J Rheum Dis 2018; 25(3): 197-202
Published online July 1, 2018
© Korean College of Rheumatology
Correspondence to : Young Ho Lee http://orcid.org/0000-0003-4213-1909
Department of Rheumatology, Korea University Anam Hospital, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea. E-mail:lyhcgh@korea.ac.kr
This is a Open Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.
Objective. This study examined the all-cause and sex-specific standardized mortality ratios (SMRs) in patients with spondyloarthropathy. Methods. Studies examining the all-cause and/or cause-specific SMRs in patients with psoriatic arthritis (PsA) and ankylosing spondylitis (AS) compared to the general population were surveyed using MEDLINE, EMBASE, and Cochrane databases and manual searches. A meta-analysis of the all-cause and sex-specific SMRs in patients with rheumatic diseases was then performed. Results. In total, 7 comparisons (5 PsA and 2 AS) from 6 reports met the inclusion criteria. Disease-specific meta-analysis showed that the pooled SMR was 1.299 (95% confidence interval [CI] 1.092~1.605, p=0.015) for PsA and 1.784 (95% CI 1.576~2.020, p<0.001) for AS. Meta-analysis showed that the SMRs of PsA and AS were significantly higher (1.299 to 1.784 times) than those in the general population. The age- and sex-adjusted SMR was highest for AS (1.784), followed by PsA (1.299). Moreover, sex-specific meta-analysis showed that the all-cause SMRs were increased in female and male patients with PsA. On the other hand, mortality increased in male patients with AS (SMR 1.834), whereas there was no significant increase in female patients with AS. Conclusion. All-cause mortality is higher in patients with PsA and AS compared to the general population. On the other hand, the mortality was higher in males with AS but not in females.
Keywords Psoriatic arthritis, Ankylosing spondylitis, Mortality, Meta-analysis
Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis that can affect peripheral and axial joints, entheses, and the skin [1]. Ankylosing spondylitis (AS) is a chronic inflammatory disorder characterized by inflammation in the spinal and sacroiliac joints that initially causes bone and joint erosion and eventually leads to new bone formation, syndesmophytes, and ankylosis [2].
These rheumatic diseases are chronic multisystemic illnesses that may be associated with significant mortality and morbidity [3]. In addition to disease-related complications, adverse events related to treatment may aggravate the risk of mortality [4]. However, mortality data for patients with PsA and AS are limited, and the few studies that have investigated mortality in rheumatic diseases yielded conflicting results, mainly owing to the small number of studies conducted, small sample sizes, and clinical heterogeneity [5-11]. The inconsistent results from different studies prompted us to conduct a meta-analysis of mortality in PsA and AS.
The standardized mortality ratio (SMR) is calculated as the ratio of deaths observed in a cohort to those expected in a group of the same size from the general population and standardized for age and sex [12]. Thus, the SMR is considered the optimal method of assessing mortality. Current studies reporting on mortality in rheumatic diseases vary widely; therefore, an accurate and weighted analysis of the SMR is critical. The present study aimed to assess the data on all-cause and sex-specific SMRs in patients with PsA and AS using a meta-analysis approach.
We performed a literature search for studies that examined mortality in patients with PsA and AS. The MEDLINE, EMBASE, and Cochrane databases were searched to identify relevant articles (from 1990 to December 2017). The following key words and subject terms were used: “psoriatic arthritis,” “ankylosing spondylitis,” “mortality,” and “SMR.” All references in the studies were reviewed to identify additional studies not included in the electronic databases. Studies were included if they met the following criteria: 1) cohorts or longitudinal observational studies with patients with PsA or AS, and 2) all-cause and/or cause-specific SMR data available with 95% confidence interval (CI). We excluded studies (1) containing overlapping or insufficient data, or (2) if they were reviews or case reports. The following information was extracted from each study: first author, year of publication, country, ethnicity, enrollment period, follow-up period, midpoint year of the study period, number of participants, number of deaths, and all-cause and/or cause-specific SMR with 95% CI. We scored the quality of each study included in the meta-analysis based on the Newcastle-Ottawa Scale [13]. Scores ranging from 6–9, with 9 being the highest score possible, indicated high methodological quality.
