Abstract
Objective: Axial spondyloarthritis (axSpA) is a chronic inflammatory joint disease that usually presents with axial symptoms, but can also present with peripheral and extra-articular manifestations. It occurs equally in females and males. The diagnostic delay for axSpA is 5–7 years, and is significantly longer in females than in males. The aim of this study is to investigate the difference in disease characteristics between females and males with axSpA and to stratify this difference according to human leucocyte antigen (HLA)-B27 status.
Method: Clinical characteristics, spondyloarthritis (SpA) features, disease activity parameters, X-rays of sacroiliac joints, and laboratory results were assessed in a real-life cross-sectional cohort of 389 patients with a clinical diagnosis of axial or peripheral SpA, and compared between genders.
Results: Of 389 patients included, 313 had a clinical diagnosis of axSpA [females vs males, 131 (42%) vs 182 (58%), respectively]. Females had less radiographic axSpA according to the modified New York criteria (38.9% vs 63.7%, respectively), had a higher erythrocyte sedimentation rate [(median (interquartile range) 11 (5–23) vs 8 (3–16) mm/h), and reported higher disease activity by the Bath Ankylosing Spondylitis Disease Activity Index (mean ± sd 5.2 ± 2.1 vs 4.6 ± 2.2). No differences were found in clinical characteristics or SpA features, or when stratifying for HLA-B27 status.
Conclusions: In this real-life cohort of patients with axSpA, although males more often had structural damage on X-rays, females had similar disease with regard to SpA features and at least equal disease activity parameters compared to males.
It is increasingly being acknowledged in many diseases that females differ from males with regard to disease presentation (Citation1), clinical symptoms, disease burden (Citation2), pain perception (Citation3), and response to medication (Citation4, Citation5). Until recently, axial spondyloarthritis (axSpA) was considered a predominantly male disease (Citation6). The recognition of non-radiographic axSpA as a disease entity and the use of magnetic resonance imaging (MRI) as a diagnostic tool showed that the prevalence of axSpA is nearly equal between females and males (Citation7). Nevertheless, recognition of axSpA is still worse in females, resulting in underdiagnosis and a prolonged time until diagnosis (Citation8). One proposed explanation is that females and males differ with regard to disease characteristics.
A major issue is that most studies on gender differences in axSpA used either the modified New York (mNY) criteria for ankylosing spondylitis (AS) or the newer Assessment of SpondyloArthritis international Society (ASAS) criteria for axSpA (Citation2, Citation9, Citation10). Whereas the use of these criteria allows more homogeneous populations to be selected, they heavily rely on the presence of sacroiliitis on imaging and may therefore select a subgroup of female patients that is not completely representative of the patients presenting in daily clinical practice.
To overcome these potential biases complicating the evaluation of gender differences in axSpA, we included a real-life cross-sectional cohort of patients with a clinical diagnosis of axial, peripheral, or combined spondyloarthritis (SpA). We evaluated differences between females and males in the prevalence of extra-articular and peripheral disease manifestations and disease activity parameters. Furthermore, we evaluated the influence of human leucocyte antigen (HLA)-B27 status on disease presentation.
Method
Study population
Patients (≥ 18 years old) with a clinical diagnosis of axial, peripheral, or combined SpA, according to the expert opinion of their treating physician who visited the specialized SpA outpatient clinics of the Academic Medical Center Amsterdam (n = 272) and the Universixy Medical Center Utrecht (n = 42) between June 2007 and August 2012, were included in this real-life cross-sectional observational study. The study was approved by the local medical ethics committees (approval number WII-032#11.17.0419). Informed consent was waived since no additional procedures were performed for this observational study and all data were available from standard patient care.
Demographic and disease characteristics, presence (past or present) of extra-articular manifestations [dactylitis, enthesitis, anterior uveitis (AU), inflammatory bowel disease (IBD), or psoriasis], and family history (defined as at least one first or second degree relative with AS, AU, reactive arthritis, IBD, or psoriasis) were recorded. HLA-B27 status, C-reactive protein (CRP) (mg/L), and erythrocyte sedimentation rate (ESR) (mm/h) were collected. X-rays of the sacroiliac joints were collected if available and scored locally according to the mNY criteria (Citation11). Current and previous medication use (non-steroidal anti-inflammatory drugs, and conventional and biological disease-modifying anti-rheumatic drugs) were recorded. Clinical assessment consisted of 66 swollen and 68 tender joints, Schober index, and chest expansion. Enthesitis and dactylitis were scored as positive if clinically apparent. Active inflammatory back pain was defined as pain at night at least once a week and/or an average morning stiffness of at least 30 min in the past week.
Disease activity was evaluated by patient and physician global disease activity [scored on a 100 mm visual analogue scale (VAS)], Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (Citation12), and Ankylosing Spondylitis Disease Activity Score (ASDAS) (Citation13). Patients were classified as having AS if they fulfilled the mNY criteria (Citation11).
Statistics
First, we compared females and males with axSpA. Secondly, to investigate whether the reported differences were consistent in AS versus non-radiographic axSpA, we compared disease parameters between females and males in both subgroups. Thirdly, to validate these results, we compared females and males with peripheral SpA. Fourthly, we compared disease parameters between HLA-B27-positive females and males and HLA-B27-negative females and males. Categorical data are presented as numbers (%), and continuous data as mean ± sd or as median and interquartile range (IQR). Categorical data were analysed using chi-squared tests, and continuous data using Mann–Whitney U-tests or unpaired t-tests. Statistical tests were two sided, and p-values less than 0.05 were considered significant.
