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Mortality in Sarcoidosis
CHAPTER 25
Mortality in Sarcoidosis ATHOL WELLS, MD • KOURANOS V, MD
INTRODUCTION Sarcoidosis is often viewed as a relatively benign chronic disease, especially by those clinicians who also manage other progressive diseases with a poor outcome. The perception of a good outcome in sarcoidosis includes patients with clinically significant pulmonary involvement, the most prevalent major organ involvement in that disease. For example, respirologists specializing in interstitial lung diseases are confronted by outcomes in idiopathic pulmonary fibrosis with a 3-year survival of 50% before the advent of disease-modifying antifibrotic agents. In other interstitial lung diseases such as hypersensitivity pneumonitis, idiopathic nonspecific interstitial pneumonia, and connective tissue disease–associated lung disease, a large subset of patients progresses inexorably or insidiously despite treatment. In contrast, in sarcoidosis, the majority of patients with lung disease stabilize with time or with therapy. Cardiac sarcoidosis and neurosarcoidosis tend to be viewed as “special cases” in which poor outcomes may be more frequent: exceptions to a generally benign outcome, applying to a small proportion of cases. The large number of sarcoidosis patients without major organ involvement, characterized by a good long-term outcome, reinforces the view that a low key approach in sarcoidosis management is appropriate in most cases. In this chapter we review and discuss outcomes in sarcoidosis with particular regard to mortality, scrutinizing whether, in truth, sarcoidosis should be regarded as essentially benign. Causes of death are highlighted with an overview of the identification of “dangerous disease”, in which a higher mortality must be expected with or without intervention.
PREVALENCE AND CAUSES OF SARCOIDOSIS-RELATED DEATHS The view that sarcoidosis-related mortality is low comes from two main sources. It reflects, in part, the major heterogeneity in disease presentation and course. In many cases, sarcoidosis is asymptomatic or incidentally detected on chest imaging. Indeed, it is known, from radiographic screening studies, that in many asymptomatic cases, the diagnosis is never made, Sarcoidosis. https://doi.org/10.1016/B978-0-323-54429-0.00025-2 Copyright © 2019 Elsevier Inc. All rights reserved.
reinforcing a perceived benign outcome. In other cases there may be prominent systemic symptoms such as fatigue and disabling arthralgia, without evidence of major organ involvement. Thus an important subgroup of patients with a more malignant disease course are disenfranchised by “whole-population statements” of the likelihood of sarcoidosis-related deaths. Clinicians managing sarcoidosis at large sometimes view such cases as “exceptions that prove the rule”. A superficial review of current data appears to support this impression. Death certificate data are notoriously imprecise, but conclusions reached from this source are concordant with recent case-cohort studies. In general, taking into account estimates made in many countries using a variety of methodologies, sarcoidosisrelated mortality is considered to exceed 5% and is probably approximately 6%–8%.1–8 As discussed later, a focus on mortality directly due to sarcoidosis progression almost certainly understates the true mortality associated with sarcoidosis. However, data emerging from selected recent studies serve as a useful starting point in the discussion that follows. In an outcome analysis of the Swedish National Patient Register, containing data from 8207 patients with sarcoidosis, the mortality rate was 11.0 per 1000 person-years in sarcoidosis patients compared with 6.7 per 1000 person-years in matched subjects in the general population.2 Although exact causes of death were not reported, sarcoidosis was the most frequent underlying and/or contributing cause of a fatal outcome. Mortality was not associated with age or gender, but there was a highly significant increase in mortality (hazard ratio [HR] 2.34 [95% CI 1.99–2.75]) in patients requiring sarcoidosis-specific treatment in the first 3 months. Based on these data, expected mortality from sarcoidosis in this patient subgroup may be up to threefold higher than in the general population. Thus perceptions of sarcoidosis-related mortality drawn from the general sarcoidosis population may be very misleading when applied to easily recognized patient subgroups. In another important recent study, a French group evaluated sarcoidosis-related mortality in their country, exploring the underlying causes of death among French 305
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decedents with sarcoidosis between 2002 and 2011. The age-adjusted sarcoidosis mortality rate of 3.6 per million was higher than the general population mortality rate, and an increase in sarcoidosis mortality during the study period was observed.4 The mean age of death in sarcoidosis patients was 70.4 years, compared with 76.2 years in the general population. Compared with the general population, sarcoidosis-related deaths were more frequent in males aged <65 years and in females aged ≥65 years, with most deaths (53%) occurring between the ages of 60 and 79 years. Mortality associated with sarcoidosis rose with increasing age, a trend that applied equally to cases in which sarcoidosis was considered to be the underlying cause of death and in the remaining sarcoidosis decedents. Sarcoidosis was the commonest cause of deaths associated with the disease, usually due to chronic respiratory or cardiovascular disease. Although mortality rates were, as expected, much lower below the age of 40 years, both in sarcoidosis patients and in the general population, the disease was the underlying cause of death in 59% of fatal sarcoidosis outcomes in that age group. In essence, these data establish that there is major adult mortality caused by sarcoidosis, irrespective of age. Sarcoidosis mortality rates in Sweden and France are broadly consistent with earlier UK data of 1019 sarcoidosis patients.8 In that study, mortality was even higher (14 per 1000 person-years) than in the Swedish report although, in contrast to Swedish observations, male gender and increased age were associated with increased mortality. A similar message emerges from all three studies discussed previously, with little to gain from a focus on minor differences between the three countries. Sarcoidosis severity was not documented (e.g., by Scadding chest radiographic criteria), and thus the impact of baseline severity on ultimate mortality cannot be captured in such a way to allow severityadjusted mortality comparisons between countries. Equally importantly the influence of genetic factors on population outcomes cannot be dissected in the three cosmopolitan countries where these population analyses were conducted. The potential importance of genetic differences is highlighted by findings in the United States. Based on two reports, it can be concluded that in the United States, sarcoidosis mortality was linked to both race and gender. Individuals of African American origin and female gender had a worse prognosis, with more extrapulmonary organ involvement, a longer duration of disease, and a higher prevalence of sarcoidosis-related hospitalization.6,7 It is unclear whether socioeconomic factors contributed to these observations: it is possible that cultural differences
exist in the detection of sarcoidosis, with a diagnosis of sarcoidosis made later in the disease course or made selectively in more severe disease in some racial or socioeconomic groups.
