Epidemiology of Rheumatoid Arthritis: Rheumatoid Arthritis and ...

Curr Rheumatol Rep (2010) 12:379–385 DOI 10.1007/s11926-010-0117-y

Epidemiology of Rheumatoid Arthritis: Rheumatoid Arthritis and Mortality Elena Myasoedova & John M. Davis III & Cynthia S. Crowson & Sherine E. Gabriel

Published online: 20 July 2010 # Springer Science+Business Media, LLC 2010

Abstract Increased mortality in rheumatoid arthritis (RA) is widely recognized but not fully explained. Despite substantial improvements in management and growing knowledge of the determinants of increased mortality, evidence for reduction in mortality in RA has lagged behind. Indeed, most studies report no apparent reduction in mortality in RA. However, emerging evidence from some recent RA inception cohorts suggests no increased mortality, including cardiovascular mortality, but this awaits further confirmation. Although it is possible that recent advances in RA treatment may manifest in improvement of survival in the near future, other factors, including undertreated or unrecognized low-grade inflammation, comorbidities, and immunogenetic factors, may contribute to the excess mortality in RA and impede its improvement. In this review, we summarize the current knowledge of the rates and determinants of mortality in RA, identify and discuss potential explanations for excess mortality, and outline promising research avenues for targeting mortality in RA. Keywords Rheumatoid arthritis . Inflammation . Mortality . CV disease . Accelerated aging

Introduction Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by chronic inflammation, progressive deterioraE. Myasoedova : C. S. Crowson : S. E. Gabriel Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA J. M. Davis III (*) : S. E. Gabriel Division of Rheumatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA e-mail: [email protected]

tion of joint function, increased comorbidity, and excess mortality. Since it was first described by Cobb and colleagues in 1953, the evidence for disproportionately increased mortality in RA has been accumulating worldwide. It is now recognized that RA patients have about a 50% increased risk of premature mortality, and their life expectancy is decreased by 3 to 10 years compared with the general population. This underscores the need to target mortality in RA. However, the underlying causes of increased mortality in RA patients are not yet fully understood. In this review, we highlight the literature on mortality in RA published during the past 2 years. We discuss potential reasons for survival disadvantage and outline the emerging trends in mortality research in RA.

Recent Trends of Mortality in Rheumatoid Arthritis Extending the earlier observations, most recent studies up to 2008 demonstrated no significant reduction in mortality in different RA populations worldwide [1–4], [5•]. Indeed, some authors reported an increase in RA-related mortality in older adults starting in the mid-1990s [3]. Contrasting with dramatic secular declines in the overall mortality rates for the general population, the differences between observed and expected mortality in RA increased substantially over time [1]. This resulted in the widening mortality gap between people with RA, particularly those positive for rheumatoid factor (RF), and the general population [2]. This phenomenon was first described in 2007 in our retrospective studies of the population-based incidence cohort of RA patients residing in Olmsted County, MN (Fig. 1). Later, a similar trend toward a widening mortality gap between individuals with and without RA was described in a prospective study of a European population, for which no improvement in survival in RA was found during the past 20 years [5•]. In contrast, a recent study

Mortality rate (per 100 patient-years)

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5 RF+ RFExpected

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compared with the general population. In the following sections, we discuss potential contributors to the increased mortality in RA.

Impact of Inflammation, Autoimmunity, and Genetic Determinants on Increased Mortality in Rheumatoid Arthritis

2 1 0 1970

1980 1990 Calendar year

2000

Fig. 1 Observed and expected mortality in patients with rheumatoid factor–positive (RF+) and rheumatoid factor–negative (RF−) rheumatoid arthritis. Expected mortality is based on the Minnesota Caucasian population. (From Gonzalez et al. [2]; with permission)

