The American Thoracic Society (ATS), in collaboration with the European Respiratory Society and the World Association of Sarcoidosis and Other Granulomatous Disorders, has issued a consensus statement on sarcoidosis. Appearing in the August 1999 issue of the American Journal of Respiratory and Critical Care Medicine, the statement provides information on the epidemiology, pathogenesis, diagnosis and treatment of sarcoidosis. It was written by a 14-member panel of authorities on sarcoidosis who primarily developed the recommendations on the basis of expert opinion and consensus.
The panel members summarized the known aspects of sarcoidosis as follows: the incidence and prevalence, the clinical features and syndromes of the disease, how to make a diagnosis, the effectiveness of corticosteroids for short-term therapy, some genetic factors that alter expression of the disease and the immunologic characteristics of the initial onset of the disease. In addition, the panel members identified questions about the disease they would like to have answered: Is there a test to predict disease progression? Do corticosteroids alter the natural history of the disease? What is the optimal length of therapy? Are there less toxic therapies than corticosteroids or cytotoxic agents? What genetic factors alter the expression of the disease? What are the mechanisms of lung injury and fibrosis? What mechanisms are associated with persistent disease? What is the cause of sarcoidosis?
The following highlights the discussion on epidemiology, pathogenesis, diagnosis and treatment of sarcoidosis.
According to the ATS consensus statement, sarcoidosis occurs primarily in adults younger than 40 years of age. The peak incidence occurs in the third decade of life. One population-based study revealed that the rates of disease in men and women are 5.9 cases and 6.3 cases, respectively, per 100,000 person-years. In the United States, the lifetime risk of sarcoidosis is estimated to be 2.4 percent for blacks and 0.85 percent for whites.
The clinical presentation and severity of the disease differ among ethnic and racial groups. For example, studies suggest that the disease is more severe in blacks, while whites are more likely to present with asymptomatic disease. Extrathoracic manifestations are more common in some groups, such as uveitis in blacks, lupus pernio in Puerto Ricans and erythema nodosum in Europeans.
Clusters of the disease have been reported, leading to speculation about person-to-person transmission or a shared exposure to an environmental agent. There have been case reports of familial clustering of sarcoidosis as well as husband–wife disease. A case-control study of residents of the Isle of Man found that 40 percent of the persons with sarcoidosis had been in contact with a person known to have the disease, compared with 1 to 2 percent of the control subjects. Studies have also revealed seasonal clustering of cases in the winter and early spring. Occupational risk factors, such as exposure to beryllium and other metal dusts, fumes and organic antigens, also have been studied. One study reported three cases of sarcoidosis among 57 firefighters who apprenticed together. In the Isle of Man study, 18.8 percent of the cases of sarcoidosis occurred in health care workers (mainly nurses), compared with an incidence of 4.2 percent in the control group. Whether environmental or occupational exposure plays a role in sarcoidosis requires further investigation.
Although the cause of sarcoidosis remains unknown, the panel members note that the hypothesis that sarcoidosis results from exposure of genetically susceptible persons to specific environmental agents is supported by three lines of evidence: (1) epidemiologic studies that show clusters of cases; (2) the inflammatory response in the lungs is most consistent with an immune response triggered by an antigen; and (3) studies of T-cell receptors in patients with sarcoidosis suggest a specific antigen that triggers the development of sarcoidosis.
Clinical Presentation and Organ Involvement
According to the consensus statement, nonspecific symptoms such as fever, fatigue, malaise and weight loss occur in approximately one third of patients with sarcoidosis. The lungs are affected in more than 90 percent of patients with the disease. Pulmonary manifestations include dyspnea, dry cough and chest pain. Roentgenographic stages in pulmonary disease range from no radiographic abnormalities (Stage 0), to bilateral hilar lymphadenopathy (Stage I), to bilateral hilar adenopathy and parenchymal infiltration (Stage II), to parenchymal infiltration without hilar adenopathy (Stage III) and, finally, to advanced fibrosis with evidence of honey-combing, hilar retraction, bullae, cysts and emphysema (Stage IV).