We performed meta-analyses to evaluate the SMRs for all-cause- and sex-specific mortality. The effect sizes of outcomes were expressed as SMRs and corresponding 95% CIs. We assessed within- and between-study variation and heterogeneities using Cochran’s Q-statistics [14]. The heterogeneity test was used to assess the null hypothesis that all studies were evaluating the same effect. When a significant Q-statistic (p<0.10) indicated heterogeneity across studies, the random effects model was used for the meta-analysis; otherwise, the fixed effects model was used. The fixed effects model assumes that all studies estimate the same underlying effect and considers only within-study variation. The random effects model assumes that different studies show substantial diversity and assesses both within-study sampling error and between-study variance. We quantified the effect of heterogeneity using
To examine the potential sources of heterogeneity observed in the meta-analysis, a meta-regression analysis was performed using the following variables: ethnicity, disease, publication year, midpoint year of the study period, and sample size. Sensitivity analysis was performed to assess the influence of each study on the pooled SMR by omitting each study. Although funnel plots are often used to detect publication bias, they require diverse study types of varying sample sizes, and their interpretation involves subjective judgment. Therefore, we assessed publication bias using Egger’s linear regression test [16], which measures funnel plot asymmetry using a natural logarithm scale of odds ratios.
In total, 72 studies were identified by electronic and manual searches, 60 of which were excluded owing to repeated publication or irrelevance. The remaining 12 studies were selected for a full-text review based on titles and abstracts. Three of these were excluded owing to the absence of SMR data. Thus, 6 articles met the inclusion criteria (Figure 1) [5,7-11]. One of these studies contained data on 2 different groups [10], which were treated independently. Thus, 7 comparisons were considered in the meta-analysis, and they consisted of 5 comparative studies of PsA and 2 of AS. The quality assessment score of each study ranged between 6 and 8, and all the studies had a quality score ≥6 (Table 1). Table 1 shows the characteristic features of each study, including the study population and quality score.
Table 1 . Characteristics of the individual studies included in the meta-analysis
Study | Country | Disease | Enrollment period | Follow-up period | Patient number | Number of deaths | Overall mortality | Mortality studied | Quality | |
---|---|---|---|---|---|---|---|---|---|---|
SMR | 95% CI | |||||||||
Juneblad, 2016 [11] | Sweden | PsA | 1995∼2011 | Retrospective study | 464 | 44 | 1.22 | 0.89∼1.63 | All-cause (male, female) | 6 |
Mok, 2011 [10] | China | PsA | 1999∼2008 | Retrospective study | 778 | 50 | 1.59 | 1.16∼2.03 | All-cause (male, female) | 6 |
Buckley, 2010 [9] | UK | PsA | 1985∼2007 | Retrospective study | 453 | 37 | 0.82 | 0.58∼1.13 | All-cause (male, female) | 6 |
Ali, 2007 [8] | UK | PsA | 1978∼2004 | NA | 680 | 106 | 1.36 | 1.12∼1.64 | All-cause (male, female) | 7 |
Wong, 1997 [7] | UK | PsA | 1978∼1993 | Median 11.4 years | 428 | 53 | 1.62 | 1.21∼2.12 | All-cause (male, female) | 8 |
Bakland, 2011 [5] | Norway | AS | 1969∼2009 | Mean 31.9 years | 677 | 98 | 1.61 | 1.29∼1.93 | All-cause (male, female) | 8 |
Mok-1, 2011 [10] | China | AS | 1999∼2008 | Retrospective study | 2,154 | 199 | 1.87 | 1.61∼2.13 | All-cause (male, female) | 6 |
SMR: standardized mortality ratio, CI: confidence interval, PsA: psoriatic arthritis, AS: ankylosing spondylitis, NA: not available.