IS SARCOIDOSIS-RELATED MORTALITY SIGNIFICANTLY UNDERRECOGNIZED? It is usual, in studies of the mortality of chronic diseases, to identify the studied disease as the underlying cause of death when a fatal outcome is primarily due to major organ involvement. However, this analytic strategy does not take into account disease comorbidities that may have a greater prevalence or impact in sarcoidosis patients than in the general population, especially when comorbidities are in part ascribable to long-term sarcoidosis therapies. Causes of death directly or indirectly ascribable to sarcoidosis are summarized in Table 25.1. In sarcoidosis, comorbidities and multimorbidity have a major effect on a patient’s quality of life, health care, and health economics and are associated with increased mortality.9–15 Sarcoidosis patients have a higher risk of developing concomitant chronic conditions than age-/sex-matched individuals in the general population. Although this observation may arise in part from the persistence of inflammatory organ damage (which may be an important cofactor in the initiation of other chronic disorders), it appears likely that side effects caused by antiinflammatory treatment are at least equally important.12–15 In a comparison between 345 sarcoidosis patients and an age-/sex-matched control group from the general population, sarcoidosis was associated with a higher cumulative incidence of coronary artery disease,
TABLE 25.1
Causes of Death Directly or Indirectly Ascribable to Sarcoidosis • Progressive pulmonary fibrosis • Pulmonary hypertension • Cardiac sarcoidosis • Other organ involvements: neurosarcoidosis, renal disease, hepatic disease, and hypercalcemia • Comorbidities resulting from prolonged sarcoidspecific treatment, especially infection, diabetes, and hypertension • Isolated undiagnosed cardiac sarcoidosis
CHAPTER 25 Mortality in Sarcoidosis congestive heart failure, arrhythmia, stroke or transient ischemic attacks, arthritis, depression, diabetes, and major osteoporotic fractures.12 Similar findings have been reported in other studies.13,15 In a recent cohort of 218 sarcoidosis patients, mortality was linked to the comorbidity burden, as shown by an association between a higher Charlson Comorbidity Index and a higher mortality rate (P < .001).13 The association of mortality with higher numbers of comorbidities (>2) was also evident in a study of 557 sarcoidosis patients.14 However, this observation must be interpreted with caution as the death rate was low (2.9%) and thyroid disease was the only individual comorbid disease that was significantly more prevalent in decedent cases than in the general sarcoidosis population. Sarcoidosis has been linked with a higher frequency of subsequent malignant disease, but whether this association makes an important contribution to sarcoidosis-related mortality is uncertain.13,16 Similar associations exist in other autoimmune inflammatory conditions such as the connective tissue diseases, possibly reflecting universal effects of persistent inflammatory process and/or antiinflammatory medication.17,18 The linkage between prolonged corticosteroid therapy and the development of hypertension and diabetes is universally recognized. Infectious disease due to immunosuppressive therapies is a major cause in many autoimmune disorders, such as the vasculitides. In individual sarcoidosis patients, it is often impossible to ascertain whether these comorbidities arise due to the deleterious effects of sarcoidosis-specific treatments, and thus fatalities due to diabetes, hypertension, and infectious disease are not generally viewed as deaths caused by sarcoidosis in cohort studies. However, it is difficult to argue, given the combined contribution of these diseases to sarcoidosis-associated mortality, that mortality ascribable to sarcoidosis-specific treatments (and thus ascribable to sarcoidosis) is not seriously underestimated. One important implication is that statements of change in sarcoidosis-ascribable mortality with time need to be interpreted with great caution. For example, the significance of observations of a decline in mortality due to sarcoidosis in recent years is uncertain. In principle, this finding might have resulted from improved sarcoidosis management. However, it is equally possible that it reflects a shift from deaths due to sarcoidosis to deaths related to sarcoidosis therapy, with the use of more aggressive and prolonged interventional strategies in patients at higher risk due to major organ involvement.
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In a recent United States report, approximately 50% of patients newly diagnosed with sarcoidosis-received therapy, with this figure inflated by more frequent treatment in the in the African American population.11 Thus the possibility exists that the excess African American mortality in sarcoidosis results, in part, from treatmentrelated deaths. The exact influence of the dose and duration of maintenance therapy on the development of comorbidities has not been delineated. However, the adverse effects of corticosteroids were underlined in the study summarized previously of 105 newly diagnosed sarcoidosis patients. Patients receiving corticosteroids were at higher risk of reaching a composite comorbidity end-point that included diabetes, hypertension, weight gain, hyperlipidemia, and osteoporosis, all known to be associated with more frequent hospitalization. The underestimation of sarcoidosis-ascribable mortality includes the underrecognition of fatal cardiac sarcoidosis, a problem that applies especially to fatal cardiomyopathy and arrhythmias in isolated cardiac sarcoidosis. The high prevalence of unrecognized cardiac involvement emerging from autopsy studies in patients with a known diagnosis of sarcoidosis is well recognized. With the recent advent of advanced cardiac imaging modalities, there are numerous anecdotal reports of the existence of underlying cardiac sarcoidosis in many patients previously considered to have idiopathic cardiac disease. It is too soon to make population statements about this phenomenon as the use of advanced imaging is still in its infancy. However, it is possible that with the correct attribution of mortality in this subset of patients, the prevalence of sarcoidosisascribable mortality will increase significantly. Research in this area should be prioritized.
MORTALITY DATA AND THE PERCEPTION THAT SARCOIDOSIS IS A BENIGN DISEASE From a superficial review of broad cohort statements, it can be concluded that sarcoidosis is usually a benign disorder, leading to an underinvestment in urgently needed interventional studies. Plainly the exclusion of treatment-related fatal comorbidities and mortality due to undiagnosed isolated cardiac sarcoidosis from population-based statements of sarcoidosis-ascribable mortality, discussed previously, can only have resulted in a major understatement of the dangers associated with a diagnosis of sarcoidosis. However, the ultimately fatal impact of comorbidities and the existence of patients with major cardiac disease due to undiagnosed sarcoidosis cannot be taken into account in the identification of newly or recently diagnosed patients at high risk of
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death. The broad population statements reviewed earlier in this chapter may have contributed to misplaced complacency with regard to this important question. In reality, complacency is wholly inappropriate. The statement that a reduction in life expectancy due to sarcoidosis exists in only 5%–8% of patients with sarcoidosis is not helpful as it understates the dangers of major organ involvement. Integrating data from many sources, it can be concluded that 50%–70% of deaths directly ascribable to sarcoidosis in cohort studies are due to interstitial lung disease or pulmonary vasculopathy. Deaths attributable to cardiac sarcoidosis make up approximately 15%–20%% of fatalities. The remaining causes of death include neurosarcoidosis, hepatic disease, renal disease, hypercalcemia, and other rare fatal outcomes. Major racial differences in the pattern of fatal organ involvement are not captured by global average statements. For example, in Japanese cohorts a fatal outcome is most often due to cardiac involvement.19 However, accepting that preventative strategies must be nuanced according to the nature of the population to which they are applied, the need for an algorithm to identify patients at high risk of death is amply justified. In this regard, the mathematics are stark. An overall mortality due to sarcoidosis of 7% occurs almost exclusively in patients with major organ involvement. In a highly influential review of sarcoidosis, widely cited throughout the world, it was estimated that 30% of sarcoidosis patients have clinically significant major organ involvement.20 Thus it would appear that sarcoidosis-ascribable mortality approximates 20%–25% (7/30) in this patient subgroup. This figure rises further, perhaps to 35%, if cases with early spontaneous regression of disease and those with complete resolution with treatment are excluded. In this large patient subset, in a disease that is not rare, complacency about the risk of death needs to be resisted. Nihilism on this point would be easier to accept if major organ involvement was difficult to identify. However, significant pulmonary interstitial involvement is obvious based on symptoms and routine baseline tests recommended in an expert group statement.21 Pulmonary vasculopathy may be more difficult to identify but will be largely contained within patients found to have clinically significant “lung involvement”. Major hepatic and renal involvement is also very evident at baseline testing or will become obvious during routine monitoring. Neurosarcoidosis is usually clinically overt. It must be acknowledged that cardiac sarcoidosis does pose special problems in risk stratification due to underdetection, as discussed briefly later. However, given the very
considerable mortality associated with readily identifiable major organ involvement, it can be argued that organ-based risk stratification is urgently required in sarcoidosis, especially in patients with interstitial lung disease, pulmonary vascular disease, or cardiac involvement.
