Timothy J. Barreiro, DO, Assistant Professor of Medicine, Department of Pulmonary and Critical Care Medicine, Northeastern Ohio Universities College
of Medicine, St Elizabeth Health Center, Youngstown, Ohio.
Robert DeMarco, MD, Professor of Medicine, Department of Pulmonary and Critical Care Medicine, Northeastern Ohio Universities College of Medicine,
St Elizabeth Health Center, Youngstown, Ohio.
David J. Gemmel, PhD, Director of Research, Humility of Mary Health Partners, Department of Research, St Elizabeth Health Center, Youngstown, Ohio.
Carl R. Schaub, MD, Associate Professor of Pathology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio; Chairman of Pathology,
St Elizabeth Health Center, Youngstown, Ohio.
Sarcoidosis is a multisystem disease of unknown etiology that most commonly affects the lungs but can also affect the skin,
liver, and heart. It typically affects patients in the 3rd and 4th decades but is also found in children and the elderly.
Spontaneous remission occurs in two thirds of patients within 2 years of presentation, while 10% to 30% of patients experience
chronic disease causing progressive organ damage. Sarcoidosis leads to death in approximately 4% of patients, typically those
with pulmonary, cardiac, or CNS involvement.
Figure 1. Transbronchial biopsy of right lower lobe of lung shows lung tissue with multiple, poorly formed, noncaseating
granulomas. Occasional multinucleated giant cells are present. This view is consistent with sarcoidosis (H&E stain, magnification
X200). ALL IMAGES: DAVE SCANNELL, HUMILITY OF MARY HEALTH PARTNERS
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The hallmark finding of sarcoidosis is noncaseating granulomas, composed of a central core of epithelioid histocytes and multinucleated
giant cells (see Figure 1). The core is surrounded by lymphocytes, scattered plasma cells, fibroblasts, collagen, proteoglycans,
and mast cells in the periphery.1 Progressive granulomatous inflammation may cause injury, dysfunction, and destruction of the affected organs.2Despite extensive investigation, the cause of sarcoidosis is unknown. Although both genetic and environmental factors likely
have a role in the clinical expression and frequency of the disease, none of the hypothesized infectious and environmental
causes have survived scrutiny. Recent investigations involving molecular biological techniques have been inconclusive.
The annual incidence of sarcoidosis in the United States is approximately 10 cases per 100,000 among whites and 36 per 100,000
among African Americans.3 The disease is most commonly seen in the mid-Atlantic and Southern Atlantic states but is rare in the Southwest. Because
the disease affects siblings of first- or second-degree relatives in 15% of patients with known disease, a genetic component
has been suggested; familial sarcoidosis has been described in 17% of African Americans but in only 6% of whites with disease.4,5 Onset of sarcoidosis in white patients is usually asymptomatic while African Americans tend to present with an earlier onset
and a more aggressive and severe clinical course.6 Chronic pulmonary sarcoidosis and the disfiguring cutaneous lesions of lupus pernio are also more common in African Americans.
From suspicion to diagnosis
The patient's presentation may provide a clue to the prognosis. For example, remission occurs in approximately 80% of patients
with sarcoidosis who have Lofgren's syndrome, a clinical variant of sarcoidosis that includes the constellation of erythema
nodosum, polyarthritis, and bilateral hilar lymphadenopathy (BHL) on chest film. A progressive course is more likely in those
patients who have lupus pernio, chronic uveitis, hypercalcemia, nasal mucosal involvement, cystic bone lesions, neurosarcoidosis,
cardiac or renal involvement, or whose disease develops after age 40. Most patients have the pulmonary manifestation, most
commonly presenting with incidental findings on chest radiography. Cough, dyspnea, or wheezing may reflect endobronchial or
parenchymal involvement. Pulmonary sarcoidosis causing hypoxemic respiratory failure is rare.
Chest examination findings in pulmonary sarcoidosis are nonspecific, and although routine laboratory test results are also
nonspecific for sarcoidosis, their results can suggest involvement of other organs, such as the liver and kidney. In addition,
the hallmark pathologic finding of noncaseating granulomas is also seen in tuberculosis, deep-seated fungal infections, lymphoma,
epithelioid tumors of the breast, and lung cancer. Specialized imaging modalities, such as high-resolution CT and MRI, are
helpful in assessing patients with suspected or confirmed sarcoidosis.
