Trends in systemic sclerosis and systemic sclerosis-related pulmonary arterial hypertension mortality in the USA

Discussion

The most important finding emerging from this nationwide epidemiological study was the significant linear decrease in age-adjusted SSc-related mortality by approximately 3% per year from 2003 to 2016. Also, a decreasing trend was found when SSc was stratified by sex, race and geographic region. Deaths in SSc subjects aged 35−74 years decreased while death among subjects older than 75 years remained stable, supporting previous studies reporting that subjects with SSc might be living longer. Similarly, the mortality rate for PAH remained stable over this period, while an increasing trend was observed in decedents aged ≥75 years.

Despite the decreasing trends in overall SSc-related mortality, like other investigators, we also observed increased disease burden in female and black decedents and in older age groups [9, 10]. In contrast with our findings, using the same database Khrisnan and Furst [5] observed a rise in SSc mortality rates from 1978 to 1998. Their study was the first to use US death certificates and report SSc mortality that varied between races and sex: mortality rates were highest among female and black decedents. Although they observed a higher death rate in black compared with white decendents (6.5 per 1 000 000 versus 3.6 per 1 000 000, respectively), our data suggest that this difference has levelled off from 2003 to 2016 (table 2). This novel finding is further supported by the fact that the southern USA (with a 55% black population), experienced the largest drop in the average age-adjusted mortality (average annual percentage change −4.2%; 95% CI −4.9 to −3.5%) which may reflect long-term declines in SSc health disparities and gaps in access to care and treatment between black and white patients. Also, the odds of PAH-related mortality between black and white patients demonstrated similar trends. Further study is needed to clarify whether the ongoing interracial differences in mortality arise from different genetic predisposition for disease or differences in behavioural or environmental risk factors.

Our data mirrors other previous nationwide mortality analyses [11], in that the UCOD/MCOD ratio tended to decline with increasing age. Given the increased incidence of comorbid conditions with ageing, improve life expectancy compare to generations past, and the development and adoption of more effective treatments, comorbid complications involving SSc are expected to become more frequent. Thus, from a public health perspective, data enhancing our understanding of the interaction of comorbidities or complications and SSc will be increasingly relevant.

The decrease in the overall age-adjusted mortality over time may be attributed to improvements in primary and secondary coronary heart prevention as we saw ischaemic heart disease-related mortality among decedents with SSc decline with an average annual percentage change of −4.9%; 95% CI −5.7 to −4.1%.

Pulmonary vascular disease in commonly seen in SSc and leads to an increased mortality [12]. In SSc, PAH can be isolated (WHO group1), secondary to left heart disease (WHO group 2), due to severe ILD and/or chronic hypoxia (WHO group 3), or pulmonary veno-occlusive disease (WHO Group 1') [13]. In our study, only PAH with concomitant left heart disease (i.e. heart failure/cardiomyopathy) or pulmonary thromboembolic disease had increased odds of PAH−related death (table 1). We observed that overall SSc−PAH mortality rates remained stable during the 2003−2008 period and significantly decreased during the 2008–2016 period similar to other studies showing no change in survival following the introduction of PAH-directed therapies in 2002 [14, 15]. This finding also complements a recent large US multi-centre prospective cohort of subjects with SSc−PAH that demonstrated higher survival rates compared with older cohorts studies [16]. The decrease in the SSc−PAH mortality in recent years may reflect improved longevity due to increased availability of approved PAH-specific therapies, increased awareness, screening and diagnosis of PAH and increased use of combination pulmonary vasodilator therapy [17].

ILD was not a leading cause of mortality in our study and trends of SSc−ILD related mortality remained stable over the study period (average annual percentage change 1.2%; 95% CI −0.2 to 2.6%). This may be mainly because in contrast to ILDs associated with other underlying rheumatological diseases, the risk stratification and treatment for SSc−ILD is much better defined [1]. Indeed, to date, SSc−ILD is the only autoimmune rheumatological-related ILD that has been studied in phase III pharmacological treatment trials [18–20]. However, consistent with the results of other studies [21–23], the observed increase in mortality rate over time of subjects with SSc−ILD–PAH represents a prevailing challenge and an area of future research. Furthermore, we also observed that the odds of death associated with an ILD was 1.2-fold higher in SSc–PAH than in SSc without PAH (table 1). Considerably more work is needed to evaluate the effectiveness and safety of targeted therapies in this subgroup.

The major strength of our study lies in the generalisability of examining national-level data and capturing longitudinal mortality trends among the US population at large. In addition to the large sample size for answering the study question, sensitivity analyses using a different approach (i.e. UCOD) showed consistent results, suggesting the robustness of the study findings. Furthermore, despite differences in study designs, estimates of SSc from other studies are in the range of the results of the present study [24]. However, there are limitations. First, miscoding and under-reporting of SSc, SSc−ILD and SSc−PAH on the death certificate by certifying physicians is possible. However, decreasing mortality trends have occurred in the context of SSc diagnostic and treatment guidelines [25, 26]. It is unlikely that declining mortality trends would be largely due to reduced recognition and diagnosis of the disease. Furthermore, although recent studies on the incidence and prevalence of SSc in the USA are not available, prior estimates suggest that disease frequency has increased or remained stable over time. Secondly, despite the potential misclassification of contributing causes of death and not been able to precisely distinguish if the contributing causes of death was due to SSc (e.g. PAH associated to SSc and/or to concurrent ILD), the size of the study population, and particularly that of those identified with PAH was likely sufficient to detect excess risk among subgroups. Finally, we had no way to assess the fidelity of the diagnoses in this dataset; thus, results should be considered best estimates.

Despite these limitations, the study suggests that SSc-related mortality is decreasing in the USA. The finding that PAH, particularly in black women, and cardiovascular complications are the leading contributing causes of SSc death have significant implications for planning the future allocation of health resources. Although mortality trends in SSc–PAH appear to have decreased during 2008−2016, the increased mortality rate among those with PAH and concomitant ILD in the past decade highlights the importance of continued efforts aimed at the early detection and management of this complication.