ORGAN-BASED MORTALITY RISK STRATIFICATION In patients with sarcoidosis a pragmatic definition of severe disease is needed, based on studies in which markers of severe disease are examined against mortality. Ideally, symptoms should be integrated with results from functional and imaging modalities and observed disease behavior in the definition of severe sarcoidosis.22 Key variables that can usefully be applied to risk stratification are summarized in Table 25.2. In patients with pulmonary sarcoidosis, progressive interstitial lung disease results in major pulmonary fibrosis in 20%–30% of cases.20 Advanced pulmonary sarcoidosis with evidence of fibrosis on high-resolution computed tomography (HRCT) has been an important predictor of mortality in several series23–25 with pulmonary fibrosis, either on chest radiography or HRCT, a predictor of mortality (independently of the presence
TABLE 25.2
Key Variables in Organ-Specific Sarcoidosis Risk Stratification PULMONARY DISEASE • Extensive fibrotic disease on HRCT • Severe reduction in pulmonary function tests, especially DLCO levels • Composite physiologic index >40 units • Presence of pulmonary hypertension (Presence of chronic pulmonary aspergillosis)a CARDIAC DISEASE • Left ventricular ejection fraction <50% • Ventricular tachycardia • Extensive late gadolinium enhancement on CMR • Prominent cardiac inflammation on PET CMR, cardiac magnetic resonance; DLCO, diffusion capacity for carbon monoxide; HRCT, high-resolution computed tomography; PET, positron emission tomography. aChronic pulmonary aspergillosis adds to risk only in patients with major hemoptysis but is associated with advanced pulmonary disease and should prompt risk stratification.
CHAPTER 25 Mortality in Sarcoidosis of pulmonary hypertension) in a cohort of 452 sarcoidosis patients from Cincinnati.23 Recent data suggest that the integration of pulmonary function parameters and HRCT findings may provide more accurate risk stratification. Walsh et al. reported a user-friendly staging system, developed using split-sample testing in more than 500 patients evaluated at a referral center.25 In this system, patients were stratified into low- and high-risk groups based on the extent of pulmonary involvement (as judged by the composite physiologic index [CPI] and the extent of fibrosis on HRCT) and, in patients with lesser pulmonary involvement, HRCT evidence of pulmonary vasculopathy (i.e., an increase in the ratio of the main pulmonary artery diameter to ascending aorta diameter to >1.0). In the validation cohort the high-risk patient group had a substantially increased mortality (HR 5.89, P < .0001). In a subsequent study of sarcoidosis patients with chronic pulmonary aspergillosis, a significant increase in mortality was observed in patients meeting criteria in the Walsh algorithm for high-risk disease.26 Individual risk components in the Walsh algorithm (CPI > 40, extent of fibrosis on HRCT >20%, pulmonary artery diameter/ascending aorta diameter >1.0) and the presence of pulmonary hypertension were also associated with increased mortality. In a general sarcoidosis population the Walsh system was predictive of mortality on univariate analysis, although age was the most malignant prognostic determinant on multivariate analysis.23 It is currently uncertain whether a CPI threshold offers advantages over a diffusion capacity for carbon monoxide (DLCO) threshold in pulmonary fibrosis risk stratification. The two variables are influenced both by the severity of interstitial lung disease and by the severity of pulmonary vasculopathy. However, impairment of DLco can be deconstructed into interstitial and vasculopathic profiles (depending on whether reduction in DLco is disproportionate to reduction lung volumes), information that may be invaluable in guiding management. Pulmonary hypertension (PH) in sarcoidosis is an independent determinant of morbidity and mortality23,27 and is present in approximately 75% of sarcoidosis patients listed for lung transplantation.27 In a series of 125 patients with sarcoidosis-related PH, the 5-year survival of 55% illustrates the importance of PH as a malignant prognostic determinant.28 In this cohort a prevalence of stage IV disease of 72% reflects the fact that in this cohort of 72% PH is most commonly associated with major pulmonary fibrosis, although there
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was a poor correlation between the severity of interstitial lung disease and pulmonary hemodynamic variables at right heart catheterization. However, PH may result from a multiplicity of underlying pathophysiologic mechanisms, including granulomatous vascular inflammation, extrinsic compression from lymphadenopathy, and/or mediastinal fibrosis, pulmonary venoocclusive disease, and left heart disease. In a series of sarcoidosis patients with proven PH, there was no evidence of pulmonary fibrosis on HRCT in 32% of cases.29 Thus effective risk stratification requires the identification of PH, irrespective of the presence or absence of severe pulmonary fibrosis. Unfortunately, no single noninvasive test has been reliable in identifying patients who should undergo right heart catheterization. Echocardiography is the most widely used screening tool, despite significant discrepancies between the echocardiographic systolic pulmonary artery pressure and right heart catheterization data.30 There is a need to validate the integration of a number of noninvasive variables associated with PH in a PH-screening algorithm, including enlargement of the pulmonary artery on HRCT,25,31 increased serum brain natriuretic peptide (BNP) levels, disproportionate reductions in gas transfer (against lung volumes), resting hypoxia, and striking oxygen desaturation during a 6-min walking test. Chronic pulmonary aspergillosis (CPA) is associated with increased mortality in pulmonary sarcoidosis and should also be taken into account in sarcoidosis risk stratification. CPA is a well-recognized complication of fibrotic pulmonary sarcoidosis, usually associated with immunosuppressive treatment in patients with extensive fibrotic lung disease.32,33 Mycetomas manifest on HRCT as a mass of soft tissue density within the lung cavity, usually located in the upper lobes and separated from the cavity itself by an air crescent.34 Erosion of the fungal ball into a hypervascular cavity wall results in hemoptysis, which is life threatening in approximately 5% of patients. However, mortality associated with CPA often reflects the severity of underlying pulmonary sarcoidosis, rather than fatal hemoptysis. In a recent case series of patients with sarcoidosis and CPA, severe fibrotic pulmonary sarcoidosis was present in 64 of 65 (98.5%) patients, with PH present in 31%.26 A proportion of 41.5% of patients died at a mean age of 55.8 years. Death seldom resulted from hemoptysis but was usually due to progression of advanced sarcoidosis. Thus the presence of CPA should alert the clinician to the likelihood of high risk from advanced pulmonary disease but adds risk only in those patients with recurrent major hemoptysis.
