5Mortality in established rheumatoid arthritis
Introduction
It has been clear since the 1950s that patients with rheumatoid arthritis (RA) experience premature mortality. The earliest mortality study1 was published before the introduction of the 1958 American Rheumatism Association (ARA) diagnostic criteria2 and included some males with ankylosing spondylitis. Most studies published since 1958 have used the ARA criteria but have varied as to whether they included patients with probable RA. Studies also varied in the method of selection of patients, the method of establishing the cause of death, the length and completeness of follow-up, the choice of controls and in the method of statistical analysis. In particular, a number of early studies used proportional mortality rather than standardised mortality ratios (SMR). Nevertheless, the great majority of these studies (Table 1) suggested that patients with RA, from whichever setting they were recruited, died earlier than members of the general population. The pattern of causes of death led Eric Bywaters, in 1961, to state, ‘Patients with rheumatoid arthritis died from the same causes as the general population but at an earlier age.’3 This observation was accepted for many years and it is only in the last 5–10 years that rheumatologists have begun to ask why RA patients experience what might be called premature ageing. Is it that the burden of chronic inflammatory activity leads to a faster ageing process, or is RA a manifestation of a premature ageing process that was already taking place within the individual? If disease activity itself contributes to premature mortality, why has improved treatment not led to improved survival? This chapter addresses these issues.
There have been many excellent reviews of the early mortality papers published in RA (e.g. Grimstadt-Kvalvik 1996; Ref. 4). This chapter, therefore, focuses on literature published since 1990. It examines the available literature on trends in mortality in RA patients and attempts to summarise the growing literature on cardiovascular mortality in this disease. It then looks at predictors of mortality within rheumatoid cohorts and finally explores the influence of treatment, in particular methotrexate and the anti-tumour necrosis factor (TNF) agents, on survival.
It is important to emphasise some of the pitfalls when comparing studies that are based on SMRs. The SMR is calculated by dividing the observed number of deaths by the number of deaths that would have been expected in a cohort of the same age and sex distribution recruited from the general population. In each case, the general population used should be that from which the RA subjects have been drawn. Background mortality rates in the general population vary by geographical site, calendar time and ethnic group. It is, therefore, not appropriate to make direct comparisons between, for example, an SMR calculated for a cohort of RA patients in London with one in the African Bush. The age- and sex-specific mortality rates in the two RA populations might be identical but the SMRs will be very different. Similarly, the SMR is influenced by the length of follow-up. The longer the length of follow-up, the more likely the SMR is to approach 1. This is because all individuals eventually die and if the length of follow-up is extended, say for 100 years, then the SMR will be 1. SMRs are, therefore, of great value and interest when trying to understand the mortality experience of an individual cohort but of less value when trying to compare the experience between cohorts.
Section snippets
Studies prior to 1990
Despite the differences in methodology already noted, all the early large mortality studies except one showed that RA patients had a reduced life expectancy (see Table 1). The one exception5 was based on all cases of RA identified by attendance at medical care within Olmsted County, Minnesota, the area served by the Mayo Clinic. Many of these cases were mildly involved.
Studies since 1990
The main large mortality studies published since 1990 are listed in Table 2. With the exception of the study performed in the
Cause-specific mortality
Most patients who die do not have a post-mortem and the cause of death must be obtained from medical records or death certificates. The advantage of using the cause of death from the death certificate is that it allows comparison to be made with the pattern of cause of death in the general population. It can, however, be frustrating as medical record review often suggests a different and more accurate cause of death from the one that has been recorded on the death certificate. In addition, RA
Demographic predictors
As in the general population, age and male gender are the strongest predictors of mortality in an RA cohort. However, females experience the highest relative risk of mortality and the highest SMRs for both all-cause and CVD mortality.28 This is only to be expected, because the expected rate of events is lowest in these sectors of the general population.
Lifestyle factors
Smoking has been observed to be a predictor of premature mortality in some cohorts15, *32 but not others.6 At least some of the detrimental
Conclusion
RA is associated with premature mortality. This excess mortality is apparent from early in the disease and becomes progressively more marked as the disease progresses. It is unclear whether the development of RA triggers premature ageing or whether RA is part of such a process, which was already established. Most excess deaths are due to infection, cardiovascular disease – especially CHD – or respiratory disease. Risk factors for early death include smoking, RF, cumulative disease activity and
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