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Sarcoidosis
is a disorder resulting in noncaseating granulomas in one or more
organs and tissues; etiology is unknown. The lungs and lymphatic
system are most often affected, but sarcoidosis may affect any organ.
Pulmonary symptoms range from none (limited disease) to exertional
dyspnea and, rarely, lung or other organ failure (advanced disease).
Diagnosis usually is first suspected because of pulmonary involvement
and is confirmed by chest x-ray, biopsy, and exclusion of other
causes of granulomatous inflammation. First-line treatment is corticosteroids.
Prognosis is excellent for limited disease but poor for more advanced
disease.
Sarcoidosis affects mostly people aged 20 to 40 but occasionally affects children and older adults. Worldwide, prevalence is greatest in black Americans and northern Europeans, especially Scandinavians. Disease presentation varies widely by racial and ethnic background, with black Americans and Puerto Ricans demonstrating more frequent extrathoracic manifestations. Sarcoidosis is slightly more prevalent in women. The incidence increases in winter and early spring, for unknown reasons.
Löfgren's syndrome:
Löfgren's syndrome is a type of acute sarcoidosis that manifests as a triad of acute polyarthritis, erythema nodosum, and hilar adenopathy. It has distinct features, including fever, malaise, joint disease, and sometimes uveitis and parotitis. It is more common among Scandinavian and Irish women.
Löfgren's syndrome is often self-limited. Patients usually respond to NSAIDs. Rate of relapse is low.
Etiology
Sarcoidosis is thought to be due to an inflammatory response to an environmental exposure in a genetically susceptible person. Proposed triggers include
Pathophysiology
The unknown antigen triggers a cell-mediated immune response that is characterized by the accumulation of T lymphocytes and macrophages, release of cytokines and chemokines, and organization of responding cells into granulomas. Clusters of disease in families and communities suggest a genetic predisposition, shared exposures, or, less likely, person-to-person transmission.
The result of the inflammatory process is formation of noncaseating granulomas, the pathologic hallmark of sarcoidosis. Granulomas are collections of mononuclear cells and macrophages that are differentiated into epithelioid and multinucleated giant cells, surrounded by lymphocytes, plasma cells, mast cells, fibroblasts, and collagen. Granulomas occur most commonly in the lung and lymph nodes but can involve the liver, spleen, eyes (see Uveitis: Sarcoidosis), sinuses, skin, bones, joints, skeletal muscle, kidney, reproductive organs, heart, salivary glands, and nervous system. Granulomas in the lungs are distributed along lymphatics, with most found in peribronchiolar, subpleural, and perilobular regions.
Symptoms and Signs
Symptoms and signs depend on the site and degree of involvement and vary over time, ranging from spontaneous remission to chronic indolent illness. Accordingly, frequent reassessment for new symptoms in different organs is needed. Most cases are probably asymptomatic and thus go undetected. Pulmonary disease occurs in > 90% of adult patients.
Symptoms and signs may include dyspnea, cough, chest discomfort, and crackles. Fatigue, malaise, weakness, anorexia, weight loss, and low-grade fever are also common; sarcoidosis is an unusual cause of fever of unknown origin. Nontender lymphadenopathy is often the only sign. Systemic involvement causes various symptoms (see Table 1: Sarcoidosis: Systemic Involvement in Sarcoidosis  ), which vary by race, sex, and age. Blacks are more likely than whites to have involvement of the eye, liver, bone marrow, peripheral lymph nodes, and skin other than erythema nodosum. Women are more likely to have erythema nodosum and eye or nervous system involvement. Men and older patients are more likely to be hypercalcemic.
In children < 4 yr, arthritis, rash, and uveitis are the most common manifestations. Sarcoidosis may be confused with juvenile RA in this age group.
