Mortality is a reliable indicator of illness severity.1 Rheumatic diseases are frequent chronic diseases with a great burden from disability and complications that ultimately lead to large losses of quality of life and cumbersome dependency, with demonstrated worse quality of life than other more serious diseases2; albeit they are considered benign diseases as a whole, because they are perceived to have a low mortality. Nevertheless, some rheumatic diseases may be mortal, especially those under the category of inflammatory diseases,3,4 and others may seem less deadly than they actually are. The recognition of the gradient of death risk among rheumatic diseases and of a decreased life expectancy in general, may subsequently lead to an acknowledgement of rheumatic diseases as relevant ones, with implications in health policies as well as in research budgets; despite the fact that those who manage rheumatic diseases, and rheumatic patients in general, find some very common health states in these diseases worse than death.5

An adequate risk assessment of patients during follow-up can help rheumatologist to improve the management in this rheumatic diseases, including an assessment of death risk, as well as of predictors of such risk.

SMRs are calculated as the ratio of deaths observed in a cohort to those expected in a group of the same size from the general population in the same area and standardized for age and sex of the individuals in the study cohort. Current literature reporting mortality in rheumatic diseases varies widely, and therefore an accurate and weighted analysis of the SMR is of importance. The objective of this systematic review and meta-analysis of published data is to provide an accurate overview of the current risk of mortality in rheumatic diseases.

We conducted a systematic review and meta-analysis by adapting the procedures of the Cochrane Collaboration (http://www.cochrane.org/training/cochrane-handbook) to a small local team. The findings are reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement9 and MOOSE.10

The electronic searches yielded 3526 articles (2121 from PubMed, 1331 from EMBASE, and 74 from Cochrane Library), in all 2776 after removing duplicates, plus 38 abstracts from congresses. The selection by title and abstract left 132 articles plus 7 abstracts for detailed review. Only 32 studies met the complete set of selection criteria and were finally included in the review. Many studies were excluded for not providing the SMR or because the quality was not high enough. Fig. 1 shows the flow chart, and the list of all excluded studies and reasons are available upon request to the corresponding author. Table 1 shows the evidence table of all included studies, and Table 2 shows the results on mortality by study. The largest individual overall SMR came from studies on inflammatory diseases, and the specific SMR were very high for infections and pulmonary events.By disease, the populations included were: 16 studies on rheumatoid arthritis12–27 including data from around 10,000 patients (weighted mean age at baseline 54, and weighted mean follow-up 11 years); 5 studies on systemic lupus erythematosus28–32 that provided information on over 17,000 patients (mean weighted age at baseline 34, mean follow-up 14 years); 7 studies on systemic sclerosis33–39 accounting for over 1700 patients, mainly women aged 44 and followed up for an average of 17 years; a study in psoriatic arthritis40 including 680 patients (we found no studies on ankylosing spondylitis or other spondyloarthritis); 2 studies on Vasculitis41,42 accounting for over 345 patients (an additional article provided SMRs in Behçet's disease, but the display of SMRs was by age bands, not as a SMR for the general population); and one study on osteoporosis43 including 4311 patients. Only a study of osteoarthritis, a retrospective cohort, was reviewed in detail, although it finally did not meet the selection criteria.44 The study analyzed mortality in 296 women with osteoarthritis and a mean age of 57. Eighteen percent of the patients died, but the duration of the observation period was not specified, and the SMR not provided. The causes of mortality were very similar to those of the general population.

Fig. 1.

Flow chart of the selection of studies.

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The results of the meta-analysis are shown in Table 3. The overall pooled SMR in the studied diseases is 2.03 (95% CI 1.79–2.29), ranging from 1.36 in psoriatic arthritis to 4.80 in vasculitis. Figs. 2 and 3 show the forest plots. Heterogeneity was large; however, the analysis of such heterogeneity within diseases (rheumatoid arthritis, lupus, and systemic sclerosis) did not provide any hint on the source, as no association was found with any of the studied: sample size, follow-up, age, percentage of women, comparator (general population versus non-rheumatoid), quality (high versus moderate), and country (US & Canada versus Europe and Others).

Fig. 2.

Meta-analysis of mortality in rheumatic diseases. Abbreviations: RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis; PsA, psoriatic arthritis; PSV, primary systemic vasculitis; ANCA-V, anca-associated vasculitis; OP, osteoporosis.

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Fig. 3.

Meta-analysis of mortality in rheumatic diseases by sex. Abbreviations: RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis; PsA, psoriatic arthritis; PSV, primary systemic vasculitis; ANCA-V, anca-associated vasculitis; OP, osteoporosis.

