where indicated otherwise, values are the mean ± SD. BASDAI = Bath Ankylosing Spondylitis Disease Activity Index; NRS = numerical rating scale; NS = not significant; BASFI = Bath Ankylosing Spondylitis Functional Index; BASMI = Bath Ankylosing Spondylitis Metrology Index.

  • Ankylosing spondylitis (AS) duration >5 years versus ≤5 years.

  • Nonradiographic axial spondylarthritis (SpA) versus AS duration ≤5 years.

BASDAI (0–10 NRS)4.0 ± 2.13.9 ± 2.04.0 ± 2.1NS3.9 ± 2.0NS
 BASDAI ≥4, %48.746.550.8NS47.7NS
 BASDAI ≥6, %21.622.820.3NS16.5NS
Total pain (0–10 NRS)5.0 ± 2.55.1 ± 2.44.8 ± 2.6NS4.8 ± 2.5NS
Nocturnal pain (0–10 NRS)4.7 ± 2.84.7 ± 2.64.7 ± 2.9NS4.7 ± 3.1NS
Fatigue (BASDAI item 1; 0–10 NRS)4.9 ± 2.65.0 ± 2.54.7 ± 2.7NS4.7 ± 2.5NS
Morning stiffness (BASDAI items 5 and 6;  0–10 NRS)4.3 ± 2.24.3 ± 2.24.3 ± 2.3NS4.0 ± 2.3NS
Patient's global assessment (0–10 NRS)5.0 ± 2.55.0 ± 2.55.0 ± 2.6NS4.9 ± 2.5NS
Physician's global assessment (0–10 NRS)4.5 ± 2.04.5 ± 2.04.4 ± 2.3NS3.6 ± 2.0<0.001
BASFI (range 0–10)3.1 ± 2.53.1 ± 2.43.1 ± 2.5NS2.5 ± 2.10.027
BASMI (range 0–10)2.0 ± 1.82.0 ± 1.81.9 ± 1.8NS1.1 ± 1.3<0.001
 Spinal mobility ≤4 cm, %69.171.866.4NS50.20.004
 Lateral spinal flexion ≤10 cm, %30.033.326.9NS13.00.002
Table 3. Baseline laboratory and radiographic parameters in the patients with AS and the patients with nonradiographic axial SpA*
ParameterAll patients with AS (n = 236)Patients with AS >5 years (n = 117)Patients with AS ≤5 years (n = 119)PPatients with nonradiographic axial SpA ≤5 years (n = 226)P
  • *

    Except where indicated otherwise, values are the percent of patients. The C-reactive protein (CRP) level was measured with conventional assays, with 6 mg/liter as the upper limit of normal. Thus, a CRP level of >6 mg/liter is considered elevated. NS = not significant; ESR = erythrocyte sedimentation rate.

  • Ankylosing spondylitis (AS) duration >5 years versus ≤5 years.

  • Nonradiographic axial spondylarthritis (SpA) versus AS duration ≤5 years.

  • §

    According to the modified New York criteria; radiographs of the sacroiliac (SI) joints were available from 181 patients with AS (82 with a symptom duration of >5 years and 99 with a symptom duration of ≤5 years) and 148 patients with nonradiographic axial SpA. The grade of sacroiliitis was determined according to both readers.

  • Radiographs of the cervical and lumbar spine were available from 179 patients with AS (82 with a symptom duration of >5 years and 97 with a symptom duration of ≤5 years) and 146 patients with nonradiographic axial SpA.

  • #

    Modified Stoke Ankylosing Spondylitis Spine Score (SASSS) of 2 or 3 for a given vertebral unit according to both readers.

  • **

    Modified SASSS score of 3 for a given vertebral unit according to both readers.

