Similar risk of cardiovascular events in idiopathic inflammatory myopathy and rheumatoid arthritis in the first 5 years after diagnosis

It is well established that several connective tissue diseases and chronic inflammatory disorders are associated with an increased risk for cardiovascular disease (CVD) secondary to accelerated atherosclerosis, including systemic lupus erythematosus (SLE) [1], rheumatoid arthritis (RA) [2] and psoriasis [3]. Traditional risk factors for atherosclerotic vascular disease do not fully explain this increased CVD risk [4‐6]. Chronic systemic inflammation is thought to play an important role in accelerating the atherosclerotic processes [7].

However, not all systemic autoimmune diseases carry the same burden. Notably, the risk appears to be greater in SLE compared to RA, likely due to differences in the immune response between these conditions [7].

The idiopathic inflammatory myopathies (IIM) dermatomyositis (DM) and polymyositis (PM) are a group of autoimmune conditions characterised by inflammation of skeletal muscle and frequently other organ systems. DM is distinguished from the other IIMs by its characteristic cutaneous features. The immune response in IIM appears more similar to that of SLE than RA; both are characterised by a relatively normal CRP and may be exacerbated or induced by anti-TNF therapy [8, 9]. In common with SLE and in contrast to RA, a large proportion of IIM patients have raised type 1 interferon levels [10] with a predominant interferon-α gene signature [11]. Data suggest that type 1 interferon may play a role in the premature atherosclerosis seen in SLE [12].

The risk of arterial events and the excess mortality seen in IIM have been compared to that reported in other systemic rheumatic diseases such as RA, ankylosing spondylitis, SLE and systemic sclerosis. However, comparisons are difficult due to the heterogeneity of published articles, and very few population-based reports have been presented [13].

The aims of the study were to estimate incidence of CV events in adult IIM in the UK and compare with RA and general population controls. To assess the differential risk for myocardial infarct (MI) and stroke, as well as magnitude of risk over time, and if an excess risk were established, assess whether the excess risk can be explained by traditional risk factors.

The initial search of the CPRD revealed 1013 subjects with at least two read codes for IIM. Review of these records excluded 199 as the diagnosis was deemed neither probable nor definite. A further 211 subjects were excluded due to other diagnoses (e.g. systemic sclerosis or polymyalgia rheumatica). In total, 603 subjects with IIM remained eligible for inclusion in the main analysis, 300 patients with DM (50%) and 303 with PM (50%). In addition, 4047 patients with RA and 4061 healthy controls were included. The baseline characteristics of these groups are shown in Table 1.

Patients diagnosed with IIM and RA were significantly older than controls within the expected range of difference (± 5 years) and had significantly more traditional risk factors for cardiovascular disease (Table 1). There were significantly more current smokers (p < 0.0001) in the RA compared to the IIM group. There was more statin use (p < 0.0001) and hypertension (p = 0.025) in the IIM group compared to the RA group but otherwise no significant differences observed for the variables between these two groups. Of the healthy individuals, 12% had used glucocorticoids (Table 1).

The rate of cardiovascular events (Table 2) was higher in the IIM and RA cohort (2.9 and 2.7 per 100 patient years, respectively) compared to the control group (1.5 per 100 patient years). IIM and RA patients had significantly higher hazard ratio (HRs) for all cardiovascular events: age and gender adjusted [HR 1.47 (95% CI 1.18–1.83)] for IIM and [HR 1.36 (95% CI 1.22–1.52)] for RA. As expected, adjustment for baseline cardiovascular risk factors reduced both HRs but there remained a significant increased risk compared to the control group. An analysis limited to cardiac events showed similar results with significantly higher HRs for cardiac events for both IIM and RA, before and after adjustment for cardiovascular risk factors (Table 2). Analysis of stroke revealed no significant increased risk in IIM or RA patients compared to controls.

The adjusted overall risk for a cardiovascular event showed similar trends in IIM and RA groups [HR 1.38 (95% CI 1.11–1.72) for IIM and HR 1.26 (95% CI 1.12–1.41) for RA], with a non-significant difference between the two diseases.

An analysis of cardiovascular event rates over time is shown in Fig. 1. The median follow-up per person was 7 years. The hazard for cardiovascular events increased in all groups over time. The excess hazard in IIM was most apparent in the first 5 years, [adjusted HR 1.32 (95% CI 0.90–1.95)], but then appeared to diminish in the 5–10 year period [0.74 (0.32–1.69)] and 10–15 year period [1.03 (0.57–1.84)]. In contrast, in RA patients, the difference in hazard was more stable over time: first 5 years [adjusted HR 1.22 (95% CI 0.91–1.65)], 5–10 years [1.22 (0.92–1.63)] and 10–15 years [1.31 (1.05–1.65)] (Table 3).

In this large and retrospective population-based study, IIM was associated with an increased risk of developing a cardiovascular event. Of note, the increased HR in the IIM cohort remained significant in multivariate analyses, suggesting that the excess risk early on cannot be explained entirely by traditional CV risk factors and suggests a role for inflammation in the increased CVD risk in IIM.