Compared with the general population, all-cause SMRs were increased in patients with PsA and AS (SMR 1.432, 95% CI 1.137∼1.728, p<0.001) (Table 2). Disease-specific meta-analysis revealed that the pooled SMR was 1.299 (95% CI 1.092∼1.605, p=0.015) for PsA and 1.784 (95% CI 1.576∼2.020, p<0.001) for AS (Table 2, Figure 2).
Table 2 . Meta-analysis of the all-cause standardized mortality ratios in patients with PsA and AS
Group | Population | Number of studies | Test of association | Test of heterogeneity | ||||
---|---|---|---|---|---|---|---|---|
SMR | 95% CI | p-value | Model | p-value | ||||
All | Overall | 7 | 1.432 | 1.137∼1.728 | <0.001 | R | <0.001 | 84.8 |
PsA | 5 | 1.299 | 1.092∼1.605 | 0.015 | R | 0.021 | 65.4 | |
AS | 2 | 1.784 | 1.576∼2.020 | <0.001 | F | 0.273 | 16.9 | |
Male | Overall | 7 | 1.410 | 1.132∼1.756 | 0.002 | R | 0.003 | 69.8 |
PsA | 5 | 1.245 | 1.043∼1.485 | 0.015 | F | 0.155 | 39.8 | |
AS | 2 | 1.834 | 1.605∼2.095 | <0.001 | F | 0.230 | 30.4 | |
Female | Overall | 7 | 1.473 | 1.245∼1.743 | <0.001 | F | 0.199 | 29.9 |
PsA | 5 | 1.457 | 1.134∼1.976 | 0.004 | R | 0.075 | 72.9 | |
AS | 2 | 1.380 | 0.807∼2.360 | 0.240 | F | 1.000 | 0 |
PsA: psoriatic arthritis, AS: ankylosing spondylitis, SMR: standardized mortality ratio, CI: confidence interval, R: random effects model, F: fixed effects model.
Sex-specific meta-analysis revealed that the pooled SMR was 1.245 (95% CI 1.043∼1.485, p=0.015) for PsA and 1.834 (95% CI 1.605∼2.095, p<0.001) for AS in males (Table 2, Figure 3). The pooled SMR was 1.457 (95% CI 1.134∼1.976, p=0.004) for PsA and 1.380 (95% CI 0.807∼2.360, p=0.240) for AS in females (Table 2, Figure 3). The risk of mortality was significantly increased in PsA and AS among males, while mortality was significantly increased in PsA but not in AS among females.
Between-study heterogeneity was identified in the meta-analyses of overall SMRs (Table 2). Meta-regression analysis showed that ethnicity and disease (p=0.012), but not sample size, midpoint year of the study period, or publication year (p>0.05), had a significant impact on the heterogeneity in the meta-analysis of overall SMRs in patients with PsA and AS. Sensitivity analysis showed that no individual study significantly affected the pooled SMR, indicating that the results of this meta-analysis are robust. It was difficult to correlate the funnel plot, which is typically used to detect publication bias, owing to the small number of studies included. Egger’s test revealed no evidence of publication bias in the meta-analysis (Egger’s test p-values >0.1).
To date, information on mortality in PsA and AS is limited and conflicting. In the present meta-analysis, we combined the published data of all-cause and sex-specific SMRs in patients with PsA and AS. Patients with PsA and AS were found to have increased SMRs from all causes (1.299, 1.784, respectively). This meta-analysis showed that the SMRs of PsA and AS were significantly higher than those in the general population by 1.299 to 1.784 times. The age- and sex-adjusted SMR was highest for AS (1.784) followed by PsA (1.299). Mortality in PsA was not found to depend on sex. However, we found that mortality was increased in male patients with AS (SMR 1.834), while there was no significant increase in female patients with AS. It is necessary to analyze what the main causes of death are in men and women and why the gender difference occurred. However, we could not investigate what the causes of death are in men and women, because there was no enough SMR data on the causes of death in men and women. The reason for this gender difference is unclear, but a similar increased mortality among male patients has also been reported in rheumatoid arthritis [17]. The longer life expectancy in women of any population would dilute an increased mortality. Considering the inclusion of only 2 AS studies in this review, further studies on mortality in female patients with AS are necessary. The common causes of death in rheumatic diseases are cardiovascular disease (CVD), infection, malignancies, uncontrolled disease activity, and adverse events related to treatment [18]. Immunosuppressive drugs for rheumatic diseases increase the incidence of infection and cancer [19]. In light of recent advances in the management of rheumatic diseases, such as therapeutic improvements, earlier diagnosis, increased physician awareness, and enhanced patient care, we expect to see an improved mortality risk in the future.