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Table 1
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Systemic Involvement in
Sarcoidosis
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System
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Estimated Frequency
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Comments
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Pulmonary
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> 90%
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Causes granulomas to form in alveolar septa, bronchiolar, and bronchial walls, causing diffuse pulmonary disease; pulmonary arteries and veins also involved
Often asymptomatic
Spontaneously resolves in many patients but can cause progressive pulmonary dysfunction leading to limitations in physical function, respiratory failure, and death in a few
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Pulmonary lymphatic
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90%
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Hilar or mediastinal involvement incidentally detected by chest x-ray in most patients; nontender peripheral or cervical lymphadenopathy in others
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Muscle
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50–80%
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Asymptomatic disease with or without enzyme elevations in most patients
Sometimes insidious or acute myopathy with muscle weakness
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Hepatic
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40–75%
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Usually asymptomatic
Manifests with mild elevations in liver function test results, hypolucent lesions on CT scans with radiopaque dye
Rarely, clinically significant cholestasis or cirrhosis
Unclear distinction between sarcoidosis and granulomatous hepatitis when sarcoidosis affects liver only
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Joint
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25–50%
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Ankle, knee, wrist, and elbow arthritis (most common)
May cause chronic arthritis with Jaccoud's deformities or dactylitis
Löfgren's syndrome (triad of acute polyarthritis, erythema nodosum, and hilar adenopathy)
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Hematologic
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< 5–30%
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Lymphopenia
Anemia of chronic disease
Anemia due to granulomatous infiltration of bone marrow, sometimes causing pancytopenia
Splenic sequestration causing thrombocytopenia
Leukopenia
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Dermatologic
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25%
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Erythema nodosum:
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Red indurated tender nodules on anterior legs
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More common among Europeans, Puerto Ricans, and Mexicans
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Usually remits in 1–2 mo
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Surrounding joints often arthritic (Löfgren's syndrome)
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May be good prognostic sign
Nonspecific skin lesions; plaques, macules and papules, subcutaneous nodules, and hypopigmentation and hyperpigmentation (also common)
Lupus pernio:
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Violaceous plaques on nose, cheeks, lips, and ears
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More common among black Americans and Puerto Ricans
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Often associated with lung fibrosis
Poor prognostic sign
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Ocular
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25%
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Uveitis (most common), causing blurred vision, photophobia, and tearing
Can cause blindness
Spontaneously resolves in most patients
May manifest with conjunctivitis, iridocyclitis, chorioretinitis, dacryocystitis, lacrimal gland infiltration causing dry eyes, optic neuritis, glaucoma, or cataracts
Ocular involvement more common among black Americans and Japanese
Annual or biannual screening indicated for early disease detection
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Psychiatric
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10%
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Depression (common), but uncertain whether it is a primary manifestation of sarcoidosis or a response to prolonged course of disease and frequent recurrences
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Renal
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10%
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Asymptomatic hypercalciuria (most common)
Interstitial nephritis
Chronic renal failure caused by nephrolithiasis and nephrocalcinosis and requiring renal replacement (dialysis or transplantation) in some patients
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Splenic
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10%
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Usually asymptomatic
Manifests with left upper quadrant pain and thrombocytopenia or as incidental finding on x-ray or CT scan
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Neurologic
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< 10%
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Cranial neuropathy, especially 7th (causing facial nerve palsy) and 8th (causing hearing loss)
Optic and peripheral neuropathy (common)
May affect any cranial nerve
CNS involvement, with nodular lesions or diffuse meningeal inflammation typically in cerebellum and brain stem
Hypothalamic diabetes insipidus, polyphagia and obesity, and thermoregulatory and libidinal changes
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Nasal sinus
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< 10%
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Acute and chronic granulomatous inflammation of sinus mucosa with symptoms indistinguishable from common allergic and infectious sinusitis
Diagnosis confirmed by biopsy
Increased in patients with lupus pernio
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Cardiac
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5%
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Conduction blocks and arrhythmias (most common), sometimes causing sudden death
Heart failure due to restrictive cardiomyopathy (primary) or pulmonary hypertension (secondary)
Transient papillary muscle dysfunction and pericarditis (rare)
More common among Japanese, in whom cardiomyopathy is most frequent cause of sarcoidosis-related death
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Bone
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5%
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Osteolytic or cystic lesions
Osteopenia
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Oral
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< 5%
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Asymptomatic parotid swelling (most common)
Parotitis with xerostomia
Heerfordt's syndrome (also called uveoparotid fever), characterized by uveitis, bilateral parotid swelling, facial palsy, and chronic fever
Oral lupus pernio, which may disfigure hard palate and may involve cheek, tongue, and gums
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Gastric or intestinal
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Rare
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Rarely, gastric granulomas
Rarely, intestinal involvement
Mesenteric lymphadenopathy that may cause abdominal pain
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Endocrine
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Rare
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Hypothalamic and pituitary stalk infiltration, possibly causing panhypopituitarism
May cause thyroid infiltration without dysfunction
Secondary hypoparathyroidism due to hypercalcemia
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Pleural
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Rare
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Causes lymphocytic exudative effusions, usually bilateral
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Reproductive
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Rare
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Case reports of endometrial, ovarian, epididymal, and testicular involvement
No effect on fertility
May subside during pregnancy and relapse postpartum
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Diagnosis
Sarcoidosis is most often suspected when hilar adenopathy is incidentally detected on chest x-ray. These changes are the most common abnormality, and the x-ray appearance is roughly predictive of the likelihood of spontaneous remission (see Table 2: Sarcoidosis: Staging Sarcoidosis) in patients with pulmonary involvement. Therefore, in patients suspected of having sarcoidosis, a chest x-ray should be the first test if it has not already been obtained.
