Factors related to health-related quality of life in ankylosing spondylitis, overall and stratified by sex

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease primarily affecting the sacroiliac joints and spine [1]. Inflammation of the spinal structures and progressive spinal changes in the vertebrae and surrounding tissue, is largely responsible for the decreased physical function and mobility experienced by patients with AS [2]. Studies of AS often describe functional disabilities and measures of disease activity, however, they less often report the quality of life experienced by patients with AS and how this is related to AS disease characteristics. Health-related quality of life (HRQoL) is a multi-dimensional concept including not only a person’s physical wellbeing, but also a person’s mental health and physical ability, both as an individual and as a participating member of the community. The Medical Outcome Survey Short Form-36 (SF-36) was designed for use in clinical practice and research, health policy evaluations, and general population surveys and is utilised in many different countries [3‐6]. Yang et al. recently performed a meta-analysis based on of 38 studies assessing HRQoL using the SF-36 in patients with AS and found that they had significantly worse HRQoL compared to persons from general populations and that to measure HRQoL should be regarded as an essential part of the overall assessment of patients with AS [7]. The SF-36 is grouped into eight domains reflecting physical and mental health and two summary scores, a physical component summary (PCS) and a mental component summary (MCS) score. Yang et al. reported that pooled mean scores ranged from 45.9 to 58.2 in the physical health domains and from 47.5 to 62.5 in the mental health domains in their meta-analysis of patients with AS [7] as compared to 72.5 to 85.2 and 60.0 to 84.6, respectively, in the normative general population database from Norway, one of the databases used for comparison with AS [8]. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) have been found to be negatively associated with some domains of the SF-36 [7, 9‐13]. The relationship between HRQoL, laboratory markers of inflammation, the Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Metrology Index (BASMI) and spinal radiographic changes, as assessed by the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS), is less studied. Since the AS phenotype differs between sexes, with men generally displaying more AS spinal radiographic changes compared to women, it is of importance to investigate factors related to HRQoL overall and also stratified by sex to be able to better personalize the care of patients with AS [14, 15].

The objectives of this study were to investigate the following in patients with AS: (1) HRQoL assessed by the SF-36 compared with HRQoL in controls from the general population, (2) HRQoL in relation to age and (3) to examine associations between the SF-36 scores and spinal radiographic changes, physical function, mobility, disease activity and demographic data overall and stratified by sex.

For the enrolment process see Fig. 1. A total of 210 patients with AS, 121 (57.6%) men and 89 (42.4%) women, with a median age of 49.0 years (40.0, 61.2) and a median symptom duration of 24.0 years (13.0, 34.0), were included in this report. HLA-B27 was present in 183 (87.1%) of the patients with AS. The mSASSS median and mean values were 5.0 (0.0, 20.0) and 13.9 ± 19.0, respectively. Concerning biological drugs, 43 (20.5%) patients were treated with a TNF-inhibitor (TNFi) out of which 32 (15.2%) were used in combination with a conventional synthetic disease modifying anti-rheumatic drug (csDMARD). In total, 73 (34.8%) patients were on a TNFi and/or a csDMARD. Characteristics of all the patients and stratified by sex are displayed in Table 1. Comparisons between men and women showed that the age and symptom duration did not differ significantly between sexes. Women with AS had a significantly higher ESR and VAS for global fatigue compared to the men. Men with AS had significantly higher mSASSS and body mass index (BMI) than the women. More men carried HLA-B27 and had ≥ 1 prevalent syndesmophyte compared to the women. Only men had severe radiographic changes in the spine, defined as ≥ 3 consecutive intervertebral bridges in the cervical spine and/or the lumbar spine. Otherwise, baseline characteristics were similar between sexes.

In this study, we have used the generic instrument SF-36 to evaluate HRQoL in a well-characterised cohort of patients with AS. The patients with AS had significantly lower HRQoL compared with controls. PCS was more affected compared to MCS in both sexes. Both disease-related and demographic factors were associated with HRQoL. Also, for the first time, to the best of our knowledge, we identified determinants of worse HRQoL separately in men and in women with AS and we found that the factors associated with HRQoL differed in part between the sexes.

We showed that the patients with AS had significantly lower SF-36 scores compared to 1055 age-matched and sex-matched controls from the general population. The patients with AS scored lower in all SF-36 domains and component summary scores. Our findings are in line with results from other countries in which SF-36 in AS has been compared indirectly with results from the general population [9, 22‐24] and with the meta-analysis by Yang et al. who compared SF-36 scores in AS using two normative general-population databases of the SF-36. They stated also that HRQoL in AS was lower than in type II diabetes mellitus, and comparable with rheumatoid arthritis [7]. Thus, these results underline the importance of taking HRQoL into consideration in the management of patients with AS.