Biopsy is warranted when the clinical picture suggests sarcoidosis, with transbronchial lung biopsy recommended in suspected
pulmonary disease. Biopsy is also warranted in making the diagnosis of extrapulmonary sarcoidosis.
Examining the chest films
Table 1. Approach to suspected sarcoid
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Although findings such as BHL and right paratracheal adenopathy suggest sarcoidosis, no single x-ray finding is considered
definitive. (The clinical significance and differential diagnosis of BHL includes granulomatous infection, tuberculosis, histoplasmosis,
coccidioidomycosis, autoimmune disorder, and malignancy, particularly lymphoma.) Although chest radiography does not correlate
with clinical or functional impairment, a staging system for pulmonary sarcoidosis based on conventional chest radiography
may be useful in assessing the prognosis and guiding therapeutic decisions (see Table 1).
Figure 2. This chest radiogram demonstrates bilateral hilar lymphadenopathy, stage 1 disease. The 2 large arrows point to
hilar node enlargement; the small arrow points to upper lobe changes (a). The mediastinal windows of the CT scan demonstrate
enlarged nodes in the mediastinum and hilar areas (b).
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In this staging system, stage 1 disease is characterized by BHL and paratracheal adenopathy (see Figure 2). Approximately
half of patients with pulmonary sarcoidosis present with stage 1 disease, which is associated with an 80% remission rate.
Stage 2 disease is characterized by mediastinal adenopathy with pulmonary parenchymal involvement and is associated with a
35% to 50% remission rate. Remission is unlikely in both stage 3, marked by pulmonary parenchymal involvement without adenopathy,
and stage 4 disease, in which pulmonary fibrosis with honeycombing is seen (see Figure 3).
Figure 3. Arrows on this chest radiogram (a) point to dense fibrosis and interstitial changes in the upper lobes consistent
with stage 4 sarcoidosis. Arrows on chest CT (b) point to area of dense fibrosis.
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The initial diagnostic workup for a patient with suspected sarcoidosis includes complement fixation tests for the presence
of fungi, tuberculosis skin testing, CBC count, and chemistries including measures of serum calcium, total protein, and albumin,
serum urea nitrogen, creatine, and liver function tests. Measurement of serum ACE level may provide an estimate of granuloma
burden. Histologic confirmation is advised when treatment is considered, especially when parenchymal infiltrates, fever, or
constitutional symptoms suggest an infectious process. In these cases, flexible fiberoptic bronchoscopy with transbronchial
and endobronchial biopsies including culturing is helpful. Although histologic confirmation in symptomatic patients may be
necessary, an aggressive workup may be unnecessary in asymptomatic patients with symmetric BHL, an unremarkable physical examination,
no history of malignancy, and normal results on routine blood work.
The course of disease usually becomes evident within 2 years of presentation. Absence of spontaneous remission within this
period predicts a chronic, persistent, or stable course.
Assessing extrapulmonary involvement
Table 2. Systems affected by sarcoidosis
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Pulmonary involvement is observed in more than 90% of patients (see Table 2). Even when extrathoracic disease dominates, subclinical
pulmonary involvement is usually present.7 Lymphatic
Intrathoracic and peripheral lymphadenopathy is common with radiographic evidence of hilar node enlargement in up to 80%
of patients. Peripheral nodes are typically nontender and may be disfiguring but rarely cause clinical problems unless they
encroach on other organs or vasculature.
Cardiac
Up to 30% of patients will have asymptomatic cardiac involvement; few have symptoms.8 Early suspicion and diagnosis of myocardial involvement is essential, since aggressive treatment improves prognosis.9 Cardiac involvement is usually found when a person presents with a ventricular arrhythmia, cardiac conduction abnormality,
or syncope, or develops these problems after the diagnosis of sarcoidosis has been made. Although serious cardiac dysfunction
is found in 10% of patients, some cases elude detection. Half of patients with cardiac sarcoidosis have ECG abnormalities
of rhythm, conduction, or repolarization. Myocardial scintigraphy with thallium-201 is helpful in making the diagnosis of
cardiac sarcoidosis.
Cutaneous
Approximately 25% of patients will have cutaneous manifestations that can range from the raised, tender, red nodules of
erythema nodosum to a remarkable array of plaques, subcutaneous nodules, macules, and papules. Lupus pernio produces indurated
violaceous lesions on the cheeks, nose, lips, and ears. Although this manifestation is rare, it shows a special predilection
for older women of West Indian and African American descent and can erode bone and cartilage, causing disfigurement. Cutaneous
involvement usually portends a more chronic course of disease. In small studies, thalidomide (Thalomid) is being used in chronic
inflammatory cutaneous sarcoidosis with favorable results.*,10
*Off-label use.