from Finland suggested that mortality was not increased in patients with incident RA diagnosed during the period of 2000 to 2007 and observed through 2008 [6]. It is unclear, however, whether these findings reflect a new trend of reduced mortality or just confirm the previous observation of no increased mortality in patients during the first several years after the onset of RA, followed thereafter by the potentially increased risk of mortality [5•]. In fact, the short follow-up (maximum of 8 years) and lack of validation of RA diagnoses by classification criteria suggest that these results are speculative and require further confirmation. Although not increasing, the relative cardiovascular (CV) mortality has not seemed to decline during recent decades. A recent study from Sweden reported no significant decrease in CV mortality in two cohorts of consecutive RA patients initiated in 1978 and 1995 compared with the general population [4]. Integrating the findings published during the past 50 years, recent meta-analyses confirm the substantial excess risk of CV death in patients with RA at 50% to 60%, with no apparent improvement in CV mortality over time [7•, 8]. However, one study of an RA inception cohort included in meta-analysis reported no increase in CV mortality [7•]. In summary, recently published studies do not yet provide enough evidence to confirm a reduction in premature mortality, especially CV mortality, in patients with RA. Some studies suggest a significant and widening mortality gap between individuals with RA and the general population. Emerging evidence of no increased risk of mortality in some inception cohorts of patients with RA is promising but requires further elucidation. Although it is possible that the improvement in survival lags behind the recent advances in RA management, other disease-specific factors likely contribute to the survival disadvantage of those with RA

The literature on prognostic factors associated with increased mortality in RA is mounting. As in the general population, older age and male sex remain significant determinants of increased mortality in patients with RA [5•]. Evidence supports the independent predictive value of inflammatory markers, including C-reactive protein and erythrocyte sedimentation rate, as well as complex measures of RA activity, such as the Disease Activity Score (DAS28), in determining the risk of premature death in RA [5•, 9, 10]. As surrogate measures of cumulative disease activity, radiographic joint damage and low bone mineral density are also associated with an increased risk of mortality [11]. Studies emphasize the importance of monitoring disease status in RA using patient questionnaires and joint counts to assess the quality of care and to predict long-term outcomes, including premature mortality [5•, 12]. In addition, clinical indicators of disease severity, including the occurrence of extra-articular manifestations and features of other systemic autoimmune disorders (eg, systemic lupus erythematosus), have been shown to confer significantly greater mortality risk [13–15]. Rheumatoid cachexia also may be an important risk factor associated with excess mortality in RA; however, the mechanism underlying this association is not well-understood [16]. Factors generally considered to be independent of RA activity (eg, presence of RF or anticitrullinated peptide antibodies) may be especially useful for the prediction of poor outcomes and increased mortality in RA patients [2, 5•, 17•, 18]. As mentioned previously, RF positivity seems to be associated with the increasing mortality gap between RA patients and the general population [2]. The presence of RF has been repeatedly linked to unfavorable CV outcomes in RA patients, including deaths following myocardial infarction and stroke [19, 20]. These findings suggest that RF positivity may be an important marker associated with increased mortality in RA. Remarkably, some recent studies have demonstrated that the mortality risk associated with markers of autoimmunity (including RF and antinuclear antibodies) is independent of the presence of clinical manifestations of rheumatic disease [17•, 21]. The reasons and clinical implications for these associations, as well as strategies to control the risks associated with autoimmunity are not clear. However, these findings underscore the broad impact of autoimmunity on mortality risk, thus guiding further research into the mechanisms underlying excess mortality in individuals with RA.