Acute-phase reactants      
 CRP, mean ± SD mg/liter14.8 ± 16.015.2 ± 14.714.4 ± 17.3NS10.9 ± 18.7<0.001
  >6 mg/liter51.954.349.6NS29.80.001
  >15 mg/liter29.631.927.4NS13.80.003
 ESR, mean ± SD mm/hour21.7 ± 18.022.9 ± 17.420.5 ± 18.6NS14.1 ± 15.20.002
  >20 mm/hour39.541.737.3NS18.3<0.001
  >30 mm/hour24.525.323.7NS9.1<0.001
  >50 mm/hour8.69.67.5NS4.1NS
Radiographic parameters      
 Left SI joint, mean ± SD grade§2.5 ± 1.02.6 ± 1.02.4 ± 1.0NS0.9 ± 0.8<0.001
  Sacroiliitis grade ≥III40.946.336.4NS0<0.001
  Sacroiliitis grade IV13.218.39.1NS0<0.001
 Right SI joint, mean ± SD grade§2.4 ± 1.02.5 ± 1.02.3 ± 1.0NS0.9 ± 0.7<0.001
  Sacroiliitis grade ≥III41.443.139.4NS0<0.001
  Sacroiliitis grade IV12.214.610.1NS0<0.001
 Modified SASSS, mean ± SD4.9 ± 9.04.9 ± 7.74.9 ± 10.1NS1.4 ± 2.40.001
  ≥1 syndesmophyte#25.128.022.7NS6.1<0.001
  ≥1 bridging syndesmophyte**13.417.110.3NS0<0.001

As shown in Table 1, not all patients with IBP during the previous 6 months (according to the clinical judgment of the rheumatologist) fulfilled the criteria proposed by Calin and colleagues (22), as formally required, suggesting that rheumatologists more often based the assessment of IBP on their own clinical judgment rather than formal criteria. Of note, IBP features that are not part of the criteria described by Calin et al were observed frequently in the patients with AS (n = 31) and those with nonradiographic axial SpA (n = 33) not fulfilling the Calin criteria (pain at night in 74.2% and 69.7% of the patients, respectively, alternating buttock pain in 48.3% and 48.5% of the patients, respectively, and no improvement of back pain with rest in 80.6% and 63.6% of the patients, respectively). These additional features were recently incorporated into another set of criteria for the diagnosis of IBP (29). Back pain in GESPIC patients was most often located in the lower back, although more patients with AS had pain located in the thoracic spine compared with patients with nonradiographic axial SpA (40.8% of patients with AS for >5 years and 37.6% of patients with AS for ≤5 years versus 25.4% of patients with nonradiographic axial SpA; P = 0.005).

Current peripheral arthritis was present in 10–18% of the patients, and enthesitis was present in 20–25% of the patients. There was a trend toward a lower frequency of uveitis ever in patients with nonradiographic axial SpA (12.4%) compared with patients with AS for ≤5 years patients (19.3%). The presence of IBD ever was reported in only 1.8–2.6% of all patients, whereas psoriasis was reported in 9.2–11.2% of all patients, with no difference between patients with AS and those with nonradiographic axial SpA (Table 1).

Disease activity, function, metrology, and acute-phase reactants.

The disease activity index (BASDAI) was similarly high in patients with AS and patients with nonradiographic axial SpA (mean BASDAI ∼4.0 across all groups) while they were receiving conventional treatments (Table 2). In addition, there was no difference in the percentage of patients with a BASDAI ≥4, the percentage of patients with a BASDAI ≥6, or the percentage of patients with a BASDAI ≥4 plus an elevated CRP level (in total, 20.9% and 22.0% in the AS group and the nonradiographic axial SpA group, respectively). Among patients treated with NSAIDs, a BASDAI ≥4 was observed in 56.6% of those with AS (36% of the total AS population) and 50% of those with nonradiographic axial SpA (35% of the total nonradiographic axial SpA population).

The mean level of general pain, pain at night, and fatigue was equally high in patients with AS and those with nonradiographic axial SpA (Table 2). Function (as assessed using the BASFI) was significantly better in patients with nonradiographic axial SpA than in patients with AS for ≤5 years (2.5 versus 3.1; P = 0.027), as was spinal mobility (as assessed using the BASMI). Conversely, physicians rated overall disease activity (physician's global assessment) lower in patients with nonradiographic axial SpA compared with patients with AS (Table 2). The mean CRP levels and the mean ESRs were significantly higher in patients with AS than in those with nonradiographic axial SpA, as was the proportion of patients with a certain level of elevation of these parameters (Table 3).