Results
Study population
The study included 389 SpA patients. Of these, 182 patients (46.7%) were diagnosed with axSpA, 76 (19.5%) with peripheral SpA, and 131 (33.7%) with combined SpA. Patients with combined SpA were included in the analysis of axSpA (n = 313). In total, 230 patients (73%) with a clinical diagnosis of axSpA fulfilled the ASAS criteria for axSpA and 83 patients (27%) did not ().
Table 1. Axial spondyloarthritis (axSpA): comparison between males and females.
Differences between females and males in axSpA
Of the 313 patients with axSpA, 131 (42%) were female and 182 (58%) were male. Females less often fulfilled the modified mNY criteria for radiographic sacroiliitis (38.9% vs 64.4%, p < 0.001) and the ASAS classification criteria for axSpA (64.9% vs 79.7%, p = 0.003). Females had a higher median ESR [median (IQR) 11 (5–23) vs 8 (3–13) mm/h, p = 0.008] and reported a slightly higher mean patient VAS disease activity (mean ± sd 56.0 ± 25.8 vs 49.7 ± 24.9 mm, p = 0.032) and BASDAI (5.2 ± 2.1 vs 4.6 ± 2.2, p = 0.008) ().
Differences between females and males in AS vs non-AS axSpA
In total, 167 patients (116 males and 51 females) were diagnosed with AS. Females had a higher median ESR [16 (6.5–30) vs 9 (5–20) mm/h, p = 0.018, females vs males, respectively]. Females with AS reported more AU (37.3% vs 21.6%, p = 0.034).
Altogether, 144 patients (64 males and 80 females) had non-AS axSpA (not fulfilling the mNY criteria). Females had a higher median ESR [9 (5–17) vs 5 (2–14) mm/h, p = 0.009], and reported a higher mean VAS disease activity (61.6 ± 23.3 vs 51.3 ± 24.4 mm, p = 0.009) and BASDAI (5.6 ± 1.8 vs 4.8 ± 2.3, p = 0.039). AU prevalence was lower in females compared to males with non-AS axSpA (11.3% vs 25.0%, p = 0.030). Other parameters showed no statistically significant differences (data not shown).
Differences between females and males in peripheral SpA
In total, 76 patients had a clinical diagnosis of peripheral SpA, of whom 39 (51.3%) were male and 37 (48.7%) female. Females reported a higher mean BASDAI (4.3 ± 2.1 vs 3.3 ± 2.2, p = 0.041). Other parameters showed no statistically significant differences (data not shown).
Differences between females and males in axSpA and relation to HLA-B27 status
HLA-B27 status was missing in 16 patients; therefore, 297 patients were included in the analysis. When comparing HLA-B27-positive females and males, females significantly less often fulfilled the mNY criteria for radiographic sacroiliitis (52.9% vs 74.3%, p = 0.008). More HLA-B27-positive males had a limited Schober index compared to HLA-B27-positive females (32.8% vs 52.9%, p = 0.010). The comparison between HLA-B27-negative females and males showed no statistically significant differences ().
Table 2. Comparison between human leucocyte antigen (HLA)-B27-positive males and females and between HLA-B27-negative males and females with a clinical diagnosis of axial spondyloarthritis (axSpA).
Discussion
In this real-life cross-sectional cohort of patients with a clinical diagnosis of axSpA, we showed that: (i) radiographic sacroiliitis according to mNY criteria prevalence is higher in males; (ii) the prevalence of extra-articular and peripheral disease manifestation is equal between males and females; and (iii) females report higher disease activity (BASDAI and patient VAS global disease activity) and have higher ESR values than males. These differences between male and female axSpA patients were consistent in the non-AS patient subgroup, while in the AS subgroup only ESR was increased. When subdividing axSpA patients according to HLA-B27 status, HLA-B27-positive females less often fulfilled the mNY for sacroiliitis and males more often had a limited Schober index.
Besides the subjective disease activity parameters, we observed increased ESR levels in females in the whole axSpA population as well as in the AS and non-AS subgroups, although all values were below the upper limit of normal (20 mm/h). This is in line with previous data on blood inflammatory markers showing conflicting results (Citation8, Citation9). Based on our findings, we can conclude that disease activity is at least as severe in males and females and that they show similar disease characteristics, supporting the suggestion by a 2018 study (Citation14) that there should be no gender-specific diagnostic strategies for early axSpA patients.
To our knowledge, this is the first study to compare gender differences in a real-life cohort of patients with a clinical diagnosis of axSpA and not classified according to classification criteria. Although we included patients with a clinical diagnosis instead of patients classified as axSpA according to classification criteria, our findings were similar to findings in the ASAS criteria-based cohorts (Citation7, Citation15).
This study has some limitations to consider. First, patients were included in this cohort when first visiting the dedicated SpA outpatient clinic, and thus not at first presentation in a rheumatology outpatient clinic. This prevents us stating anything about differences in first presentation of disease between females and males. Secondly, MRI of the sacroiliac joints was available for very few patients, and therefore these data are not included or shown in the present study. Thirdly, we do not have data on comorbidities of the patients included. Therefore, we cannot make a statement on the presence or absence of comorbidities such as fibromyalgia as an explanation for the higher VAS pain and disease activity as scored in this cohort.
Conclusion
This investigation and previous studies show that axSpA is, except for the presence of structural damage, at least as severe in females as in males, and this should be recognized when treating patients with axSpA. Because it was long thought that axSpA is mainly a male disease, it could be of importance also to focus on the physicians’ perspectives on gender differences in axSpA.
Disclosure statement
No potential conflict of interest was reported by the authors.
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