The present meta-analysis has several shortcomings. First, the heterogeneity of the clinical features, such as the study design and period, severity of organ impairment, and the proportion of patients with CVD, tended to confuse our findings and may have biased our analysis. Despite performing a meta-regression analysis using variables such as ethnicity, publication year, midpoint year of the study period, and sample size, we were unable to fully explain the source of the observed heterogeneity among the studies for all-cause mortality. Second, the SMR was adjusted only for age and sex, and we were unable to adjust for other confounding factors. Third, our findings regarding cause-specific SMR in PsA and AS are based on a small number of studies, and therefore may be affected by random errors and insufficient statistical power. Since only 2 studies were included in our analysis of the all-cause SMRs for AS, our findings should be interpreted with caution. Fourth, it is necessary to analyze the cause-specific outcomes, as well as the overall and sex-specific mortality. However, we could not investigate them, because most of studies did not provide SMR on the cause-specific outcomes due to CVD, infection, and cancer, etc. Nonetheless, an important strength of this meta-analysis is its increased sample size leading to statistical power and precision. To the best of our knowledge, this is the first and most comprehensive meta-analysis evaluating all-cause and sex-specific mortality in PsA and AS to date.
In conclusion, our meta-analysis demonstrates that all-cause mortality is increased in patients with PsA and AS, compared with the general population, and that the all-cause SMRs in PsA do not depend on sex. However, mortality was significantly increased in male, but not female, patients with AS. Given the small number of studies, further investigations of sex-specific and cause-specific mortality in patients with rheumatic diseases are warranted.
No potential conflict of interest relevant to this article was reported.
J Rheum Dis 2018; 25(3): 197-202
Published online July 1, 2018 https://doi.org/10.4078/jrd.2018.25.3.197
Copyright © Korean College of Rheumatology.
Young Ho Lee, Gwan Gyu Song
Department of Rheumatology, Korea University College of Medicine, Seoul, Korea
Correspondence to:Young Ho Lee http://orcid.org/0000-0003-4213-1909
Department of Rheumatology, Korea University Anam Hospital, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Korea. E-mail:lyhcgh@korea.ac.kr
This is a Open Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.
Objective. This study examined the all-cause and sex-specific standardized mortality ratios (SMRs) in patients with spondyloarthropathy. Methods. Studies examining the all-cause and/or cause-specific SMRs in patients with psoriatic arthritis (PsA) and ankylosing spondylitis (AS) compared to the general population were surveyed using MEDLINE, EMBASE, and Cochrane databases and manual searches. A meta-analysis of the all-cause and sex-specific SMRs in patients with rheumatic diseases was then performed. Results. In total, 7 comparisons (5 PsA and 2 AS) from 6 reports met the inclusion criteria. Disease-specific meta-analysis showed that the pooled SMR was 1.299 (95% confidence interval [CI] 1.092~1.605, p=0.015) for PsA and 1.784 (95% CI 1.576~2.020, p<0.001) for AS. Meta-analysis showed that the SMRs of PsA and AS were significantly higher (1.299 to 1.784 times) than those in the general population. The age- and sex-adjusted SMR was highest for AS (1.784), followed by PsA (1.299). Moreover, sex-specific meta-analysis showed that the all-cause SMRs were increased in female and male patients with PsA. On the other hand, mortality increased in male patients with AS (SMR 1.834), whereas there was no significant increase in female patients with AS. Conclusion. All-cause mortality is higher in patients with PsA and AS compared to the general population. On the other hand, the mortality was higher in males with AS but not in females.