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Table 2
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Staging Sarcoidosis
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Stage
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Definition
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Incidence of Spontaneous Remission
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0
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Normal chest x-ray
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Usually remits
No correlation with prognosis
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I
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Bilateral hilar, paratracheal, and mediastinal lymphadenopathy without parenchymal infiltrates
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60–80%
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II
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Bilateral hilar and mediastinal adenopathy with interstitial infiltrates (usually upper lung fields)
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50–65%
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III
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Diffuse interstitial infiltrates without hilar adenopathy
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< 30%
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IV
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Diffuse fibrosis, often associated with fibrotic-appearing conglomerate masses, traction bronchiectasis, and traction cysts
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0%
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A normal chest x-ray generally excludes the diagnosis; however, high-resolution CT may be indicated in patients if sarcoidosis is strongly suspected because CT is more sensitive for detecting hilar and mediastinal lymphadenopathy. CT findings in more advanced stages (II to IV) include thickening of the bronchovascular bundles and bronchial walls; beading of the interlobular septa; ground-glass opacification; parenchymal nodules, cysts, or cavities; or traction bronchiectasis.
When imaging suggests sarcoidosis, the diagnosis is confirmed by demonstration of noncaseating granulomas on biopsy and exclusion of alternative causes of granulomatous disease (see Table 3: Sarcoidosis: Differential Diagnosis of Sarcoidosis).
The diagnostic evaluation, therefore, requires the following:
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Table 3
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Differential Diagnosis
of Sarcoidosis
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Type
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Specific Disorder
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Mycobacterial infection
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Atypical mycobacteria
TB
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Fungal infection
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Aspergillosis
Blastomycosis
Coccidioidomycosis
Cryptococcal infection
Histoplasmosis
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Other infections
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Brucellosis
Cat-scratch disease (lymph nodes only)
Mycoplasmal infection
Pneumocystis jiroveci infection
Syphilis
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Rheumatologic disorders
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Juvenile RA
Kikuchi's lymphadenitis (lymph nodes only)
Necrotizing sarcoid granulomatosis
RA
Sjögren's syndrome
Wegener's granulomatosis
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Hematologic cancer
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Hodgkin lymphoma
Non-Hodgkin lymphoma
Splenic lymphoma
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Hypersensitivity
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Occupational metals: Aluminum, beryllium, titanium, zirconium
Organic antigens causing hypersensitivity pneumonitis: Actinomycetes, atypical mycobacterial antigens, fungi, mushroom spores, other bioaerosols
Inorganic antigens causing hypersensitivity pneumonitis: Isocyanate, pyrethrins
Drug reaction
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Other
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Inflammatory bowel disease
Foreign body aspiration or inoculation
Granulomatous hepatitis
Granulomatous lesion of unknown significance
Lymphoid interstitial pneumonia
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Sites for biopsy:
Appropriate biopsy sites may be obvious from physical examination and initial assessment: peripheral lymph nodes, skin lesions, and conjunctivae are all easily accessible. However, bronchoscopic transbronchial biopsy is the diagnostic procedure of choice in patients with intrathoracic involvement, because the sensitivity is as high as 90% when carried out by an experienced clinician. Video-assisted thoracoscopy can provide access to lung tissue when bronchoscopic transbronchial biopsy is nondiagnostic. Mediastinoscopy is sometimes done when hilar or mediastinal lymphadenopathy exists in the absence of pulmonary infiltrates, especially if lymphoma is in the differential diagnosis. However, even in patients with only mediastinal adenopathy on x-ray or CT, transbronchial biopsies are often diagnostic. Open lung biopsy provides another way to obtain tissue but requires general anesthesia and is now rarely necessary. Clinical and x-ray findings may be accurate enough for diagnosis in stage I disease or in stage II disease when biopsy is not possible.