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The presence of cardiac sarcoidosis has historically been considered as indicative of “dangerous sarcoidosis”, based on the considerable morbidity and mortality associated with this form of disease. In a Japanese cohort of 95 cardiac sarcoidosis patients, patients with clinically overt cardiac sarcoidosis (a presentation with sustained ventricular tachycardia and a left ventricular ejection fraction [LVEF] < 50%) had a worse outcome with sudden cardiac death in 27% of cases. The 5-year survival of 60% was significantly higher in patients treated with steroids and/or preserved cardiac function (LVEF >50%).35 The adverse outcomes associated with cardiac dysfunction and rhythm disturbances (particularly sustained ventricular tachycardia) was confirmed in a cohort of 73 cardiac sarcoidosis patients, with age greater than 46 years being an independent predictor of mortality.36 General statements of outcomes associated with cardiac sarcoidosis in historical series were to some extent skewed by the difficulty in identifying milder forms of cardiac sarcoidosis before the advent of advanced imaging modalities. One of the main challenges in evaluating risks associated with cardiac involvement in the general sarcoidosis population is the lack of a gold standard for the diagnosis of cardiac sarcoidosis. A histological diagnosis is seldom pursued as the diagnostic yield of cardiac biopsy is reduced by the patchy nature of the disease, and the procedure is not without risk. Application of the Japanese Ministry and Welfare diagnostic criteria suggests a prevalence of 5%–10% of clinically overt cardiac sarcoidosis. However, these criteria do not identify subclinical disease, detectable only by advanced imaging modalities (cardiac resonance magnetic [CMR] imaging and positron emission tomography [PET]).37–39 Recent data indicate that CMR and PET provide important prognostic information in identifying sarcoidosis patients at higher risk of mortality and life-threatening cardiac complications.37–40 Based on these findings, CMR and PET were recently highlighted as recommended noninvasive diagnostic tests in suspected cardiac sarcoidosis in an expert consensus statement.41 In the Heart Rhythm Society consensus statement, patients with biopsy-proven extracardiac sarcoidosis are considered to have a highly probable diagnosis of cardiac sarcoidosis if there is otherwise unexplained advanced atrioventricular block, sustained ventricular tachycardia, new onset heart failure (LVEF <40%), or a suggestive pattern of myocardial fibrosis or inflammation on CMR and/or PET. With the use of these criteria, the prevalence of cardiac sarcoidosis in the general sarcoidosis population increases to 25%–30%, increasing further
in patients with suspected cardiac sarcoidosis. In a study of 321 patients with biopsy-proven sarcoidosis, screening with CMR revealed evidence of cardiac involvement in 29% of cases.38 However, although the use of advanced imaging modalities has identified a large subgroup of sarcoidosis patients with subclinical cardiac disease, the optimal use of these tests in risk stratification remains uncertain. In the study discussed previously, adverse cardiac outcomes were present in patients with evidence of cardiac involvement on CMR only when it was associated with cardiac symptoms and/or electrocardiogram (ECG) abnormalities.38 Preliminary data indicate that the integration of advanced imaging findings is likely to have an important future role in risk stratification, with the severity of cardiac dysfunction and the presence of late gadolinium enhancement (LGE) on CMR-independent determinants of mortality. In a recent cohort an extent of LGE >20% of the myocardial mass was associated with a worse outcome, even after adjustment for the degree of left ventricular impairment.42 Evidence of cardiac inflammation as judged by PET signal has also been associated with increased mortality in suspected cardiac sarcoidosis, but it is unclear whether this remains the case if PET signal is viewed as an indication for antiinflammatory/immunosuppressive therapy. Currently it would seem that prominent cardiac abnormalities on advanced imaging can reasonably be viewed as indicative of an increased risk of mortality to be integrated with LVEF <50% and ventricular tachycardia as a means of enhancing risk stratification in cardiac sarcoidosis. However, much work remains to be carried out to define exact thresholds indicative of a higher risk of mortality when advanced imaging abnormalities are less extensive.
CONCLUSION In this chapter we have emphasized that sarcoidosis should not be viewed as a benign disease in patients with major organ involvement, despite apparently reassuring statements that in the general sarcoidosis populations, deaths directly ascribable to sarcoidosis occur in only 5%–8% of cases. Deaths due to comorbidities associated with sarcoidosis-specific therapies are not included in such estimates. Importantly it is possible to stratify risk in patients with interstitial lung disease, pulmonary vascular disease, and cardiac involvement which, taken together, accounts for more than 80% of deaths caused by sarcoidosis. It should be emphasized that treatment algorithms aimed at reducing mortality are yet to be validated in
CHAPTER 25 Mortality in Sarcoidosis those patients believed to have dangerous sarcoidosis. Severe major organ involvement may identify patients who have increased mortality despite treatment. However, it is not logical to introduce therapies for potentially dangerous disease only when excess mortality is unavoidable. Ideally, risk stratification should also identify those patients at higher risk of mortality if disease continues to progress, with a view to therapeutic intervention before “the train has left the station”.