Therapy.

NSAIDs, either nonselective or cyclooxygenase 2 selective, were taken by 64% of patients with AS and 70% of those with nonradiographic axial SpA. The percentage of patients receiving disease-modifying antirheumatic drugs was also equally distributed between the groups, with ∼17–20% treated with sulfasalazine and ∼8–10% treated with methotrexate. The low percentage of patients receiving TNF blockers (1.7–2.2%) reflects the fact that TNF blockers were yet not approved in Germany for AS when GESPIC was started.

Radiography findings.

Centrally digitized radiographs were scored in a blinded manner by 2 readers. Although there was excellent agreement for the mSASSS (intraclass correlation coefficient [ICC] 0.915, 95% confidence interval [95% CI] 0.886–0.937), agreement regarding the grade of sacroiliitis was moderate at most (for the left SI joint, ICC 0.364 [95% CI 0.222–0.490]; for the right SI joint, ICC 0.360 [95% CI 0.219–0.486]), indicating general difficulties in grading radiographic sacroiliitis. By definition, radiography findings were significantly different between patients with nonradiographic axial SpA and those with AS (Table 3). In patients with AS, grade III sacroiliitis (according to both readers) was observed in ∼41% of SI joints, and ankylosis was observed in ∼12% of SI joints. There was a clear trend toward a greater proportion of patients with grade III or grade IV sacroiliitis among AS patients with longer symptom duration (>5 years) as compared with AS patients with a symptom duration of ≤5 years (Table 3).

In the spine, the mean mSASSS was 4.9 scoring points in AS patients, with no difference between those with a disease duration of ≤5 years versus a disease duration of >5 years. However, there was a tendency for a higher proportion of patients with syndesmophytes and bridging syndesmophytes in AS patients with a longer disease duration as compared with a shorter disease duration (Table 3 and Figure 1A).

Figure 1.

Cumulative probability plots showing the distribution of the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) at baseline in patients with AS (n = 179) in relation to symptom duration (A), sex (B), HLA–B27 status (C), and C-reactive protein (CRP) level (D). There were no significant differences between patients with a symptom duration of ≤5 years and those with a symptom duration of 5–10 years (A), nor between HLA–B27–positive and HLA–B27–negative patients (C), but significant differences were observed between male and female patients (P = 0.025) (B) and between patients with a normal CRP level (≤6 mg/liter) and those with an elevated CRP level (>6 mg/liter) (P = 0.001) (D).

Association of male sex with definite radiographic sacroiliitis.

Centrally digitized radiographs from patients with AS (available in 77% of patients) and patients with nonradiographic axial SpA (available in 66%) were scored by 2 readers blinded to all clinical data including the clinical classification. This allowed analysis of the effects of sex, symptom duration, HLA–B27 status, CRP level, the ESR, and the BASDAI on the presence of definite radiographic sacroiliitis in 247 patients with axial SpA and a symptom duration of ≤5 years (99 patients with AS and 148 patients with nonradiographic axial SpA). For this analysis, definite radiographic sacroiliitis (defined as at least grade II bilaterally or grade III–IV unilaterally) had to be present according to both readers. The proportion of men was significantly higher among patients with definite radiographic sacroiliitis than among those without definite radiographic sacroiliitis (68.8% versus 49.7%; odds ratio [OR] 2.51, 95% CI 1.3–4.9, P = 0.006), as was the proportion of patients with an elevated CRP level (52.1% versus 35.4%; OR 1.98, 95% CI 1.05–3.76, P = 0.046). There was no difference in the frequency of HLA–B27 positivity in patients with and those without definite radiographic sacroiliitis (75.0% versus 77.8%) nor any effect of age at onset (33.2 versus 34.3 years), symptom duration, the BASDAI, or the ESR. The crude ORs and the adjusted ORs are shown in Table 4.