Furthermore, we observed that the PCS score was more affected compared to the MCS score. This was noted in the whole cohort and also in men and in women analysed individually. Yang et al. reported a pooled mean PCS score of 37.5 and MCS score of 44.7 [7]. Our results were similar, with a mean PCS score ± SD of 41.4 ± 10.0 and MCS score of 44.8 ± 12.5 (n = 210). This suggests that AS has a larger impact on physical components of HRQoL compared to mental components, although both dimensions are reduced compared to the general population.

It is known that the phenotype of AS differs between the sexes. For instance, at a group level, men with AS have more AS-related spinal radiographic changes [25]. This finding is one reason why it could be hypothesized that there should be more effect on HRQoL in men than in women with AS. However, we found that the women with AS scored worse in two mental domains and one physical domain compared to the men with AS. Similar sex differences in SF-36 scores have been reported previously [22, 26, 27]. Interestingly, results from the SF-36 Swedish normative population database, consisting of 8930 persons from the general population in different parts of Sweden, showed a clear difference in mean scores between men and women, with women generally reporting lower HRQoL. This indicates a general phenomenon that women report worse HRQoL compared to men [4].

We also explored the impact of age on the PCS and MCS scores. Concerning the MCS, the median MCS score was stable among the four different age groups in our study and was not correlated with age. However, the median PCS score was significantly worse in the age group with the oldest patients (≥ 61 years) compared to the group with the youngest patients (≤ 40 years). The pattern was similar in the SF-36 Swedish and Norwegian normative population databases displaying associations with age and the physical health domains but small differences for the mental domains across age groups [4, 28].

The multivariable logistic regression analysis in our study revealed that a patient was twice as likely to have a worse PCS score if they lived without a partner, and three times more likely to have a worse PCS score if they had ASDAS-CRP ≥ 2.1 vs ASDAS-CRP < 2.1. A longer symptom duration and higher BASFI were also associated with a worse PCS score. Analyses by sex revealed that a high BASFI and ASDAS-CRP were the most important determinants of a worse PCS score in the men, while in the women high BASFI/reduced physical function was associated with a worse PCS score. Salaffi et al. also found that high disease activity and chronic comorbidity were significantly associated with a lower PCS [9], and Özdemir reported inverse correlation between BASDAI, BASFI and most of the SF-36 domains [12]. We found that the pattern was somewhat different for the MCS score. A global fatigue score above the median value was associated with a six-fold increase in the risk of a worse MCS score. Patients living without a partner and patients who had an ASDAS-CRP ≥ 2.1 were three times more likely to have a worse MCS score. In analyses stratified by sex the same variables were significant in women, while in men, high levels of fatigue, longer education and absence of severe spinal radiographic changes, defined as ≥ 3 consecutive intervertebral bridges in the cervical spine and/or the lumbar spine were factors associated with worse MCS score. Opposite results on the level of education have previously been reported by some, with a low level of education or ≤ 12 years of education associated with worse HRQoL [9, 22, 26]. The discrepancy may have to do with our sex-stratified analyses and differences in selection and demographics between studies. We did not find the mSASSS for radiographic changes or the presence of syndesmophytes in the spine to be significant determinants of SF-36 scores, but severe spinal radiographic changes in men, defined as ≥ 3 consecutive intervertebral bridges in the cervical spine and/or the lumbar spine, were associated with better mental health, with MCS in multivariable analyses and with worse physical health, worse physical health, PCS in univariate but not in multivariable analyses. Importantly, it was only men in our study that had ≥ 3 consecutive intervertebral bridges in the cervical spine and/or the lumbar spine. Only a few previous studies have addressed if there is a relation between radiographic changes in the spine and HRQoL in AS. A Chinese study conducted in 245 patients with AS found that patients with severe kyphosis had a significantly worse PF domain score compared to patients with milder kyphosis [10]. In a study of 962 patients with AS, Bodur et al. identified weak but significant inverse correlation between the Bath Ankylosing Spondylitis Radiology Index (BASRI) and some of the SF-36 domains (PF, GH and MH) [29] similar to findings in a study of 100 patients with AS from Morocco [30]. Weak significant correlation was identified between the BASRI and worse Ankylosing Spondylitis Quality of Life questionnaire (ASQoL) scores in univariate but not in multivariate regression analyses in early axial SpA [31]. Conversely, a small study conducted in 36 patients with AS found no significant correlation between the mSASSS and SF-36 scores [32] and Machado et al. did not find significant association between the PCS or MCS scores and the mSASSS [13], while a higher mSASSS was significantly associated with better ASQoL in another study [33]. In a longitudinal study, the mSASSS at baseline was not associated with worse ASQoL over time [34]. In summary, previous results are not consistent, which can be explained by the use of different methods for grading spinal radiographic changes; the mSASSS, BASRI, kyphosis and ≥ 3 consecutive intervertebral bridges, different questionnaires assessing HRQoL; SF-36 and ASQoL, different statistical approaches; univariate and multivariable analyses and differences in methods of recruiting the patients etc. However, there seems to be some direct association between HRQoL and AS-related spinal radiographic changes. Interestingly, for the first time, to the best of our knowledge, we found that men who had severe spinal radiographic changes had better mental health compared to men without such changes and we hypothesize that it can be explained by adaptive coping strategies in patients with a longstanding chronic disease [35].