Keywords: Psoriatic arthritis, Ankylosing spondylitis, Mortality, Meta-analysis
Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis that can affect peripheral and axial joints, entheses, and the skin [1]. Ankylosing spondylitis (AS) is a chronic inflammatory disorder characterized by inflammation in the spinal and sacroiliac joints that initially causes bone and joint erosion and eventually leads to new bone formation, syndesmophytes, and ankylosis [2].
These rheumatic diseases are chronic multisystemic illnesses that may be associated with significant mortality and morbidity [3]. In addition to disease-related complications, adverse events related to treatment may aggravate the risk of mortality [4]. However, mortality data for patients with PsA and AS are limited, and the few studies that have investigated mortality in rheumatic diseases yielded conflicting results, mainly owing to the small number of studies conducted, small sample sizes, and clinical heterogeneity [5-11]. The inconsistent results from different studies prompted us to conduct a meta-analysis of mortality in PsA and AS.
The standardized mortality ratio (SMR) is calculated as the ratio of deaths observed in a cohort to those expected in a group of the same size from the general population and standardized for age and sex [12]. Thus, the SMR is considered the optimal method of assessing mortality. Current studies reporting on mortality in rheumatic diseases vary widely; therefore, an accurate and weighted analysis of the SMR is critical. The present study aimed to assess the data on all-cause and sex-specific SMRs in patients with PsA and AS using a meta-analysis approach.
We performed a literature search for studies that examined mortality in patients with PsA and AS. The MEDLINE, EMBASE, and Cochrane databases were searched to identify relevant articles (from 1990 to December 2017). The following key words and subject terms were used: “psoriatic arthritis,” “ankylosing spondylitis,” “mortality,” and “SMR.” All references in the studies were reviewed to identify additional studies not included in the electronic databases. Studies were included if they met the following criteria: 1) cohorts or longitudinal observational studies with patients with PsA or AS, and 2) all-cause and/or cause-specific SMR data available with 95% confidence interval (CI). We excluded studies (1) containing overlapping or insufficient data, or (2) if they were reviews or case reports. The following information was extracted from each study: first author, year of publication, country, ethnicity, enrollment period, follow-up period, midpoint year of the study period, number of participants, number of deaths, and all-cause and/or cause-specific SMR with 95% CI. We scored the quality of each study included in the meta-analysis based on the Newcastle-Ottawa Scale [13]. Scores ranging from 6–9, with 9 being the highest score possible, indicated high methodological quality.
We performed meta-analyses to evaluate the SMRs for all-cause- and sex-specific mortality. The effect sizes of outcomes were expressed as SMRs and corresponding 95% CIs. We assessed within- and between-study variation and heterogeneities using Cochran’s Q-statistics [14]. The heterogeneity test was used to assess the null hypothesis that all studies were evaluating the same effect. When a significant Q-statistic (p<0.10) indicated heterogeneity across studies, the random effects model was used for the meta-analysis; otherwise, the fixed effects model was used. The fixed effects model assumes that all studies estimate the same underlying effect and considers only within-study variation. The random effects model assumes that different studies show substantial diversity and assesses both within-study sampling error and between-study variance. We quantified the effect of heterogeneity using
To examine the potential sources of heterogeneity observed in the meta-analysis, a meta-regression analysis was performed using the following variables: ethnicity, disease, publication year, midpoint year of the study period, and sample size. Sensitivity analysis was performed to assess the influence of each study on the pooled SMR by omitting each study. Although funnel plots are often used to detect publication bias, they require diverse study types of varying sample sizes, and their interpretation involves subjective judgment. Therefore, we assessed publication bias using Egger’s linear regression test [16], which measures funnel plot asymmetry using a natural logarithm scale of odds ratios.