Exclusion of
other diagnoses:
Exclusion of other diagnoses is critical, especially when symptoms and x-ray signs are minimal, because many other disorders and processes can cause granulomatous inflammation (see Table 3: Sarcoidosis: Differential Diagnosis of Sarcoidosis). Biopsy tissue should be cultured for fungi and mycobacteria. Exposure history to occupational (silicates, beryllium), environmental (moldy hay, birds, and other antigenic triggers of hypersensitivity pneumonitis), and infectious (TB, coccidioidomycosis, histoplasmosis) antigens should be explored. PPD skin testing should be done early in the assessment along with anergy controls.
Disease severity
assessment:
Severity is assessed with
Pulmonary function test results are often normal in early stages but demonstrate restriction and reduced diffusing capacity for carbon monoxide (DLco) in advanced disease. Airflow obstruction also occurs and may suggest involvement of the bronchial mucosae. Pulse oximetry is often normal when measured at rest but may show effort desaturation with more extensive lung involvement. ABG analysis at rest and during exercise is more sensitive than pulse oximetry.
Recommended screening
tests for extrapulmonary disease include
Echocardiography, neuroimaging, lumbar puncture, bone films or MRI, and electromyography may be appropriate when symptoms suggest cardiac, neurologic, or rheumatologic disorders. Abdominal CT with radiopaque dye is not routinely recommended but can provide evidence of hepatic or splenic involvement (eg, enlargement, hypolucent lesions).
Laboratory testing plays an adjunctive role in establishing the diagnosis and extent of organ involvement. CBC may show anemia, eosinophilia, or leukopenia. Serum Ca may be elevated because of production of vitamin D analogs by activated macrophages. BUN, creatinine, and liver function test results may be elevated in renal and hepatic sarcoidosis. Total protein may be elevated because of hypergammaglobulinemia. Elevated ESR is common but nonspecific. Measurement of Ca in a urine specimen collected over 24 h is recommended to exclude hypercalciuria, even in patients with normal serum Ca levels. Elevated serum ACE levels also suggest sarcoidosis but are nonspecific and may be low in patients taking ACE inhibitors or elevated in patients with various other conditions (eg, hyperthyroidism, Gaucher's disease, silicosis, mycobacterial disease, hypersensitivity pneumonitis). However, ACE levels may be useful for monitoring disease activity and therapeutic response in patients with confirmed sarcoidosis. Increased ACE levels in CSF may be useful for diagnosing CNS sarcoidosis.
Other
adjunctive tests include bronchoalveolar lavage (BAL) and gallium scanning. BAL is used to help exclude other forms of interstitial lung disease if the diagnosis of sarcoidosis is in doubt and to rule out infection. The findings on BAL vary considerably, but lymphocytosis (lymphocytes > 10%), a CD4+/CD8+ ratio of > 3.5 in the lavage fluid cell differential, or both suggests the diagnosis in the proper clinical context. Absence of these findings does not exclude sarcoidosis, however.
Whole-body gallium scanning may provide useful supportive evidence in the absence of tissue confirmation. Symmetric increased uptake in mediastinal and hilar nodes (lambda sign) and in lacrimal, parotid, and salivary glands (panda sign) are patterns highly suggestive of sarcoidosis. A negative result in patients taking prednisone is unreliable.
Prognosis
Although spontaneous improvement is common, the manifestations of the disorder and its severity are highly variable, and many patients require corticosteroids some time during the course of their disease. Thus, serial monitoring for evidence of relapse is imperative. In about 90% of patients who have spontaneous remission, remission occurs within the first 2 yr after diagnosis; < 10% of these patients have relapses after 2 yr. Those patients who do not experience remission within 2 yr are likely to have chronic disease.