Table 4. Odds ratios (ORs) for radiographic damage in the patients with early axial spondylarthritis*
 Radiographic sacroiliitis≥1 syndesmophyte≥1 bridging syndesmophyte
OR (95% CI)POR (95% CI)POR (95% CI)P
  • *

    Radiographic sacroiliitis was defined as radiographic changes in the sacroiliac joints of at least grade II bilaterally or grade III or IV unilaterally, using the mean from both readers for each sacroiliac joint (analysis was performed on 247 patients with axial spondylarthritis [either ankylosing spondylitis or nonradiographic axial spondylarthritis] and a symptom duration of ≤5 years. The presence of ≥1 syndesmophyte was defined as a modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) of 2 or 3 assigned by both readers to the same vertebral edge in the joints of 179 patients with definite ankylosing spondylitis. The presence of ≥1 bridging (ankylosed) syndesmophyte was defined as an mSASSS of 3 assigned by both readers to the same vertebral edge in the joints of 179 patients with definite ankylosing spondylitis. 95% CI = 95% confidence interval; ESR = erythrocyte sedimentation rate; BASDAI = Bath Ankylosing Spondylitis Disease Activity Index.

  • Symptom duration, sex, and the C-reactive protein (CRP) level were included.

Univariate regression analysis, parameter at inclusion      
 Sex, male vs. female2.51 (1.28–4.91)0.0072.54 (1.13–5.67)0.0242.91 (0.95–8.93)0.062
 HLA–B27, positive vs. negative0.86 (0.41–1.79)0.681.57 (0.60–4.09)0.362.64 (0.59–11.85)0.21
 CRP, >6 mg/liter vs. ≤6 mg/liter1.98 (1.05–3.76)0.0362.73 (1.31–5.68)0.0073.12 (1.17–8.29)0.022
 ESR, >20 mm/hour vs. ≤20 mm/hour1.82 (0.93–3.57)0.0792.63 (1.31–5.25)0.0062.58 (1.06–6.28)0.036
 ESR, >30 mm/hour vs. ≤30 mm/hour1.46 (0.63–3.35)0.0791.96 (0.94–4.09)0.0731.95 (0.79–4.83)0.15
 BASDAI (1 unit; scale 0–10)0.99 (0.85–1.16)0.921.04 (0.89–1.22)0.620.94 (0.77–1.16)0.58
 Symptom duration, years1.05 (0.86–1.28)0.661.11 (0.98–1.25)0.0911.14 (0.98–1.33)0.095
Multivariate regression analysis, parameter at inclusion      
 Sex, male versus female2.38 (1.19–4.73)0.0142.40 (1.05–5.51)0.0392.88 (0.92–9.02)0.070
 CRP, ≤6 mg/liter vs. >6 mg/liter1.85 (0.96–3.56)0.0662.59 (1.23–5.45)0.0122.89 (1.07–7.79)0.036

Association of male sex and elevated CRP level but not HLA–B27 with radiographic changes in the spine.

Similar effects of sex and the CRP level on radiographic changes were seen in the spine when patients with AS (n = 179 with centrally digitized radiographs) were analyzed. The mean ± SD mSASSS score in the spine was 5.8 ± 9.9 in male patients with AS (n = 118) compared with 3.1 ± 6.8 in female patients with AS (n = 61; P = 0.025). Male patients were more likely than female patients to have at least 1 syndesmophyte (OR 2.54, 95% CI 1.13–5.67, P = 0.024) or at least 1 bridging (ankylosed) syndesmophyte (OR 2.91, 95% CI 0.95–8.93, P = 0.062) (Table 4 and Figure 1B). Furthermore, the mean ± SD mSASSS was significantly increased in patients with an elevated CRP level compared with patients without an elevated CRP level (6.8 ± 10.9 versus 2.7 ± 5.6; P = 0.001) (Figure 1D). There was only a trend toward symptom duration being predictive of radiographic damage (Table 4). Multivariate logistic regression analysis after adjustment for symptom duration revealed both sex and the CRP level as independent determinants of syndesmophytes in the spine (Table 4). In contrast, there was no significant difference between HLA–B27–positive and HLA–B27–negative patients regarding either the mSASSS (Figure 1C) or the proportion of patients with syndesmophytes (Table 4). Thus, male sex and an elevated CRP level at the time of inclusion, but not HLA–B27 positivity, symptom duration, or the BASDAI, were associated with radiographic changes in the spine.