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38. Kouranos V, Tzelepis GE, Rapti A, et al. Complementary role of CMR to conventional screening in the diagnosis and prognosis of cardiac sarcoidosis. JACC Cardiovasc Imaging. 2017;10:1437–1447. 39. Blankstein R, Osborne M, Naya M, et al. Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis. J Am Coll Cardiol. 2014;63:329–336. 40. Hulten E, Agarwal V, Cahill M, et al. Presence of late gadolinium enhancement by cardiac magnetic resonance among patients with suspected cardiac sarcoidosis is associated with adverse cardiovascular prognosis: a systematic review and meta-analysis. Circ Cardiovasc Imaging. 2016;9:e005001. 41. Birnie DH, Sauer WH, Bogun F, et al. HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis. Heart Rhythm. 2014;11:1305–1323. 42. Osborne MT, Hulten EA, Singh A, et al. Reduction in 18F-fluorodeoxyglucose uptake on serial cardiac positron emission tomography is associated with improved left ventricular ejection fraction in patients with cardiac sarcoidosis. J Nucl Cardiol. 2014;21:166–174.
Mortality in Sarcoidosis ATHOL WELLS, MD • KOURANOS V, MD
INTRODUCTION Sarcoidosis is often viewed as a relatively benign chronic disease, especially by those clinicians who also manage other progressive diseases with a poor outcome. The perception of a good outcome in sarcoidosis includes patients with clinically significant pulmonary involvement, the most prevalent major organ involvement in that disease. For example, respirologists specializing in interstitial lung diseases are confronted by outcomes in idiopathic pulmonary fibrosis with a 3-year survival of 50% before the advent of disease-modifying antifibrotic agents. In other interstitial lung diseases such as hypersensitivity pneumonitis, idiopathic nonspecific interstitial pneumonia, and connective tissue disease–associated lung disease, a large subset of patients progresses inexorably or insidiously despite treatment. In contrast, in sarcoidosis, the majority of patients with lung disease stabilize with time or with therapy. Cardiac sarcoidosis and neurosarcoidosis tend to be viewed as “special cases” in which poor outcomes may be more frequent: exceptions to a generally benign outcome, applying to a small proportion of cases. The large number of sarcoidosis patients without major organ involvement, characterized by a good long-term outcome, reinforces the view that a low key approach in sarcoidosis management is appropriate in most cases. In this chapter we review and discuss outcomes in sarcoidosis with particular regard to mortality, scrutinizing whether, in truth, sarcoidosis should be regarded as essentially benign. Causes of death are highlighted with an overview of the identification of “dangerous disease”, in which a higher mortality must be expected with or without intervention.
PREVALENCE AND CAUSES OF SARCOIDOSIS-RELATED DEATHS The view that sarcoidosis-related mortality is low comes from two main sources. It reflects, in part, the major heterogeneity in disease presentation and course. In many cases, sarcoidosis is asymptomatic or incidentally detected on chest imaging. Indeed, it is known, from radiographic screening studies, that in many asymptomatic cases, the diagnosis is never made, Sarcoidosis. https://doi.org/10.1016/B978-0-323-54429-0.00025-2 Copyright © 2019 Elsevier Inc. All rights reserved.
reinforcing a perceived benign outcome. In other cases there may be prominent systemic symptoms such as fatigue and disabling arthralgia, without evidence of major organ involvement. Thus an important subgroup of patients with a more malignant disease course are disenfranchised by “whole-population statements” of the likelihood of sarcoidosis-related deaths. Clinicians managing sarcoidosis at large sometimes view such cases as “exceptions that prove the rule”. A superficial review of current data appears to support this impression. Death certificate data are notoriously imprecise, but conclusions reached from this source are concordant with recent case-cohort studies. In general, taking into account estimates made in many countries using a variety of methodologies, sarcoidosisrelated mortality is considered to exceed 5% and is probably approximately 6%–8%.1–8 As discussed later, a focus on mortality directly due to sarcoidosis progression almost certainly understates the true mortality associated with sarcoidosis. However, data emerging from selected recent studies serve as a useful starting point in the discussion that follows. In an outcome analysis of the Swedish National Patient Register, containing data from 8207 patients with sarcoidosis, the mortality rate was 11.0 per 1000 person-years in sarcoidosis patients compared with 6.7 per 1000 person-years in matched subjects in the general population.2 Although exact causes of death were not reported, sarcoidosis was the most frequent underlying and/or contributing cause of a fatal outcome. Mortality was not associated with age or gender, but there was a highly significant increase in mortality (hazard ratio [HR] 2.34 [95% CI 1.99–2.75]) in patients requiring sarcoidosis-specific treatment in the first 3 months. Based on these data, expected mortality from sarcoidosis in this patient subgroup may be up to threefold higher than in the general population. Thus perceptions of sarcoidosis-related mortality drawn from the general sarcoidosis population may be very misleading when applied to easily recognized patient subgroups. In another important recent study, a French group evaluated sarcoidosis-related mortality in their country, exploring the underlying causes of death among French 305
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decedents with sarcoidosis between 2002 and 2011. The age-adjusted sarcoidosis mortality rate of 3.6 per million was higher than the general population mortality rate, and an increase in sarcoidosis mortality during the study period was observed.4 The mean age of death in sarcoidosis patients was 70.4 years, compared with 76.2 years in the general population. Compared with the general population, sarcoidosis-related deaths were more frequent in males aged <65 years and in females aged ≥65 years, with most deaths (53%) occurring between the ages of 60 and 79 years. Mortality associated with sarcoidosis rose with increasing age, a trend that applied equally to cases in which sarcoidosis was considered to be the underlying cause of death and in the remaining sarcoidosis decedents. Sarcoidosis was the commonest cause of deaths associated with the disease, usually due to chronic respiratory or cardiovascular disease. Although mortality rates were, as expected, much lower below the age of 40 years, both in sarcoidosis patients and in the general population, the disease was the underlying cause of death in 59% of fatal sarcoidosis outcomes in that age group. In essence, these data establish that there is major adult mortality caused by sarcoidosis, irrespective of age. Sarcoidosis mortality rates in Sweden and France are broadly consistent with earlier UK data of 1019 sarcoidosis patients.8 In that study, mortality was even higher (14 per 1000 person-years) than in the Swedish report although, in contrast to Swedish observations, male gender and increased age were associated with increased mortality. A similar message emerges from all three studies discussed previously, with little to gain from a focus on minor differences between the three countries. Sarcoidosis severity was not documented (e.g., by Scadding chest radiographic criteria), and thus the impact of baseline severity on ultimate mortality cannot be captured in such a way to allow severityadjusted mortality comparisons between countries. Equally importantly the influence of genetic factors on population outcomes cannot be dissected in the three cosmopolitan countries where these population analyses were conducted. The potential importance of genetic differences is highlighted by findings in the United States. Based on two reports, it can be concluded that in the United States, sarcoidosis mortality was linked to both race and gender. Individuals of African American origin and female gender had a worse prognosis, with more extrapulmonary organ involvement, a longer duration of disease, and a higher prevalence of sarcoidosis-related hospitalization.6,7 It is unclear whether socioeconomic factors contributed to these observations: it is possible that cultural differences
exist in the detection of sarcoidosis, with a diagnosis of sarcoidosis made later in the disease course or made selectively in more severe disease in some racial or socioeconomic groups.