Sarcoidosis is thought to be chronic in up to 30% of patients, and 10 to 20% experience permanent sequelae. The disease is fatal in 1 to 5% of patients. Pulmonary fibrosis with respiratory failure is the most common cause of death worldwide, followed by pulmonary hemorrhage from aspergilloma. In Japan, however, infiltrative cardiomyopathy causing heart failure and arrhythmias is the most common cause of death.
Prognosis is worse for patients with extrapulmonary sarcoidosis and for blacks. Recovery occurs in 89% of whites and 76% of blacks with no extrathoracic disease and in 70% of whites and 46% of blacks with extrathoracic disease.
Good prognostic
signs include
Poor prognostic
signs include
However, little difference is demonstrable in long-term outcome between treated and untreated patients, and relapse is common when treatment ends.
Treatment
Because sarcoidosis often spontaneously resolves, asymptomatic patients and patients with mild symptoms do not require treatment, although they should be monitored for signs of deterioration. These patients can be followed with serial x-rays, pulmonary function tests (including diffusing capacity), and markers of extrathoracic involvement (eg, routine renal and liver function testing). Patients who require treatment regardless of stage include those with the following:
Treatment is with corticosteroids. A standard protocol is prednisone 0.3 to 1 mg/kg po once/day depending on symptoms and severity of findings. Alternate-day regimens are also used (eg, prednisone 40 to 60 mg po once every other day). Although patients rarely require > 40 mg/day, higher doses may be needed to reduce complications in patients with ocular, myocardial, or neurologic disease. Response usually occurs within 2 to 4 wk, so symptoms and results of chest x-ray and pulmonary function tests may be reassessed between 4 and 12 wk. Chronic, insidious cases may respond more slowly. Corticosteroids are tapered to a maintenance dose (eg, prednisone ≤ 10 mg every other day if possible) after evidence of response and are continued for a minimum of 12 mo if improvement occurs. The optimal duration of treatment is unknown. Premature taper can result in relapse. The drug is slowly stopped if response is absent or equivocal. Corticosteroids can ultimately be stopped in most patients, but because relapse occurs up to 50% of the time, monitoring should be repeated, usually every 3 to 6 mo. Corticosteroid treatment should be resumed for recurrence of symptoms and signs, including dyspnea, arthralgia, fever, hepatic insufficiency, cardiac arrhythmia, CNS involvement, hypercalcemia, ocular disease uncontrolled by local drugs, and disfiguring skin lesions.
Data on use of inhaled corticosteroids for pulmonary sarcoidosis are not definitive, but some evidence suggests that this route of administration can relieve cough in patients with endobronchial involvement. Topical corticosteroids may be useful in some cases of dermatologic and ocular disease.
About 10% of patients requiring therapy are unresponsive to tolerable doses of a corticosteroid and should be given a 6-mo trial of methotrexate starting at 2.5 mg po once/wk and increasing in increments of 2.5 mg /wk to a total of 10 to 15 mg/wk as tolerated to keep the WBC count > 3000/μL. Initially, methotrexate and corticosteroids are both given; over 8 wk, the corticosteroid dose can be tapered and, in many cases, stopped. The maximal response to methotrexate , however, may take 6 to 12 mo. In such cases, prednisone must be tapered more slowly. Serial blood counts and liver enzyme tests should be done every 1 to 2 wk initially and then every 4 to 6 wk once a stable dose is achieved. Folic acid (1 mg po once/day) is recommended for patients treated with methotrexate .
Other drugs reported to be effective in small numbers of patients who are corticosteroid-resistant or who experience complicating adverse effects include azathioprine , cyclophosphamide , chlorambucil , chloroquine or hydroxychloroquine , thalidomide , pentoxifylline , and infliximab .
Hydroxychloroquine 200 mg po bid to tid can be as effective as corticosteroids for treating hypercalcemia or disfiguring skin sarcoidosis. Although immunosuppressants are often more effective in refractory cases, relapse is common after cessation.
No available drugs have consistently prevented pulmonary fibrosis.
Lung transplantation is an option for patients with end-stage pulmonary involvement, although disease may recur in the transplanted organ.
Last full review/revision July 2009 by Lee S. Newman, MD, MA
Content last modified July 2009
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