Age at onset of axial SpA determined by HLA–B27 positivity but not sex.

The mean ± SD age at the onset of AS in GESPIC patients was 30.4 ± 10.6 years, with no difference between male (30.2 ± 11.3 years) and female (30.8 ± 9.1 years) patients. Of note, the mean ± SD age at onset was significantly lower in HLA–B27–positive patients with AS compared with HLA–B27–negative patients with AS (28.9 ± 9.7 versus 37.4 ± 11.7 years; P < 0.001); no influence of sex was observed. Similarly, among the patients with nonradiographic axial SpA, the mean ± SD age at disease onset was significantly lower in HLA–B27–positive patients than in HLA–B27–negative patients (31.6 ± 10.0 versus 37.7 ± 10.6 years; P < 0.001). Because the age at disease onset was lower in male patients with nonradiographic axial SpA (30.8 ± 10.0 years) than in female patients with nonradiographic axial SpA (34.9 ± 10.6 years), we also assessed male and female patients in this group separately and found a significant effect of HLA–B27 in both sexes (mean ± SD age at disease onset in HLA–B27–positive and HLA–B27–negative men, 29.6 ±10.1 years and 35.7 ± 8.2 years, respectively [P = 0.016]; age at disease onset in HLA–B27–positive and HLA–B27–negative women, 33.3 ± 9.8 years and 38.8 ± 11.6 years, respectively [P = 0.007]).

When dividing the category of age at disease onset into subcategories of ≤20 years, 21–30 years, 31–40 years, and >40 years, HLA–B27 positivity was found in 94.6%, 90.2%, 74.1%, and 61.2% of patients with AS, respectively (P < 0.001). Among the patients with nonradiographic axial SpA, the respective proportions in these 4 groups were 95.2%, 82.4%, 71.4%, and 60.0%, respectively (P = 0.005) and, therefore, were very similar to the proportions in patients with AS. Thus, HLA–B27 positivity was associated with a younger age at the onset of both AS and nonradiographic axial SpA (Figure 2).

Figure 2.

Effect of HLA–B27 positivity on age at disease onset. Patients with ankylosing spondylitis (AS) and patients with nonradiographic axial spondylarthritis (SpA) were categorized into subgroups according to their age at the time of disease onset. In both groups of patients, a younger age at disease onset was associated with a higher proportion of HLA–B27 positivity.

DISCUSSION

GESPIC is the first cohort comparing directly patients with early established AS and patients with nonradiographic axial SpA. The unique study design of this cohort resulted in interesting findings. First, the frequency of clinical manifestations including IBP, arthritis, enthesitis, and uveitis as well as the frequency of HLA–B27 positivity were similar between the 2 groups. Second, the level of disease activity as measured by the BASDAI, morning stiffness, fatigue, and pain at night was also highly comparable between patients with AS and those with nonradiographic axial SpA. Third, male sex and an elevated CRP level, but not HLA–B27 positivity, were associated with structural damage on radiographs in early axial SpA. Fourth, the age at the onset of both AS and nonradiographic axial SpA was determined by the patient's HLA–B27 status.