IS SARCOIDOSIS-RELATED MORTALITY SIGNIFICANTLY UNDERRECOGNIZED? It is usual, in studies of the mortality of chronic diseases, to identify the studied disease as the underlying cause of death when a fatal outcome is primarily due to major organ involvement. However, this analytic strategy does not take into account disease comorbidities that may have a greater prevalence or impact in sarcoidosis patients than in the general population, especially when comorbidities are in part ascribable to long-term sarcoidosis therapies. Causes of death directly or indirectly ascribable to sarcoidosis are summarized in Table 25.1. In sarcoidosis, comorbidities and multimorbidity have a major effect on a patient’s quality of life, health care, and health economics and are associated with increased mortality.9–15 Sarcoidosis patients have a higher risk of developing concomitant chronic conditions than age-/sex-matched individuals in the general population. Although this observation may arise in part from the persistence of inflammatory organ damage (which may be an important cofactor in the initiation of other chronic disorders), it appears likely that side effects caused by antiinflammatory treatment are at least equally important.12–15 In a comparison between 345 sarcoidosis patients and an age-/sex-matched control group from the general population, sarcoidosis was associated with a higher cumulative incidence of coronary artery disease,
TABLE 25.1
Causes of Death Directly or Indirectly Ascribable to Sarcoidosis • Progressive pulmonary fibrosis • Pulmonary hypertension • Cardiac sarcoidosis • Other organ involvements: neurosarcoidosis, renal disease, hepatic disease, and hypercalcemia • Comorbidities resulting from prolonged sarcoidspecific treatment, especially infection, diabetes, and hypertension • Isolated undiagnosed cardiac sarcoidosis
CHAPTER 25 Mortality in Sarcoidosis congestive heart failure, arrhythmia, stroke or transient ischemic attacks, arthritis, depression, diabetes, and major osteoporotic fractures.12 Similar findings have been reported in other studies.13,15 In a recent cohort of 218 sarcoidosis patients, mortality was linked to the comorbidity burden, as shown by an association between a higher Charlson Comorbidity Index and a higher mortality rate (P < .001).13 The association of mortality with higher numbers of comorbidities (>2) was also evident in a study of 557 sarcoidosis patients.14 However, this observation must be interpreted with caution as the death rate was low (2.9%) and thyroid disease was the only individual comorbid disease that was significantly more prevalent in decedent cases than in the general sarcoidosis population. Sarcoidosis has been linked with a higher frequency of subsequent malignant disease, but whether this association makes an important contribution to sarcoidosis-related mortality is uncertain.13,16 Similar associations exist in other autoimmune inflammatory conditions such as the connective tissue diseases, possibly reflecting universal effects of persistent inflammatory process and/or antiinflammatory medication.17,18 The linkage between prolonged corticosteroid therapy and the development of hypertension and diabetes is universally recognized. Infectious disease due to immunosuppressive therapies is a major cause in many autoimmune disorders, such as the vasculitides. In individual sarcoidosis patients, it is often impossible to ascertain whether these comorbidities arise due to the deleterious effects of sarcoidosis-specific treatments, and thus fatalities due to diabetes, hypertension, and infectious disease are not generally viewed as deaths caused by sarcoidosis in cohort studies. However, it is difficult to argue, given the combined contribution of these diseases to sarcoidosis-associated mortality, that mortality ascribable to sarcoidosis-specific treatments (and thus ascribable to sarcoidosis) is not seriously underestimated. One important implication is that statements of change in sarcoidosis-ascribable mortality with time need to be interpreted with great caution. For example, the significance of observations of a decline in mortality due to sarcoidosis in recent years is uncertain. In principle, this finding might have resulted from improved sarcoidosis management. However, it is equally possible that it reflects a shift from deaths due to sarcoidosis to deaths related to sarcoidosis therapy, with the use of more aggressive and prolonged interventional strategies in patients at higher risk due to major organ involvement.
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In a recent United States report, approximately 50% of patients newly diagnosed with sarcoidosis-received therapy, with this figure inflated by more frequent treatment in the in the African American population.11 Thus the possibility exists that the excess African American mortality in sarcoidosis results, in part, from treatmentrelated deaths. The exact influence of the dose and duration of maintenance therapy on the development of comorbidities has not been delineated. However, the adverse effects of corticosteroids were underlined in the study summarized previously of 105 newly diagnosed sarcoidosis patients. Patients receiving corticosteroids were at higher risk of reaching a composite comorbidity end-point that included diabetes, hypertension, weight gain, hyperlipidemia, and osteoporosis, all known to be associated with more frequent hospitalization. The underestimation of sarcoidosis-ascribable mortality includes the underrecognition of fatal cardiac sarcoidosis, a problem that applies especially to fatal cardiomyopathy and arrhythmias in isolated cardiac sarcoidosis. The high prevalence of unrecognized cardiac involvement emerging from autopsy studies in patients with a known diagnosis of sarcoidosis is well recognized. With the recent advent of advanced cardiac imaging modalities, there are numerous anecdotal reports of the existence of underlying cardiac sarcoidosis in many patients previously considered to have idiopathic cardiac disease. It is too soon to make population statements about this phenomenon as the use of advanced imaging is still in its infancy. However, it is possible that with the correct attribution of mortality in this subset of patients, the prevalence of sarcoidosisascribable mortality will increase significantly. Research in this area should be prioritized.