Peripheral lymph nodes, most frequently cervical, axillary, epitrochlear and inguinal, are palpable in about one third of patients. Myocardial involvement, found in approximately 5 percent of patients, ranges from benign arrhythmias or high-degree heart block to sudden death. The electrocardiogram may be negative. Studies suggest that as many as 50 to 80 percent of patients are found to have hepatic granulomas on biopsy, but the liver is palpable in less than 20 percent of patients. Abnormalities on liver function tests are common in patients with sarcoidosis.
Erythema nodosum and lupus pernio are two cutaneous lesions associated with sarcoidosis. Erythema nodusum, the hallmark of acute sarcoidosis, is common in European, Puerto Rican and Mexican patients. Lupus pernio is characterized by indurated plaques in association with discoloration of the nose, cheeks, lips and ears. It is more common in black women.
Uveitis is the most common ocular manifestation. Other ocular lesions include conjunctival follicles, lacrimal gland enlargement, keratoconjunctivitis sicca, dacryocystitis and retinal vasculitis.
Neurosarcoidosis occurs in less than 10 percent of patients. Common nervous system manifestations include facial palsies, and hypothalamic and pituitary lesions.
The joints most commonly affected by sarcoidosis include the knees, ankles, elbows, wrists and small joints of the hands and feet. Joint pain has been reported in 25 to 39 percent of patients, but deforming arthritis is rare. Symptomatic muscle involvement is rare.
The gastrointestinal tract is affected in less than 1 percent of patients. The stomach is the most commonly involved part.
Hematologic abnormalities in sarcoidosis are frequent but nonspecific. Anemia may occur in 4 to 20 percent of patients, and leukopenia may be found in as many as 40 percent. Other abnormalities in patients with sarcoidosis include parotitis, hypercalcemia, hypercalciuria, asymptomatic granulomas of the female reproductive tract, interstitial nephritis and renal failure related to hypercalcemia and nephrocalcinosis.
According to the ATS statement, the diagnosis of sarcoidosis requires the blend of a compatible clinical picture, the demonstration of noncaseating granulomas and exclusion of other disorders capable of producing a similar clinical or histologic picture. Four goals of the diagnostic work-up are cited: to provide histologic confirmation, to determine the extent and severity of disease, to assess whether the disease is stable or is likely to progress and to determine if therapy will be beneficial.
Transbronchial lung biopsy is recommended in most cases. However, lung biopsy may not be required in some patients, such as those who present with fever, erythema nodosum, arthralgias and bilateral hilar lymphadenopathy and who subsequently have rapid, spontaneous remission of the disease.
After the diagnosis of sarcoidosis has been established, recommended studies include urinalysis, electrocardiography, ophthalmologic examination, tuberculin skin test, peripheral blood count, serum chemistries (calcium, liver enzymes, creatinine, blood urea nitrogen) and pulmonary function testing.
Topical steroid therapy may be all that is required in patients with mild manifestations such as skin lesions, anterior uveitis or cough. Oral corticosteroids are often used to treat systemic symptomatic disease. According to the ATS statement, systemic therapy is clearly indicated for cardiac disease, neurologic disease, eye disease unresponsive to topical therapy and hypercalcemia. Oral corticosteroids often result in improvement of pulmonary symptoms, but recurrence is common after discontinuation of therapy. The panel of experts notes that no randomized prospective trials have been conducted to determine the optimal dosage and duration of corticosteroid therapy.
Other agents used in the treatment of sarcoidosis include cytotoxic agents, antimalarial agents and non-steroidal anti-inflammatory drugs. Methotrexate and azathioprine are the preferred cytotoxic agents for most patients with refractory disease. In a study of 50 patients with sarcoidosis, methotrexate alone produced a response in 33 patients, and nine additional patients responded to low-dose prednisone combined with methotrexate. The efficacy of azathioprine appears to be similar to that of methotrexate. There have been no studies to determine when cytotoxic drugs are indicated in the treatment of sarcoidosis. Chloroquine and hydroxychloroquine are also used in the treatment of sarcoidosis. Nonsteroidal anti-inflammatory drugs are effective, particularly for musculoskeletal symptoms and erythema nodosum. Pulmonary rehabilitation may be beneficial in patients with systemic symptoms, such as myalgias and fatigue, and in patients with significant respiratory insufficiency.