Most cohorts reported thus far have included patients with AS with rather long disease durations (15–30 years) (15–20). Interestingly, when comparing these studies, the frequencies of clinical manifestations were not different in GESPIC patients with AS with a symptom duration of ≤5 years, except for 2 manifestations: uveitis was found in 21% of GESPIC patients but in 22–61% of patients with longstanding AS (16–19), and IBD was present in only 2.6% of GESPIC patients but in 8–12% of patients with longstanding AS (16–18). These findings indicate that these manifestations may develop over time, whereas other manifestations such as peripheral arthritis or enthesitis occur frequently in early disease.

Similar clinical manifestations and similar proportions of HLA–B27–positive patients and patients with a positive family history for SpA strongly support the concept that patients included as having nonradiographic axial SpA in GESPIC in fact had axial SpA. Direct comparisons between AS and nonradiographic axial SpA were generally not performed in previous studies on (early) uSpA, because usually no differentiation between predominant axial and predominant peripheral involvement was made. For these reasons, a direct comparison of the study by Amor et al (3) or the ESSG study (4) with our data is not possible. A small prospective study in 68 patients with uSpA included 33 patients with IBP, 48% of whom were positive for HLA–B27 (30). Again, a comparison of that study with our data is difficult, because patients with AS were not included, and the parameters for disease activity were not reported (30).

The unique design of GESPIC enabled us to study possible effects of sex, age at disease onset, symptom duration, the BASDAI, CRP level, and HLA–B27 positivity on radiographic sacroiliitis, because radiographs for a great proportion of patients (77% of those with AS and 66% of those with nonradiographic axial SpA) were scored centrally by 2 readers who were blinded for all clinical data including disease classification (AS versus nonradiographic axial SpA). Among 247 patients with axial SpA with a symptom duration of ≤5 years, we found male sex and, to a lesser extent, an elevated CRP level but not symptom duration, HLA–B27 positivity, and the BASDAI to be associated with definite radiographic sacroiliitis.

It has been reported previously that among patients with longstanding AS, male patients have worse radiographic outcomes in the spine than do female patients (20, 31–33). This was also the case in GESPIC, because male sex but neither HLA–B27 positivity, symptom duration, nor the BASDAI was independently associated with the presence of syndesmophytes in the spines of patients with AS. An effect of sex on the development of radiographic sacroiliitis, however, is a new finding from this study that has not been previously reported. Based on our results, we hypothesize that in patients with early axial SpA, male sex may be a risk factor for the development of radiographic sacroiliitis, and, therefore, for the evolution to AS. This hypothesis is consistent with the observed male predominance in AS, although a rather balanced sex distribution is often reported in uSpA (34–38).

In this cross-sectional analysis, we have also shown for the first time that an elevated CRP level is associated with radiographic sacroiliitis. A role for CRP in the development of definite radiographic sacroiliitis was also suggested in the small study by Huerta-Sil et al (38) in 50 patients with uSpA; after 3–5 years, uSpA evolved to AS in 21 of those patients. CRP was also associated with syndesmophytes in the spines of GESPIC patients with AS. Followup data will elucidate whether an elevated CRP level would also be predictive of the development of structural damage, in either the SI joints or the spine. In a retrospective study (39), an elevated ESR was one of the parameters associated with worse outcome in the whole group of patients with SpA.

A strong effect of HLA–B27 on the age at disease onset was observed. HLA–B27–positive patients with AS were, on average, 8.5 years younger than HLA–B27–negative patients, which is in accordance with previous studies reporting differences of 2.9 years (10), 14 years (40), 8.5 years (41), and 9 years (42). Of note, among patients with nonradiographic axial SpA, HLA–B27–positive men and women were younger than their HLA–B27–negative counterparts (an average of 6.1 years younger among men and 5.5 years younger among women, respectively). The effect of HLA–B27 on the age at disease onset not only in AS but also in nonradiographic axial SpA supports further the concept of axial SpA being one disease continuum irrespective of the presence and extent of radiographic changes (14).