MORTALITY DATA AND THE PERCEPTION THAT SARCOIDOSIS IS A BENIGN DISEASE From a superficial review of broad cohort statements, it can be concluded that sarcoidosis is usually a benign disorder, leading to an underinvestment in urgently needed interventional studies. Plainly the exclusion of treatment-related fatal comorbidities and mortality due to undiagnosed isolated cardiac sarcoidosis from population-based statements of sarcoidosis-ascribable mortality, discussed previously, can only have resulted in a major understatement of the dangers associated with a diagnosis of sarcoidosis. However, the ultimately fatal impact of comorbidities and the existence of patients with major cardiac disease due to undiagnosed sarcoidosis cannot be taken into account in the identification of newly or recently diagnosed patients at high risk of
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death. The broad population statements reviewed earlier in this chapter may have contributed to misplaced complacency with regard to this important question. In reality, complacency is wholly inappropriate. The statement that a reduction in life expectancy due to sarcoidosis exists in only 5%–8% of patients with sarcoidosis is not helpful as it understates the dangers of major organ involvement. Integrating data from many sources, it can be concluded that 50%–70% of deaths directly ascribable to sarcoidosis in cohort studies are due to interstitial lung disease or pulmonary vasculopathy. Deaths attributable to cardiac sarcoidosis make up approximately 15%–20%% of fatalities. The remaining causes of death include neurosarcoidosis, hepatic disease, renal disease, hypercalcemia, and other rare fatal outcomes. Major racial differences in the pattern of fatal organ involvement are not captured by global average statements. For example, in Japanese cohorts a fatal outcome is most often due to cardiac involvement.19 However, accepting that preventative strategies must be nuanced according to the nature of the population to which they are applied, the need for an algorithm to identify patients at high risk of death is amply justified. In this regard, the mathematics are stark. An overall mortality due to sarcoidosis of 7% occurs almost exclusively in patients with major organ involvement. In a highly influential review of sarcoidosis, widely cited throughout the world, it was estimated that 30% of sarcoidosis patients have clinically significant major organ involvement.20 Thus it would appear that sarcoidosis-ascribable mortality approximates 20%–25% (7/30) in this patient subgroup. This figure rises further, perhaps to 35%, if cases with early spontaneous regression of disease and those with complete resolution with treatment are excluded. In this large patient subset, in a disease that is not rare, complacency about the risk of death needs to be resisted. Nihilism on this point would be easier to accept if major organ involvement was difficult to identify. However, significant pulmonary interstitial involvement is obvious based on symptoms and routine baseline tests recommended in an expert group statement.21 Pulmonary vasculopathy may be more difficult to identify but will be largely contained within patients found to have clinically significant “lung involvement”. Major hepatic and renal involvement is also very evident at baseline testing or will become obvious during routine monitoring. Neurosarcoidosis is usually clinically overt. It must be acknowledged that cardiac sarcoidosis does pose special problems in risk stratification due to underdetection, as discussed briefly later. However, given the very
considerable mortality associated with readily identifiable major organ involvement, it can be argued that organ-based risk stratification is urgently required in sarcoidosis, especially in patients with interstitial lung disease, pulmonary vascular disease, or cardiac involvement.
ORGAN-BASED MORTALITY RISK STRATIFICATION In patients with sarcoidosis a pragmatic definition of severe disease is needed, based on studies in which markers of severe disease are examined against mortality. Ideally, symptoms should be integrated with results from functional and imaging modalities and observed disease behavior in the definition of severe sarcoidosis.22 Key variables that can usefully be applied to risk stratification are summarized in Table 25.2. In patients with pulmonary sarcoidosis, progressive interstitial lung disease results in major pulmonary fibrosis in 20%–30% of cases.20 Advanced pulmonary sarcoidosis with evidence of fibrosis on high-resolution computed tomography (HRCT) has been an important predictor of mortality in several series23–25 with pulmonary fibrosis, either on chest radiography or HRCT, a predictor of mortality (independently of the presence
TABLE 25.2
Key Variables in Organ-Specific Sarcoidosis Risk Stratification PULMONARY DISEASE • Extensive fibrotic disease on HRCT • Severe reduction in pulmonary function tests, especially DLCO levels • Composite physiologic index >40 units • Presence of pulmonary hypertension (Presence of chronic pulmonary aspergillosis)a CARDIAC DISEASE • Left ventricular ejection fraction <50% • Ventricular tachycardia • Extensive late gadolinium enhancement on CMR • Prominent cardiac inflammation on PET CMR, cardiac magnetic resonance; DLCO, diffusion capacity for carbon monoxide; HRCT, high-resolution computed tomography; PET, positron emission tomography. aChronic pulmonary aspergillosis adds to risk only in patients with major hemoptysis but is associated with advanced pulmonary disease and should prompt risk stratification.
CHAPTER 25 Mortality in Sarcoidosis of pulmonary hypertension) in a cohort of 452 sarcoidosis patients from Cincinnati.23 Recent data suggest that the integration of pulmonary function parameters and HRCT findings may provide more accurate risk stratification. Walsh et al. reported a user-friendly staging system, developed using split-sample testing in more than 500 patients evaluated at a referral center.25 In this system, patients were stratified into low- and high-risk groups based on the extent of pulmonary involvement (as judged by the composite physiologic index [CPI] and the extent of fibrosis on HRCT) and, in patients with lesser pulmonary involvement, HRCT evidence of pulmonary vasculopathy (i.e., an increase in the ratio of the main pulmonary artery diameter to ascending aorta diameter to >1.0). In the validation cohort the high-risk patient group had a substantially increased mortality (HR 5.89, P < .0001). In a subsequent study of sarcoidosis patients with chronic pulmonary aspergillosis, a significant increase in mortality was observed in patients meeting criteria in the Walsh algorithm for high-risk disease.26 Individual risk components in the Walsh algorithm (CPI > 40, extent of fibrosis on HRCT >20%, pulmonary artery diameter/ascending aorta diameter >1.0) and the presence of pulmonary hypertension were also associated with increased mortality. In a general sarcoidosis population the Walsh system was predictive of mortality on univariate analysis, although age was the most malignant prognostic determinant on multivariate analysis.23 It is currently uncertain whether a CPI threshold offers advantages over a diffusion capacity for carbon monoxide (DLCO) threshold in pulmonary fibrosis risk stratification. The two variables are influenced both by the severity of interstitial lung disease and by the severity of pulmonary vasculopathy. However, impairment of DLco can be deconstructed into interstitial and vasculopathic profiles (depending on whether reduction in DLco is disproportionate to reduction lung volumes), information that may be invaluable in guiding management. Pulmonary hypertension (PH) in sarcoidosis is an independent determinant of morbidity and mortality23,27 and is present in approximately 75% of sarcoidosis patients listed for lung transplantation.27 In a series of 125 patients with sarcoidosis-related PH, the 5-year survival of 55% illustrates the importance of PH as a malignant prognostic determinant.28 In this cohort a prevalence of stage IV disease of 72% reflects the fact that in this cohort of 72% PH is most commonly associated with major pulmonary fibrosis, although there
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was a poor correlation between the severity of interstitial lung disease and pulmonary hemodynamic variables at right heart catheterization. However, PH may result from a multiplicity of underlying pathophysiologic mechanisms, including granulomatous vascular inflammation, extrinsic compression from lymphadenopathy, and/or mediastinal fibrosis, pulmonary venoocclusive disease, and left heart disease. In a series of sarcoidosis patients with proven PH, there was no evidence of pulmonary fibrosis on HRCT in 32% of cases.29 Thus effective risk stratification requires the identification of PH, irrespective of the presence or absence of severe pulmonary fibrosis. Unfortunately, no single noninvasive test has been reliable in identifying patients who should undergo right heart catheterization. Echocardiography is the most widely used screening tool, despite significant discrepancies between the echocardiographic systolic pulmonary artery pressure and right heart catheterization data.30 There is a need to validate the integration of a number of noninvasive variables associated with PH in a PH-screening algorithm, including enlargement of the pulmonary artery on HRCT,25,31 increased serum brain natriuretic peptide (BNP) levels, disproportionate reductions in gas transfer (against lung volumes), resting hypoxia, and striking oxygen desaturation during a 6-min walking test. Chronic pulmonary aspergillosis (CPA) is associated with increased mortality in pulmonary sarcoidosis and should also be taken into account in sarcoidosis risk stratification. CPA is a well-recognized complication of fibrotic pulmonary sarcoidosis, usually associated with immunosuppressive treatment in patients with extensive fibrotic lung disease.32,33 Mycetomas manifest on HRCT as a mass of soft tissue density within the lung cavity, usually located in the upper lobes and separated from the cavity itself by an air crescent.34 Erosion of the fungal ball into a hypervascular cavity wall results in hemoptysis, which is life threatening in approximately 5% of patients. However, mortality associated with CPA often reflects the severity of underlying pulmonary sarcoidosis, rather than fatal hemoptysis. In a recent case series of patients with sarcoidosis and CPA, severe fibrotic pulmonary sarcoidosis was present in 64 of 65 (98.5%) patients, with PH present in 31%.26 A proportion of 41.5% of patients died at a mean age of 55.8 years. Death seldom resulted from hemoptysis but was usually due to progression of advanced sarcoidosis. Thus the presence of CPA should alert the clinician to the likelihood of high risk from advanced pulmonary disease but adds risk only in those patients with recurrent major hemoptysis.
