Sarcoidosis is a multi-organ disease with a variable clinical course. Although many patients experience disease resolution within a few years of diagnosis, some patients require long-term chronic therapy (1).
In addition, some patients develop chronic disease that may be refractory to conventional therapy and require cytotoxic or biological agents for disease control. The overall risk of death from sarcoidosis ranges from 1 to 8%, with the higher rates reported from tertiary referral centers (2).
By relying on death certificates, Swigris and coworkers report in this issue of the Journal (pp.
- Original Article:
) the mortality from sarcoidosis in the United States (3). The authors reveal a disturbing 30-year trend of increased rate of death associated with sarcoidosis along with higher mortality in older patients with sarcoidosis. They confirmed previously reported increased mortality for women and in non-Hispanic black versus white patients (4).
Limitations exist for this report, including the primary source data of unverified death certificates. Because the authors do not report the overall and subgroup incidence of sarcoidosis in the United States, they are unable to estimate the relative risk of death from sarcoidosis. Hence the increased risk for mortality in black and older patients may represent the increased cumulative incidence of the disease. Also compared with non-Hispanic whites, black Americans are more likely to die at a younger age. The methodology of the current study captures information regarding an unselected, large number of patients. Some of their findings have been previously observed (5–7). Prior studies that report single institution mortality (8, 9) have been criticized because tertiary clinics are frequently populated by patients with more advanced disease (2).
The major causes of death from sarcoidosis include respiratory, cardiac, neurologic, and hepatic involvement (8). Cardiac involvement represents a major cause of death in patients with active sarcoidosis, with one autopsy study identifying cardiac involvement as the cause of death in 14 of 28 patients (10). Utilizing implantable defibrillators has reduced the risk of sudden death in sarcoidosis according to most sarcoidosis experts and is supported by the current report.
Unfortunately, respiratory failure remains the most common cause of death in patients with active sarcoidosis (8). In addition, Swigris and colleagues noted an increased risk for death with advancing age. Other investigators have also reported this increased rate of mortality in older patients with sarcoidosis (6, 11).
Several possible explanations may underlie this increase in mortality with age. Not surprisingly, in general the older the person, the more likely death is to occur. Perhaps older patients with sarcoidosis are acquiring other mortal diseases (9). In one epidemiologic study, patients with cancer with a previous diagnosis of sarcoidosis experienced an increased rate of mortality compared with matched patients with cancer without sarcoidosis (12). As we age, we develop other lethal diseases, including coronary artery disease and diabetes. Also, corticosteroid therapy may increase the risk for these comorbidities, and hospitalized patients with sarcoidosis often experience these diseases (5). In the study by Swigris and coworkers, cardiac disease was often mentioned as contributing to the cause of death. Certainly having sarcoidosis does not make one immune from cancer or coronary artery disease.
The acquisition of complications from long-standing lung disease represents another cause for increased older patient mortality. Sarcoidosis-associated pulmonary hypertension is correlated with increased death (13). In the report by Swigris and colleagues, pulmonary hypertension was increasingly recognized as a contributor to death. Patients with chronic pulmonary sarcoidosis are often receiving immunosuppressive agents that can increase the risk for opportunistic infections (14). In the setting of fibrotic sarcoidosis, mycetomas which can cause subsequent massive hemoptysis can be fatal. It is important to recognize these superimposed infections, since patients may respond to reduction of immunosuppression and appropriate antifungal therapy (15).
Swigris and coworkers focus on the importance of pulmonary fibrosis as a cause of death in patients with sarcoidosis. Others have also reported that dying patients with sarcoidosis are more likely to possess Stage 4 fibrotic lung disease (8, 9). In one prospective study, patients who experienced progression of lung disease from Stages 2 or 3 to Stage 4 were more likely to die (9). Evidence of pulmonary fibrosis is identified in many patients with chronic pulmonary sarcoidosis. Some of these patients remain on chronic antiinflammatory therapy. It is this group that seems most likely to die from respiratory failure.
So why do some patients with sarcoidosis develop progressive fibrosis, while others do not? Swigris and colleagues offer the interesting hypothesis that age is a risk factor for sarcoidosis pulmonary fibrosis. In support of this theory, they cite the example of idiopathic pulmonary fibrosis whereby older patients clearly have increased mortality (6). It has also been reported that older patients with sarcoidosis are more likely to have chronic disease requiring ongoing systemic therapy (7). As our population with sarcoidosis ages, we may see more long-term complications from the chronic inflammation experienced by some patients with sarcoidosis.
Therapy for sarcoidosis focuses on inflammation reduction. Corticosteroids, cytotoxic drugs, and anti-TNF agents have all proved useful in treating this disease, but failures occur with each of these regimens. Inflixmab has proved an effective treatment in refractory sarcoidosis; however, not all patients with chronic pulmonary sarcoidosis respond to infliximab (15). In an interesting report by Milman and coworkers (16), a patient with sarcoidosis with active granulomatous disease received one dose of infliximab and subsequent lung transplant 11 days later. Although no granulomas were identified in the explanted lung, the presence of extensive fibrosis caused the patient’s respiratory failure and need for transplant.
Over the past 20 years, many new drugs have been developed to treat sarcoidosis. It is disappointing that the report by Swigris and colleagues suggests that these drugs have not improved survival from the disease. Although the antiinflammatory drugs can improve the outcome of most patients, these drugs appear less beneficial for patients with advanced disease. In these patients, the clinician needs to identify disease complications, such as pulmonary hypertension, infections, and fibrosis, that may require other treatments. As new agents are developed for the treatment of pulmonary fibrosis, their role in advanced sarcoidosis should be studied.