Function (as measured with the BASFI) and spinal mobility (as measured with the BASMI) were significantly less impaired in patients with nonradiographic axial SpA compared with patients with AS, despite these 2 groups of patients having similar levels of disease activity. These differences are most likely explained by the relationship of spinal mobility with radiographic changes (43) and the relationship of function with spinal mobility. The fact that 48% of the patients with nonradiographic axial SpA had a BASDAI of ≥4 despite conventional treatment illustrates the need for effective treatment options for this group of patients. Two recent clinical trials suggest that anti-TNF agents work at least as well in patients with nonradiographic axial SpA as in those with AS (44, 45). However, anti-TNF agents are currently approved for established AS only, not for nonradiographic axial SpA (46).

GESPIC was set up as an inception cohort in order to study prospectively the course of axial SpA. Inception cohorts aim to capture patients at the earliest possible time point, ideally when the disease starts (47). Identifying AS patients when the disease starts is nearly impossible given the diagnostic delay of 6–8 years on average even in recent reports (18, 19, 48–50). Thus, the allowance for a symptom duration of up to 10 years was likely to generate a cohort that is representative for the majority of AS patients and still implicates early disease. We believe that a mean duration since diagnosis of only 2.8 years in AS and of 1.7 years in nonradiographic axial SpA indeed reflects the intended inception character of the study. Further, GESPIC patients are likely to be representative, because they were included consecutively at several centers across Germany, and because there were no further inclusion restrictions apart from a maximum symptom duration.

In summary, this study of the results from the GESPIC allowed for the first time a direct comparison between patients with AS and patients with nonradiographic axial SpA. Signs and symptoms during the first years of disease are substantial and highly comparable between these 2 groups. Although HLA–B27 positivity is a determinant of the age at onset of axial SpA, male sex and the CRP level are associated with structural damage. The role of these parameters for disease progression will be elucidated in followup studies of this cohort. Finally, our findings illustrate the inappropriateness of the requirement of advanced radiographic sacroiliitis for defining AS/axial SpA and the need for new criteria that accommodate all SpA patients with predominant axial involvement, including those with nonradiographic axial SpA. Such new classification criteria for axial SpA are currently being developed by the Assessment of SpondyloArthritis international Society.

Acknowledgements

We thank Prof. M. Leirisalo-Repo (Finland), Prof. D. van der Heijde (The Netherlands), and Prof. M. Dougados (France) for scientific advice on the design of the cohort. We are grateful to Mrs. Beate Buss for monitoring the cohort, Martina Niewerth (Deutsches Rheumaforschungszentrum Berlin) for data management support, and all patients who voluntarily participate in this cohort. We also thank the following rheumatologists for the inclusion of their patients: Jan Brandt (Berlin), Gerd-Rüdiger Burmester (Berlin), Helmut Deister (Mainz), Edmund Edelmann (Bad Aiblingen), Jan Emmerich (Berlin), Markus Enderlein (Dresden), Anke Gauliard (Berlin), Erika Gromnica-Ihle (Berlin), Frank Heldmann (Herne), Ulrich von Hinüber (Hildesheim), Ulrich Hübner (Dresden), Kirsten Karberg (Berlin), Hubert Nüsslein (Dresden), R. Pelle-Lohfink (Mainz), Dorothea Pick (Grafschaft Holzweiler), Gisela Reichmuth (Herne), Markus Rihl (Hannover), Sebastian Schnarr (Hannover), Udo Schneider (Berlin), Inge Spiller (Berlin), Volker Walz (Ratingen), Siegfried Wassenberg (Ratingen), Hans Martin Wisseler (Bensheim), Silke Zinke (Berlin).

AUTHOR CONTRIBUTIONS

Dr. Rudwaleit had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Rudwaleit, Märker-Hermann, Zeidler, Braun, Sieper.

Acquisition of data. Rudwaleit, Märker-Hermann, Zeidler, Braun.

Analysis and interpretation of data. Rudwaleit, Haibel, Baraliakos, Listing, Märker-Hermann, Zeidler, Braun, Sieper.

Manuscript preparation. Rudwaleit, Sieper.

Statistical analysis. Rudwaleit, Listing.

Blinded reading of radiographs. Haibel, Baraliakos.

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