Previous studies have suggested an increased incidence of cardiovascular disease in myositis. In a study from Taiwan, 907 DM patients diagnosed from a national insurance claims database had an adjusted HR 3.37 for MI compared tocontrols in the first 2 years [17]. However, this study did not exclude patients with other connective tissue diseases or validate the diagnosis beyond the ICD code; perhaps for these reasons, the incidence of DM was over twice that described for all IIM in another Taiwanese study [18]. A Swedish study looked at patients hospitalised for autoimmune disease in Sweden; the standardised incident ratio for subsequent hospitalisation for coronary heart disease was 3.81 in the first year, also higher than our estimates. Nevertheless, again this study did not exclude patients with other connective tissue diseases or validate the diagnosis beyond the ICD code. In addition, the study assessed patients with severe disease requiring hospital admission [19]. A further study of 607 Canadian IIM patients, which used billing, hospitalisation and pharmacy databases, had slightly more stringent inclusion criteria and had an age- and sex-adjusted standardised incident ratio compared to the normal population of 1.95, more in keeping with our findings [20]. A study from British Columbia which used ICD codes alone to validate cases, identified 774 new cases of IIM over 14 years in a population of 4.7 million, over twice the expected figure [21]. They reported a HR for MI of 3.89 for PM, 2.92 for DM and non-increased risk for ischaemic stroke in IIM. This study showed similar, but not significant trends between the increased risk for MI and stroke in DM and PM patients compared to the general population. A smaller number of outcomes was reported as the possible reason for their results. Another hypothesis of the discrepancy between our results and other studies is the inclusion of ischaemic and haemorrhagic stroke in our analysis instead of just ischaemic cerebrovascular events [17, 22, 23]. The limitation of stroke event ascertainment may have also contributed to our findings.

In previous large meta-analyses, rheumatoid arthritis has been associated with a 48% increased risk of cardiovascular events (relative risk 1.48, 95% CI 1.36–1.62) compared with the general population [24]. We compared the incidence of CV events in IIM with controls and RA, enabling comparison of the incidence with more a studied disease, providing an anchor point for the data and internal validation. Although the adjusted overall risk for a cardiovascular event was slightly greater for IIM than for RA in our study, the difference was small and not significant. As IIM may occur in association with other connective tissue diseases including SLE and systemic sclerosis, we excluded patients with additional diagnoses of connective tissue disease. Due to the data available on the CPRD, we were also able to be more stringent in our case assignment. As a result of this approach, we identified fewer than expected cases which may have led to an unexpected case selection bias and reduced the power of the study. This might have contributed to the difference between the excess of increased CV risk seen in IIM patients in comparison with RA cohort in our research. However, it also highlights the complexity of autoimmune diseases in their pathogenesis, with common factors in their aetiology but different mechanisms of autoimmunity.

Notably, whilst the HR for a cardiovascular event in RA was fairly stable across the 15-year period after diagnosis, the risk for IIM varied markedly over time. The HR was increased in IIM compared to RA and healthy controls in the first 5 years but subsequently appeared to return to that of the general population. Similar results have been suggested in prior IIM studies, in particular, beyond the first year follow-up [25]. Rai et al. also reported a significant attenuation of the cardiovascular risk in the 5 years following the PM diagnosis, not seen in the DM group [21]. These results would be more in keeping with the observed perivascular changes, endothelial damage and myocardial involvement of IIM rather than the traditional pattern of premature atherosclerosis.

Disease activity is a predictor of cardiovascular disease in many inflammatory diseases including RA and SLE [26‐28]. If the same is true for IIM, one might hypothesise that disease activity is greatest in the first 5 years subsequently settling with the CV risk following suit. Nevertheless, whilst the disease is perhaps likely to be at its most inflammatory in the initial stages, the limited literature available to date does not suggest a resolution of the inflammation after 5 years. Over a 20-year period, Sultan and colleagues reported that 67.5% of the surviving patients in their cohort had a chronic relapsing-remitting course or chronic progressive disease, with only 17.5% going into complete remission [29]. In juvenile dermatomyositis (JDM), Sanner and colleagues reported that after 16.8 years, 51–73% of JDM patients still had active disease [30]. Whilst steroid use is almost universal in the initial management of both rheumatoid and IIM, the initial dosage is generally much higher in IIM and is a potential cause for the higher initial CVD risk in IIM patients.

A further possibility is that in the early stages of IIM, raised troponin levels either due to myocarditis or a high creatine kinase may lead to the incorrect diagnosis of a non-ST elevation myocardial infarct [31, 32]. This might lead to false high-recorded MI event rates. In keeping with this hypothesis, a cardiac MR study showed 62% of an IIM cohort had inflammatory cardiac lesions [33]. However, the results need to be interpreted in the context of the CPRD data limitations.

There are a number of limitations associated with our study. Case ascertainment bias and also survivorship bias, which may impact on event rates over time, cannot be excluded as partial explanations for the findings observed. In addition, there was significant attrition in numbers over the later periods (from 5 to 10 and 10 to 15 years) which affected the power of our study in these periods of time.

Our database is UK only and therefore might be subject to bias relating to the UK population, including local prescribing and treatment practices for this condition which could impact on cardiac risk. Notably, a high proportion of the healthy individuals (12%) included in our study had used glucocorticoids. In comparison, a previous CPRD study of the use of oral corticosteroids in the UK [34] reported a prevalence of oral corticosteroid treatment in the total adult CPRD population of 0.9%, increasing up to 2.5% in the elderly population. In the vast majority of the cases, the indication of that therapy was due to respiratory disease, being prescribed by the General Practitioners of which prescriptions are automatically collected on the CPRD. As such, these results may not be generalisable to other IIM populations.

Further studies, ideally in large well-characterised prospective cohort, are required to confirm the reduction of the cardiovascular risk following 5 years the initial IIM diagnosis and to ensure that the events early in the disease are atherosclerotic rather than inflammatory.

In conclusion, our study demonstrated an excess of cardiovascular events in IIM of a similar order to that found in RA, with a greater excess risk during the first 5 years following the diagnosis. Consequently, guidelines on the assessment and management in IIM need to be developed to take into account cardiovascular risk in IIM. This would help reduce mortality in IIM which remains high [35, 36] despite immunosuppressive treatment, with cardiac disease being a major cause of death [37‐39].