Other emerging predictors of mortality in RA include genetic determinants, particularly those associated with disease susceptibility; severity; and the presence of RF or anticitrullinated peptide antibodies. The HLA-DRB1 gene, previously associated with increased mortality resulting from ischemic heart disease and cancer in RA patients, is now linked to increased all-cause and CV mortality in patients with inflammatory polyarthritis and RA [22••]. However, the PTPN22 locus was not associated with mortality in this study. Evidence for the relationship of TRAF1/C5—another recently discovered RA susceptibility locus—with mortality is somewhat contradictory, likely due to differences in the study populations. Specifically, almost fourfold increased mortality (particularly from malignancies and sepsis, but not CV disease) has been suggested in TRAF1/C5 carriers with established RA [23]. However, no apparent association of the TRAF1/C5 polymorphism with increased all-cause or CV mortality was found among patients in an RA inception cohort [24]. More studies are needed for us to better understand the nature of these genetic associations. If replicated in large prospective studies, these genetic findings could provide guidance for novel diagnostic approaches to early identification of patients at increased genetic risk of mortality and early use of preventive therapies in these groups of patients. In summary, known markers of disease activity and severity and recently identified genetic markers appear to be significant determinants of increased mortality in RA patients. The effects of these determinants may be mediated in part by chronic systemic inflammation, which appears to confer a substantial disadvantage on survival over time in patients with RA compared with the general population. Although a logical approach is to target patients with these determinants for aggressive therapy in an attempt to ameliorate their increased mortality risk, the reduction in risk may be incomplete, as factors unrelated to RA activity also seem to confer excess mortality risk. Understanding the mechanisms underlying these determinants will facilitate the identification and validation of new molecular targets for therapy to improve disease control and potentially improve the outcomes of RA in the future.

Targeting of Inflammation in Rheumatoid Arthritis: Potential Implications for Mortality Outcomes In the past decade, new discoveries of disease pathogenesis have advanced a considerable armamentarium of targeted biologic therapies for treating patients with RA. Furthermore, clinical trials have devised improved strategies of using conventional and biologic therapies and have improved the capability of achieving tight control of disease activity among patients with RA. Despite the apparent improvement of RA control in recent years, several lines of evidence suggest that

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inflammation—particularly chronic low-grade inflammation in RA—remains undertreated. Achieving true disease remission is currently an elusive goal, and residual low-grade inflammation that is associated with increased mortality may remain unrecognized [25]. Patients and physicians may underestimate the importance of treating the low-grade inflammation. As such, patients with lower levels of inflammatory markers may be less likely to start disease-modifying antirheumatic drugs (DMARDs) early and may be less compliant with the treatment than those with higher levels of inflammation [26, 27]. Consequently, the time to the initiation of DMARDs and, even more so, the time to their effect may exceed the period of the “therapeutic window of opportunity.” In addition, some inequities in access to antirheumatic treatment may prevent certain disadvantaged populations at risk of poor outcomes from obtaining adequate and timely therapy. For instance, older age and lower income (both known predictors of poor outcomes in RA) have been associated with decreased use of biologic response modifiers (particularly the use of tumor necrosis factor [TNF]-α inhibitors) after adjusting for comorbidity and RA characteristics [28]. As a consequence, the burden of residual, low-grade inflammatory activity in RA patients may remain untreated or undertreated, gradually leading to disease progression, development of comorbidities, and increased mortality. Therefore, more attention should be paid to continuous monitoring and thorough targeting of inflammation in all patients to improve long-term outcomes of RA.

Challenges in Comorbidity Management in Rheumatoid Arthritis: The Example of Cardiovascular Disease The significant contribution of comorbidities to the excess mortality in RA is increasingly recognized. The pattern of cause-specific mortality in RA seems to be relatively constant over time, with the major attributable causes of death in RA similar to those of the general population [2, 5•, 29]. CV disease, as well as respiratory diseases, hematologic disorders, infectious diseases, malignancies, and genitourinary and gastrointestinal system disorders constitute the vast majority of pathologic conditions associated with excess mortality. Of these disorders, CV disease confers the greatest risk. Thus, increased awareness and proper management of comorbidity—particularly CV comorbidity—is a logical strategy for targeting the increased mortality in RA. However, the conventional approaches for reducing CV risk do not seem as effective in RA as in the general population. The lack of decline in CV mortality in RA patients over the years despite the sharp declines in CV mortality in the general population has heightened attention to the nature of CV disease. Consequently, more evidence has emerged underscoring the unique paradigms of CV disease in RA