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We have performed a systematic review and meta-analysis on the standardized mortality in rheumatic diseases. The major result is that mortality is generally increased, especially in inflammatory conditions, and it is supported by moderate to high quality cohort studies. The causes of death in our review actually match those of the general population, where cardiovascular events and cancer are the most frequent causes, but notably, infections and respiratory complications of the underlying inflammatory diseases are actually the causes related to an excess mortality in the diseases of interest.

It draws our attention that many mortality studies do not report an SMR neither an expected rate, despite drawing conclusions on mortality rates in individual diseases apparently higher than expected. In some cases, instead of an SMR, the authors reported survival curves with the disease versus expected survival curves, thus providing graphic evidence but no numbers.

Another finding of this comparative study is that the two diseases in which mortality has been studied in higher depth and with better quality studies are rheumatoid arthritis and systemic sclerosis. Two meta-analyses have been published previously on the issue of mortality in rheumatoid arthritis51,52; however, they were centered in cardiovascular mortality, not reporting data on overall mortality. In both studies, cardiovascular mortality was higher than expected, although not clearly in the inception cohorts included, indirectly supporting an aggressive early approach in rheumatoid arthritis to control inflammation and therefore controlling cardiovascular inflammation. Ioannidis et al. published an outstanding meta-analysis on mortality in systemic sclerosis of patient reported data from several scleroderma cohorts.45 Unfortunately, a pooled estimate was not deemed adequate given the heterogeneity of SMRs. The main cause of death was cardiovascular disease, followed by pulmonary disease, or mostly both. Less frequent causes were cancer, renal crisis, and infection. After the review was finished, Wolfe et al. published a mortality study in fibromyalgia,46 with an overall SMR of 0.90 (95% CI 0.61–1.26), thus not demonstrating an increased death risk in this condition. Our review shows important gaps in the knowledge of mortality in osteoarthritis and spondyloarthritis.

Regarding meta-analysis of mortality of other diseases, Canavan et al. published a meta-analysis on the mortality of Crohn's disease, reporting a pooled SMR of 1.52 (95% CI 1.32–1.74),47 and Jess et al. one in ulcerative colitis, with SMRs varying from 0.7 to 1.4.48 A pooled analysis in HIV reported SMRs of 1.30 (95% CI 1.06–1.58) among homosexual men and 9.37 (95% CI 8.13–10.75) in drug abusers,49 and another one in Cushing's disease showed an SMR of 2.2 (1.45–3.41).50 Therefore our findings may be described as worse than other inflammatory diseases, such as bowel diseases, and even worse than HIV, except for HIV in drug abusers.

Our study has several limitations, the main one being the broad scope of the population. By studying many diseases at the same time, we are gaining perspective on the specialty, but loosing precision and detailed information. An analysis by disease would have been more adequate to understand predictive factors, as well as causes of death and other variables related to severity.

An adequate risk assessment of patients during follow-up must include an assessment of death risk, as well as of predictors of such risk.6,7 Nowadays, it is possible to develop automatic systems that capture specific signals from patients’ data and then alert the physician; such systems are invaluable to improve safety and quality of care, as they increase physician's awareness of a worse prognosis, or of specific risks, such as allergies, interactions, or others, without increasing consultation times.8 As a first step towards developing such an IT solution, our group deemed important to feed the system with data on frequent comorbidities, risk of death, and most frequent causes of death in the rheumatic diseases. In order to apply our results, we will introduce algorithms in our computer system, by which situations such as an admission due to a respiratory condition, or to an infectious disease, will prompt the system to increase awareness about the individual patient, based on risk and priorities.

Based on our results and on the good quality of the included studies, we can conclude that rheumatic diseases increase in general the risk of death, and especially inflammatory diseases.

The major result is that mortality is generally increased, especially in inflammatory conditions, and it is supported by moderate to high quality cohort studies. The causes of death in our review actually match those of the general population, where cardiovascular events and cancer are the most frequent causes, but notably, infections and respiratory complications of the underlying inflammatory diseases are actually the causes related to an excess mortality in the diseases of interest.

Based on our results and on the good quality of the included studies, we can conclude that rheumatic diseases increase in general the risk of death, and especially inflammatory diseases.

Protection of human and animal subjects. The authors declare that no experiments were performed on humans or animals for this investigation.

Confidentiality of Data. The authors declare that no patient data appears in this article.

Right to privacy and informed consent. The authors declare that no patient data appears in this article.

This work was partially supported by the RETICS Program, RD08/0075 (RIER), from Instituto de Salud Carlos III (ISCIII), within the VI Plan Nacional de I+D+I 2008–2011 (FEDER).

All authors declare no conflicts of interest.