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The presence of cardiac sarcoidosis has historically been considered as indicative of “dangerous sarcoidosis”, based on the considerable morbidity and mortality associated with this form of disease. In a Japanese cohort of 95 cardiac sarcoidosis patients, patients with clinically overt cardiac sarcoidosis (a presentation with sustained ventricular tachycardia and a left ventricular ejection fraction [LVEF] < 50%) had a worse outcome with sudden cardiac death in 27% of cases. The 5-year survival of 60% was significantly higher in patients treated with steroids and/or preserved cardiac function (LVEF >50%).35 The adverse outcomes associated with cardiac dysfunction and rhythm disturbances (particularly sustained ventricular tachycardia) was confirmed in a cohort of 73 cardiac sarcoidosis patients, with age greater than 46 years being an independent predictor of mortality.36 General statements of outcomes associated with cardiac sarcoidosis in historical series were to some extent skewed by the difficulty in identifying milder forms of cardiac sarcoidosis before the advent of advanced imaging modalities. One of the main challenges in evaluating risks associated with cardiac involvement in the general sarcoidosis population is the lack of a gold standard for the diagnosis of cardiac sarcoidosis. A histological diagnosis is seldom pursued as the diagnostic yield of cardiac biopsy is reduced by the patchy nature of the disease, and the procedure is not without risk. Application of the Japanese Ministry and Welfare diagnostic criteria suggests a prevalence of 5%–10% of clinically overt cardiac sarcoidosis. However, these criteria do not identify subclinical disease, detectable only by advanced imaging modalities (cardiac resonance magnetic [CMR] imaging and positron emission tomography [PET]).37–39 Recent data indicate that CMR and PET provide important prognostic information in identifying sarcoidosis patients at higher risk of mortality and life-threatening cardiac complications.37–40 Based on these findings, CMR and PET were recently highlighted as recommended noninvasive diagnostic tests in suspected cardiac sarcoidosis in an expert consensus statement.41 In the Heart Rhythm Society consensus statement, patients with biopsy-proven extracardiac sarcoidosis are considered to have a highly probable diagnosis of cardiac sarcoidosis if there is otherwise unexplained advanced atrioventricular block, sustained ventricular tachycardia, new onset heart failure (LVEF <40%), or a suggestive pattern of myocardial fibrosis or inflammation on CMR and/or PET. With the use of these criteria, the prevalence of cardiac sarcoidosis in the general sarcoidosis population increases to 25%–30%, increasing further
in patients with suspected cardiac sarcoidosis. In a study of 321 patients with biopsy-proven sarcoidosis, screening with CMR revealed evidence of cardiac involvement in 29% of cases.38 However, although the use of advanced imaging modalities has identified a large subgroup of sarcoidosis patients with subclinical cardiac disease, the optimal use of these tests in risk stratification remains uncertain. In the study discussed previously, adverse cardiac outcomes were present in patients with evidence of cardiac involvement on CMR only when it was associated with cardiac symptoms and/or electrocardiogram (ECG) abnormalities.38 Preliminary data indicate that the integration of advanced imaging findings is likely to have an important future role in risk stratification, with the severity of cardiac dysfunction and the presence of late gadolinium enhancement (LGE) on CMR-independent determinants of mortality. In a recent cohort an extent of LGE >20% of the myocardial mass was associated with a worse outcome, even after adjustment for the degree of left ventricular impairment.42 Evidence of cardiac inflammation as judged by PET signal has also been associated with increased mortality in suspected cardiac sarcoidosis, but it is unclear whether this remains the case if PET signal is viewed as an indication for antiinflammatory/immunosuppressive therapy. Currently it would seem that prominent cardiac abnormalities on advanced imaging can reasonably be viewed as indicative of an increased risk of mortality to be integrated with LVEF <50% and ventricular tachycardia as a means of enhancing risk stratification in cardiac sarcoidosis. However, much work remains to be carried out to define exact thresholds indicative of a higher risk of mortality when advanced imaging abnormalities are less extensive.
CONCLUSION In this chapter we have emphasized that sarcoidosis should not be viewed as a benign disease in patients with major organ involvement, despite apparently reassuring statements that in the general sarcoidosis populations, deaths directly ascribable to sarcoidosis occur in only 5%–8% of cases. Deaths due to comorbidities associated with sarcoidosis-specific therapies are not included in such estimates. Importantly it is possible to stratify risk in patients with interstitial lung disease, pulmonary vascular disease, and cardiac involvement which, taken together, accounts for more than 80% of deaths caused by sarcoidosis. It should be emphasized that treatment algorithms aimed at reducing mortality are yet to be validated in
CHAPTER 25 Mortality in Sarcoidosis those patients believed to have dangerous sarcoidosis. Severe major organ involvement may identify patients who have increased mortality despite treatment. However, it is not logical to introduce therapies for potentially dangerous disease only when excess mortality is unavoidable. Ideally, risk stratification should also identify those patients at higher risk of mortality if disease continues to progress, with a view to therapeutic intervention before “the train has left the station”.
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