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patients, including early age at onset, atypical presentation, increased likelihood of unfavorable outcomes, and a tendency toward manifesting as a fatal event. For instance, we recently reported markedly increased mortality rates during the first year after the onset of heart failure in RA patients compared with non-RA individuals despite lower rates of hypertension, ischemic heart disease, and obesity; lack of heart failure symptoms; and higher prevalence of preserved ejection fraction in typical RA patients [30]. A recent autopsy-based study showed that some comorbidities (primarily coronary heart disease and gastrointestinal disease) remain undetected and thus untreated during the lifetime of many RA patients [31•]. The unrecognized pattern of CV disease and other comorbidities in RA represents a critical barrier potentially preventing RA patients from successful management. This underscores the importance of CV disease prevention among RA patients. However, conventional methods of screening for and diagnosing CV disease (eg, conventional serum lipids and routine electrocardiography) may have limited utility in the RA population [32, 33]. Thus, a gap also exists in knowledge of CV disease pathogenesis in RA and the means to detect and manage this excess CV risk in RA. In particular, there is a lack of specific predictors, scoring tools, and evidence-based algorithms for the effective prevention and management of CV risk in RA patients. To address this gap, a multidisciplinary European League Against Rheumatism (EULAR) expert committee developed a list of key recommendations summarizing the evidence for CV risk management in RA and other forms of inflammatory arthritis based on extensive literature on CV disease in RA patients published during the past approximately 40 years [34]. Although they are a useful tool, these recommendations lack a stepwise description of treatment approaches to CV management in RA patients. Thus, validated algorithms addressing in detail the particular issues surrounding the management of CV risk and CV disease in RA are still lacking. In summary, undertreated comorbidity is one of the major contributors to the excess mortality among RA patients. As the leading cause of death in RA, CV disease represents an excellent example of the complexities in managing comorbid diseases in RA. Despite the increasing awareness of excess risk, CV disease often remains undiagnosed and undertreated in patients with RA, resulting in unfavorable CV outcomes. Although conventional modalities of CV care may underperform in the management of CV disease in RA patients, models of specialized CV care for RA patients are not yet welldeveloped. Hence, the optimal preventive and therapeutic approaches to CV disease in RA are not fully explored. This underscores the importance of developing and validating new CV risk assessment tools in conjunction with improved approaches to team-based and systems-driven care to target the excess CV mortality in patients with RA.


Antirheumatic Treatment: Impact on Comorbidity and Mortality in Rheumatoid Arthritis With the advent of new therapies, research on the impact of antirheumatic medications on morbidity and mortality in RA has gained momentum. Although the increased risk of serious infections and some malignancies in RA patients using biologic response modifiers remains a significant concern, the use of conventional DMARDs and perhaps biologic response modifiers does not seem to confer a significantly increased risk of all-cause mortality or adverse CV outcomes [31•, 35–39]. A recent safety report demonstrated that mortality for RA patients during treatment with adalimumab does not exceed that seen in the general population [37]. Substantial reductions in the risk of CV events among patients treated with methotrexate as well as patients with longer duration of exposure to methotrexate, leflunomide, TNF-α inhibitors, sulfasalazine, and corticosteroids were reported in a study of quantitative clinical assessment of patients with RA (the QUEST-RA [Questionnaires in Standard Monitoring of Patients With Rheumatoid Arthritis] study) [38]. One study reported a decrease in deaths associated with glucocorticoid toxicities [3]. However, the effect of treatment with corticosteroids on morbidity and mortality outcomes in RA remains controversial. The results of a study of combination therapy in early RA (the COBRA [Combination Therapy in Rheumatoid Arthritis] study) suggest a beneficial effect on mortality and no increase in comorbidity risk (including CV comorbidity) in patients with early RA after brief and intensive combination therapy, including an oral pulse of glucocorticoids [40]. However, studies reporting an increased risk of CV disease and associated conditions with increasing doses of glucocorticoids still prevail [41–43]. Consequently, using the lowest possible dose of glucocorticoids was recently suggested in the EULAR recommendations for CV risk management in RA patients [34]. Whereas the adverse effects of coxibs on the risk of CV events are well-recognized [42], the nature of the unfavorable CV effects of NSAIDs in RA patients is less well-understood. Some authors report no increased CV risk and even some beneficial effects on CV outcomes and all-cause mortality after treatment with NSAIDs [44]. Others have found that the use of certain NSAIDs in RA patients may be associated with significantly increased CV risk [45]. Thus, caution should be taken when using coxibs and NSAIDs to treat RA patients. In summary, although the growing evidence for benign effects of some antirheumatic treatments (primarily DMARDs) may appear promising, the risks of adverse effects of others (particularly corticosteroids and biologic response modifiers) may be a significant concern with regard to unfavorable morbidity and mortality outcomes. Given that RA patients are likely to receive combination therapy, increased awareness of unfavorable events and the balance of risks and benefits while