In total, 72 studies were identified by electronic and manual searches, 60 of which were excluded owing to repeated publication or irrelevance. The remaining 12 studies were selected for a full-text review based on titles and abstracts. Three of these were excluded owing to the absence of SMR data. Thus, 6 articles met the inclusion criteria (Figure 1) [5,7-11]. One of these studies contained data on 2 different groups [10], which were treated independently. Thus, 7 comparisons were considered in the meta-analysis, and they consisted of 5 comparative studies of PsA and 2 of AS. The quality assessment score of each study ranged between 6 and 8, and all the studies had a quality score ≥6 (Table 1). Table 1 shows the characteristic features of each study, including the study population and quality score.
Table 1 . Characteristics of the individual studies included in the meta-analysis.
Study | Country | Disease | Enrollment period | Follow-up period | Patient number | Number of deaths | Overall mortality | Mortality studied | Quality | |
---|---|---|---|---|---|---|---|---|---|---|
SMR | 95% CI | |||||||||
Juneblad, 2016 [11] | Sweden | PsA | 1995∼2011 | Retrospective study | 464 | 44 | 1.22 | 0.89∼1.63 | All-cause (male, female) | 6 |
Mok, 2011 [10] | China | PsA | 1999∼2008 | Retrospective study | 778 | 50 | 1.59 | 1.16∼2.03 | All-cause (male, female) | 6 |
Buckley, 2010 [9] | UK | PsA | 1985∼2007 | Retrospective study | 453 | 37 | 0.82 | 0.58∼1.13 | All-cause (male, female) | 6 |
Ali, 2007 [8] | UK | PsA | 1978∼2004 | NA | 680 | 106 | 1.36 | 1.12∼1.64 | All-cause (male, female) | 7 |
Wong, 1997 [7] | UK | PsA | 1978∼1993 | Median 11.4 years | 428 | 53 | 1.62 | 1.21∼2.12 | All-cause (male, female) | 8 |
Bakland, 2011 [5] | Norway | AS | 1969∼2009 | Mean 31.9 years | 677 | 98 | 1.61 | 1.29∼1.93 | All-cause (male, female) | 8 |
Mok-1, 2011 [10] | China | AS | 1999∼2008 | Retrospective study | 2,154 | 199 | 1.87 | 1.61∼2.13 | All-cause (male, female) | 6 |
SMR: standardized mortality ratio, CI: confidence interval, PsA: psoriatic arthritis, AS: ankylosing spondylitis, NA: not available..
Compared with the general population, all-cause SMRs were increased in patients with PsA and AS (SMR 1.432, 95% CI 1.137∼1.728, p<0.001) (Table 2). Disease-specific meta-analysis revealed that the pooled SMR was 1.299 (95% CI 1.092∼1.605, p=0.015) for PsA and 1.784 (95% CI 1.576∼2.020, p<0.001) for AS (Table 2, Figure 2).
Table 2 . Meta-analysis of the all-cause standardized mortality ratios in patients with PsA and AS.
Group | Population | Number of studies | Test of association | Test of heterogeneity | ||||
---|---|---|---|---|---|---|---|---|
SMR | 95% CI | p-value | Model | p-value | ||||
All | Overall | 7 | 1.432 | 1.137∼1.728 | <0.001 | R | <0.001 | 84.8 |
PsA | 5 | 1.299 | 1.092∼1.605 | 0.015 | R | 0.021 | 65.4 | |
AS | 2 | 1.784 | 1.576∼2.020 | <0.001 | F | 0.273 | 16.9 | |
Male | Overall | 7 | 1.410 | 1.132∼1.756 | 0.002 | R | 0.003 | 69.8 |
PsA | 5 | 1.245 | 1.043∼1.485 | 0.015 | F | 0.155 | 39.8 | |
AS | 2 | 1.834 | 1.605∼2.095 | <0.001 | F | 0.230 | 30.4 | |
Female | Overall | 7 | 1.473 | 1.245∼1.743 | <0.001 | F | 0.199 | 29.9 |
PsA | 5 | 1.457 | 1.134∼1.976 | 0.004 | R | 0.075 | 72.9 | |
AS | 2 | 1.380 | 0.807∼2.360 | 0.240 | F | 1.000 | 0 |
PsA: psoriatic arthritis, AS: ankylosing spondylitis, SMR: standardized mortality ratio, CI: confidence interval, R: random effects model, F: fixed effects model..