Ophthalmic
This manifestation of sarcoidosis develops in fewer than 20% of patients, with anterior uveitis the most common ophthalmic
involvement, characterized by rapid onset, blurred vision, photophobia, and excessive lacrimation. Spontaneous resolution
within 2 years is typical. An ophthalmologic examination is mandatory in the initial evaluation of the patient with sarcoidosis.
CNS
Approximately 5% of patients have CNS involvement. Although any part of the CNS can be affected, unilateral facial nerve
palsy is the most commonly recognized symptom.
Renal, hepatic
Although clinically significant renal tubular, glomerular, or arterial involvement is rare, overproduction of 1,25-dihydroxyvitamin-D
is common and can lead to nephrocalcinosis and renal failure.11 Hepatic dysfunction is rare.
When to treat and how
Although sarcoidosis is considered a benign disease that is often associated with spontaneous remission, experts agree that
corticosteroid therapy is warranted in patients with severe, chronic, or progressive disease. In pulmonary disease, a corticosteroid
trial is warranted in patients whose symptoms have worsened, and whose pulmonary function has declined—particularly in forced
vital capacity—and who has radiographically demonstrated worsening disease. When feasible, topical therapy should be used
for cutaneous or ophthalmic disease. Systemic corticosteroid therapy is indicated for cardiac, neurologic, and progressive
pulmonary involvement; ophthalmic manifestations that do not respond to topical therapy; and hypercalcemia.
Treatment involves observation, initiating corticosteroid therapy when appropriate, monitoring response to therapy, and discontinuing
corticosteroids when clinically or physiologically indicated.* Prednisone, 20 to 40 mg/d in divided doses, may be considered
for organ involvement that is not life threatening; a higher dosage may be used in potentially life-threatening disease.*
Alternate-day dosing may be considered in some patients. A lack of improvement after 3 months of treatment suggests that continued
treatment is unlikely to be beneficial. High-dose inhaled corticosteroids may be used to suppress markers of alveolitis. The
inhaled form may be particularly useful in patients with mild pulmonary disease, cough, wheezing, or bronchial hyperreactivity.12
*Off-label use.
Long-term corticosteroid use is associated with weight gain, mood swings, cataract formation, and gastroesophageal reflux.13,14 An additional adverse effect, osteoporosis, warrants initiation of bisphosphates and judicious use of dual-energy x-ray absorptiometry
(DEXA) scans. Use of supplemental calcium should be avoided in these patients because of the risk of renal tubal damage.
Clinical improvement should be assessed after 3 months of corticosteroid therapy. If no improvement is found, further use
of a corticosteroid is unlikely to be effective. Before considering whether to initiate alternative therapies, first consider
whether the corticosteroid dosage is correct, that the patient has complied with the treatment regimen, and rule out the presence
of irreversible fibrotic disease.
Table 3. Alternatives to corticosteroid therapy in sarcoidosis
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If no cause for treatment failure is suggested, or if adverse effects arise, consider initiating an alternative to corticosteroids,
summarized in Table 3; agents listed are off-label uses. Azathioprine (Imuran), methotrexate (Rheumatrex), and the antimalarial
hydroxychloroquine (Plaquenil) are most commonly used as corticosteroid-sparing agents or when corticosteroid therapy has
failed. Methotrexate tends to be the most favored second line therapy, but all the drugs are associated with significant adverse
effects. Hydroxychloroquine is used with some success in the treatment of cutaneous sarcoidosis. Azathioprine is usually reserved
for refractory severe disease, but its association with cancer has limited its use. Newer tumor necrosis factor alpha drugs
have shown dramatic results against sarcoidosis in early studies, and further studies are needed.
Lung or heart-lung transplantation has been successful in sarcoidosis patients with end-stage pulmonary or cardiac disease.
Sarcoid granulomas frequently recur in the allograft following lung transplant but rarely give rise to clinical symptoms.
This article was contributed by Drs Barreiro, DeMarco, Gemmel, and Schaub and edited by Julia M. Russell.
Drs Barreiro, DeMarco, Gemmel, and Schaub disclose that they have no financial relationship with any manufacturer in this
area of medicine.
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