prescribing the antirheumatic medications may be a key to improved outcomes. Further investigations of the safety of antirheumatic medications are needed.

Accelerated Aging in Rheumatoid Arthritis: Are We Ready for New Targets in Rheumatoid Arthritis Treatment? Another emerging dimension associated with increased mortality in patients with RA is accelerated aging, primarily accelerated aging of the immune system. In recent studies, telomeric dysfunction and DNA instability leading to excessive apoptosis of T cells in patients have been recognized as key mechanisms of premature immune senescence [46•]. The same authors have reported decreased functional competence in hematopoietic precursor cells (CD34+) in RA, independent of RA activity, suggesting impaired repair mechanisms associated with accelerated aging in RA patients [47]. Furthermore, some experimental evidence suggests the ability of TNF-α inhibitors to delay the onset of CD8+ T-cell senescence and to enhance telomerase activity in vitro [48]. Understanding the mechanisms of premature senescence in certain cell lines of RA patients may reveal novel insights regarding the etiology of RA disease and its outcomes, thus providing new and exciting opportunities for disease management and targeting of mortality outcomes in patients with RA. Explicating the knowledge of premature senescence at the population level, we recently used mathematical models to suggest that at diagnosis, seropositive RA patients have already aged about 2 years more than their peers, and they continue to age at an accelerated pace during their disease course [49•]. These findings point to the need to reconsider the underlying causes of the excess mortality in RA and the lack of apparent improvement over time. The emerging hypothesis is that accelerated aging affects multiple organs and systems (particularly the CV system). This may partially explain the disadvantaged pattern of morbidity and mortality whereby CV risk in individuals with RA equates approximately to the risk in individuals in the general population who are 5 to 10 years older [50]. However, the association of accelerated aging with morbidity and mortality risk in RA is not fully understood. In particular, the nature of premature senescence (ie, the time of start, relation to immunologic changes, and its primary drivers), as well as the ways to control accelerating aging (ie, its potential prevention and/or reversibility) need further investigation. Thus, the concept of accelerated aging in RA seems to be a novel and promising area of research, bringing our understanding of pathogenesis closer to the etiology of RA. The concept of accelerated aging may provide novel insights regarding the disadvantaged mortality pattern in RA patients and may advance some novel therapeutic targets for further investiga-

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tion. Many more studies are needed to elucidate the biology of accelerated aging and to translate this knowledge into new treatment strategies with the potential for improved outcomes and survival among patients with RA.

Conclusions Despite substantial improvements in RA management and increasing knowledge of the determinants of increased mortality, there is little epidemiologic evidence for the improvement of mortality, particularly CV mortality, in RA patients in recent years. Emerging evidence for no increased mortality, including CV mortality, in some inception cohorts of RA patients is promising for improvement in mortality in RA but requires further elucidation. Several factors (including genes, autoimmune inflammatory burden, and increased comorbidity risk) may be suggested as potential determinants of mortality in RA. Of these, some factors (eg, inflammation and comorbidities) may be modifiable with currently available therapies, whereas available means to control other potential contributors are lacking (eg, immunogenetic factors). Much more work is needed to better understand the contributory mechanisms and determinants of premature mortality in RA in order to refine and redefine the treatment approaches for targeting this excess mortality and reducing the mortality gap in RA.

Disclosure Drs. Davis and Gabriel are co-inventors listed on a provisional patent application for a cytokine assay technology to predict therapeutic response in RA patients. No other potential conflicts of interest relevant to this article were reported.

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