Sex-specific meta-analysis revealed that the pooled SMR was 1.245 (95% CI 1.043∼1.485, p=0.015) for PsA and 1.834 (95% CI 1.605∼2.095, p<0.001) for AS in males (Table 2, Figure 3). The pooled SMR was 1.457 (95% CI 1.134∼1.976, p=0.004) for PsA and 1.380 (95% CI 0.807∼2.360, p=0.240) for AS in females (Table 2, Figure 3). The risk of mortality was significantly increased in PsA and AS among males, while mortality was significantly increased in PsA but not in AS among females.
Between-study heterogeneity was identified in the meta-analyses of overall SMRs (Table 2). Meta-regression analysis showed that ethnicity and disease (p=0.012), but not sample size, midpoint year of the study period, or publication year (p>0.05), had a significant impact on the heterogeneity in the meta-analysis of overall SMRs in patients with PsA and AS. Sensitivity analysis showed that no individual study significantly affected the pooled SMR, indicating that the results of this meta-analysis are robust. It was difficult to correlate the funnel plot, which is typically used to detect publication bias, owing to the small number of studies included. Egger’s test revealed no evidence of publication bias in the meta-analysis (Egger’s test p-values >0.1).
To date, information on mortality in PsA and AS is limited and conflicting. In the present meta-analysis, we combined the published data of all-cause and sex-specific SMRs in patients with PsA and AS. Patients with PsA and AS were found to have increased SMRs from all causes (1.299, 1.784, respectively). This meta-analysis showed that the SMRs of PsA and AS were significantly higher than those in the general population by 1.299 to 1.784 times. The age- and sex-adjusted SMR was highest for AS (1.784) followed by PsA (1.299). Mortality in PsA was not found to depend on sex. However, we found that mortality was increased in male patients with AS (SMR 1.834), while there was no significant increase in female patients with AS. It is necessary to analyze what the main causes of death are in men and women and why the gender difference occurred. However, we could not investigate what the causes of death are in men and women, because there was no enough SMR data on the causes of death in men and women. The reason for this gender difference is unclear, but a similar increased mortality among male patients has also been reported in rheumatoid arthritis [17]. The longer life expectancy in women of any population would dilute an increased mortality. Considering the inclusion of only 2 AS studies in this review, further studies on mortality in female patients with AS are necessary. The common causes of death in rheumatic diseases are cardiovascular disease (CVD), infection, malignancies, uncontrolled disease activity, and adverse events related to treatment [18]. Immunosuppressive drugs for rheumatic diseases increase the incidence of infection and cancer [19]. In light of recent advances in the management of rheumatic diseases, such as therapeutic improvements, earlier diagnosis, increased physician awareness, and enhanced patient care, we expect to see an improved mortality risk in the future.
The present meta-analysis has several shortcomings. First, the heterogeneity of the clinical features, such as the study design and period, severity of organ impairment, and the proportion of patients with CVD, tended to confuse our findings and may have biased our analysis. Despite performing a meta-regression analysis using variables such as ethnicity, publication year, midpoint year of the study period, and sample size, we were unable to fully explain the source of the observed heterogeneity among the studies for all-cause mortality. Second, the SMR was adjusted only for age and sex, and we were unable to adjust for other confounding factors. Third, our findings regarding cause-specific SMR in PsA and AS are based on a small number of studies, and therefore may be affected by random errors and insufficient statistical power. Since only 2 studies were included in our analysis of the all-cause SMRs for AS, our findings should be interpreted with caution. Fourth, it is necessary to analyze the cause-specific outcomes, as well as the overall and sex-specific mortality. However, we could not investigate them, because most of studies did not provide SMR on the cause-specific outcomes due to CVD, infection, and cancer, etc. Nonetheless, an important strength of this meta-analysis is its increased sample size leading to statistical power and precision. To the best of our knowledge, this is the first and most comprehensive meta-analysis evaluating all-cause and sex-specific mortality in PsA and AS to date.