The impact on HRQoL of living alone and/or to be unmarried has previously been investigated in other diseases and in the general population, and to the best of our knowledge, for the first time in this study of patients with AS. The literature displays inconsistent results. In patients with chronic diseases such as cancer and multiple sclerosis, living alone is mostly associated with worse HRQoL, which is in line with the findings in our study [36‐38]. However, in a longitudinal study, decline in the MCS score in patients with diabetes mellitus was associated with not living alone [39]. In a study from China, participants living alone had worse HRQoL [40], while the opposite was reported from another part of China, Shanghai [41]. Women in the Nurses’ Health Study who lived alone had lower risk of decline in the MH and VT domains compared with those living with a spouse. Furthermore, contact with friends and relatives and level of social engagement significantly protected against a decline in MH in women living alone but not among women living with a partner [42]. Thus, the influence of living alone on HRQoL is complex and seems to be related to the persons’ state of health, culture and gender, among other factors.

The sex-stratified analyses in our study revealed some differences; the disease activity seemed to be a more important factor in the physical component of HRQoL in men while the civil state was more important for the mental component of HRQoL in women, which are aspects that can be taken into account in the management of the patients with AS.

There are some limitations to be acknowledged; first this study is cross-sectional and thus we cannot draw any conclusions about the variables identified as associated with worse HRQoL and causality. To investigate this a longitudinal study is required. Second, the SF-36 Swedish normative population database was created in the 1990s and HRQoL in the general population might have changed over the years. However, HRQoL in the general population assessed by the SF-36 was stable from 1996 to 2004 in Norway [43], our neighbouring country, indicating that the difference in time may not be a significant problem. Third, we chose to divide the patients with AS according to their median values of PCS and MCS. Since there is no established cutoff for better or worse HRQoL we used this pragmatic approach. Furthermore, the modest number of subjects in the sex-stratified analyses result in broad confidence intervals and thus results need to be interpreted with some caution. Strengths of this study comprise first, a well-characterised patient cohort with an adequate number of patients allowing subgroup analyses of the sexes to be carried out for the first time. Second, SF-36 scores in patients with AS were compared to those in a large sample of controls from the general population who were precisely matched on sex and age.

Possible implications of our findings include that we have identified variables associated with worse HRQoL, which are modifiable. Even though our study is cross-sectional, and thus not able to show causality, by using these variables as a guide, patients may be treated more efficiently, leading to reduction in disease activity, pain and fatigue, thus potentially improving both the PCS and MCS scores as has been shown in some clinical trials [44‐46]. To live alone without a partner was also associated with worse HRQoL in particular in women in the MCS score. A focus on social activities and community support for women with AS might help to improve MCS scores in this subset of patients with AS.

In this study we show that the patients with AS had significantly lower HRQoL when assessed by the SF-36, compared with the general population. The PCS score was more affected than the MCS score in both sexes. Both demographic and disease-related factors were associated with worse HRQoL, with partial overlap for the PCS and MCS. There were some differences between sexes in the factors associated with HRQoL. By modifying factors such as ASDAS-CRP and fatigue, HRQoL may potentially be improved. There is a need for longitudinal studies investigating predictors related to the development of HRQoL in AS over time. We intend to investigate factors related to the change in HRQoL over a 5-year period in this same cohort of patients with AS in a future study.