In conclusion, our meta-analysis demonstrates that all-cause mortality is increased in patients with PsA and AS, compared with the general population, and that the all-cause SMRs in PsA do not depend on sex. However, mortality was significantly increased in male, but not female, patients with AS. Given the small number of studies, further investigations of sex-specific and cause-specific mortality in patients with rheumatic diseases are warranted.
No potential conflict of interest relevant to this article was reported.
Table 1 . Characteristics of the individual studies included in the meta-analysis.
Study | Country | Disease | Enrollment period | Follow-up period | Patient number | Number of deaths | Overall mortality | Mortality studied | Quality | |
---|---|---|---|---|---|---|---|---|---|---|
SMR | 95% CI | |||||||||
Juneblad, 2016 [11] | Sweden | PsA | 1995∼2011 | Retrospective study | 464 | 44 | 1.22 | 0.89∼1.63 | All-cause (male, female) | 6 |
Mok, 2011 [10] | China | PsA | 1999∼2008 | Retrospective study | 778 | 50 | 1.59 | 1.16∼2.03 | All-cause (male, female) | 6 |
Buckley, 2010 [9] | UK | PsA | 1985∼2007 | Retrospective study | 453 | 37 | 0.82 | 0.58∼1.13 | All-cause (male, female) | 6 |
Ali, 2007 [8] | UK | PsA | 1978∼2004 | NA | 680 | 106 | 1.36 | 1.12∼1.64 | All-cause (male, female) | 7 |
Wong, 1997 [7] | UK | PsA | 1978∼1993 | Median 11.4 years | 428 | 53 | 1.62 | 1.21∼2.12 | All-cause (male, female) | 8 |
Bakland, 2011 [5] | Norway | AS | 1969∼2009 | Mean 31.9 years | 677 | 98 | 1.61 | 1.29∼1.93 | All-cause (male, female) | 8 |
Mok-1, 2011 [10] | China | AS | 1999∼2008 | Retrospective study | 2,154 | 199 | 1.87 | 1.61∼2.13 | All-cause (male, female) | 6 |
SMR: standardized mortality ratio, CI: confidence interval, PsA: psoriatic arthritis, AS: ankylosing spondylitis, NA: not available..
Table 2 . Meta-analysis of the all-cause standardized mortality ratios in patients with PsA and AS.
Group | Population | Number of studies | Test of association | Test of heterogeneity | ||||
---|---|---|---|---|---|---|---|---|
SMR | 95% CI | p-value | Model | p-value | ||||
All | Overall | 7 | 1.432 | 1.137∼1.728 | <0.001 | R | <0.001 | 84.8 |
PsA | 5 | 1.299 | 1.092∼1.605 | 0.015 | R | 0.021 | 65.4 | |
AS | 2 | 1.784 | 1.576∼2.020 | <0.001 | F | 0.273 | 16.9 | |
Male | Overall | 7 | 1.410 | 1.132∼1.756 | 0.002 | R | 0.003 | 69.8 |
PsA | 5 | 1.245 | 1.043∼1.485 | 0.015 | F | 0.155 | 39.8 | |
AS | 2 | 1.834 | 1.605∼2.095 | <0.001 | F | 0.230 | 30.4 | |
Female | Overall | 7 | 1.473 | 1.245∼1.743 | <0.001 | F | 0.199 | 29.9 |
PsA | 5 | 1.457 | 1.134∼1.976 | 0.004 | R | 0.075 | 72.9 | |
AS | 2 | 1.380 | 0.807∼2.360 | 0.240 | F | 1.000 | 0 |
PsA: psoriatic arthritis, AS: ankylosing spondylitis, SMR: standardized mortality ratio, CI: confidence interval, R: random effects model, F: fixed effects model..
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