Sarcoidosis
Sarcoidosis most commonly affects people aged 20 to 40 but occasionally affects children and older adults. Worldwide, prevalence is greatest in black Americans and ethnic northern Europeans, especially Scandinavians. Disease presentation varies widely by racial and ethnic background, with black Americans having more frequent extrathoracic manifestations. Sarcoidosis is more prevalent in women. The incidence increases in winter and early spring for unknown reasons.
Löfgren syndrome
Löfgren syndrome manifests as a triad of acute polyarthritis, erythema nodosum, and hilar adenopathy. It often causes fever, malaise, and uveitis, and sometimes parotitis. It is more common among Scandinavian and Irish women. Löfgren syndrome is often self-limited. Patients usually respond to nonsteroidal anti-inflammatory drugs (NSAIDs). Rate of relapse is low.
Heerfordt syndrome
Blau syndrome
Blau syndrome is a sarcoidosis-like disease inherited in a autosomal dominant fashion that manifests in children. It is not known whether Blau syndrome arises through the same mechanism as sarcoidosis diagnosed in adults. In Blau syndrome, children present before the age of 4 years with arthritis, rash, and uveitis. Blau syndrome is often self-limited. Symptoms usually are relieved with NSAIDs.
Etiology
Sarcoidosis is thought to be due to an inflammatory response to an environmental antigen in a genetically susceptible person. Proposed triggers include
Tobacco use is inversely correlated with sarcoidosis.
Evidence supporting genetic susceptibility includes the following:
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Higher rate of disease concordance in monozygotic than dizygotic twins
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Increased prevalence of sarcoidosis (about 3.6 to 9.6%) among 1st- or 2nd-degree relatives of patients who have sarcoidosis
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Fivefold increase in relative risk of developing sarcoidosis in siblings of patients who have sarcoidosis
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Identification of several possible human leukocyte antigen (HLA) and non-HLA genes associated with sarcoidosis
Pathophysiology
The unknown antigen triggers a cell-mediated immune response that is characterized by the accumulation of T cells 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 inflammatory process leads to formation of noncaseating granulomas, the pathologic hallmark of sarcoidosis. Granulomas are collections of mononuclear cells and macrophages that differentiate into epithelioid and multinucleated giant cells and are surrounded by lymphocytes, plasma cells, fibroblasts, and collagen. Granulomas occur most commonly in the lungs and lymph nodes but can involve any organ and cause significant dysfunction. Granulomas in the lungs are distributed along lymphatics, with most occurring in peribronchiolar, subpleural, and perilobular regions.
Hypercalcemia may occur because of increased conversion of vitamin D to the activated form by activated macrophages. Hypercalciuria may be present, even in patients with normal serum calcium levels. Nephrolithiasis and nephrocalcinosis may occur, sometimes leading to chronic kidney disease.
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 can manifest as fever of unknown origin. Systemic involvement causes various symptoms (see table Systemic Involvement in Sarcoidosis), which vary by race, sex, and age. Blacks are more likely than whites to have involvement of the eyes, liver, bone marrow, peripheral lymph nodes, and skin; erythema nodosum is an exception. Women are more likely to have erythema nodosum and eye or nervous system involvement. Men and older patients are more likely to be hypercalcemic.
This image shows dacryocystitis manifesting as inflammation of the palpebral lobe of the lacrimal glands in both upper eyelids in a patient with sarcoidosis.
This photo shows erythematous facial plaques in a patient with sarcoidosis.
Erythema nodosum is a form of panniculitis characterized by palpable, tender, red or violet subcutaneous nodules most typically appearing on the shins. It most often accompanies systemic diseases, including streptococcal infection, sarcoidosis, and inflammatory bowel disease.
This photo shows violaceous plaques on the nose of a patient with sarcoidosis.
Children with sarcoidosis may present with Blau syndrome (arthritis, rash, uveitis), or manifestations similar to those of adults. Sarcoidosis may be confused with juvenile idiopathic arthritis (juvenile rheumatoid arthritis) in this age group.
Systemic Involvement in Sarcoidosis
System |
Estimated Frequency |
Comments |
|
Pulmonary |
> 90% |
Granulomas form in alveolar septa and 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 |
|
Pulmonary lymphatic |
90% |
Hilar or mediastinal involvement incidentally detected by chest x-ray in most patients; nontender peripheral or cervical lymphadenopathy in others |
|
Muscle |
50–80% |
Asymptomatic disease with or without enzyme elevations in most patients Sometimes insidious or acute myopathy with muscle weakness |
|
Hepatic |
40–75% |
Usually asymptomatic Manifests with mild elevations in liver function test results, hypolucent lesions on CT scans with contrast Rarely, clinically significant cholestasis or cirrhosis Unclear distinction between sarcoidosis and granulomatous hepatitis when sarcoidosis affects the liver only |
|
Joint |
25–50% |
Ankle, knee, wrist, and elbow arthritis (most common) May cause chronic arthritis with Jaccoud deformities or dactylitis Löfgren syndrome (triad of acute polyarthritis, erythema nodosum, and hilar adenopathy) |
|
Hematologic |
< 5–30% |
Anemia due to granulomatous infiltration of bone marrow, sometimes causing pancytopenia Splenic sequestration causing thrombocytopenia |
|
Dermatologic |
25% |
Biopsy of erythema nodosum lesions is unnecessary because granulomas, characteristic of sarcoidosis, are absent Common skin lesions: Lupus pernio: |
|
Ocular |
25% |
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 people of Japanese descent Annual screening indicated for early disease detection |
|
Psychiatric |
10% |
Depression (common), but uncertain whether it is a primary manifestation of sarcoidosis or a response to the prolonged course of disease and frequent recurrences |
|
Renal |
10% |
Asymptomatic hypercalciuria (most common) Chronic kidney disease caused by nephrolithiasis and nephrocalcinosis and requiring renal replacement (dialysis or transplantation) in some patients |
|
Splenic |
10% |
Usually asymptomatic Manifests with left upper quadrant pain and thrombocytopenia or as an incidental finding on x-ray or CT |
|
Neurologic |
< 10% |
Cranial neuropathy, especially the 7th nerve (causing facial nerve palsy) or 8th nerve (causing hearing loss) Optic and peripheral neuropathy (common) May affect any cranial nerve CNS involvement, with nodular lesions or diffuse meningeal inflammation typically in the cerebellum and brain stem Central diabetes insipidus, polyphagia and obesity, and thermoregulatory and libidinal changes |
|
Nasal sinus |
< 10% |
Acute and chronic granulomatous inflammation of sinus mucosa with symptoms indistinguishable from common allergic and infectious sinusitis Diagnosis confirmed by biopsy More common in patients with lupus pernio |
|
Cardiac |
5% |
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 the most frequent cause of sarcoidosis-related death |
|
Bone |
5% |
Osteolytic or cystic lesions Osteopenia |
|
Oral |
< 5% |
Asymptomatic parotid swelling (most common) Parotitis with xerostomia Heerfordt syndrome (uveoparotid fever), characterized by uveitis, bilateral parotid swelling, facial palsy, and chronic fever Oral lupus pernio, which may disfigure the hard palate and may involve the cheek, tongue, and gums |
|
Gastric or intestinal |
Rare |
Rarely gastric granulomas Rarely intestinal involvement Mesenteric lymphadenopathy that may cause abdominal pain |
|
Endocrine |
Rare |
Hypothalamic and pituitary stalk infiltration, possibly causing panhypopituitarism May cause thyroid infiltration without dysfunction Secondary hypoparathyroidism due to hypercalcemia |
|
Pleural |
Rare |
Causes lymphocytic exudative effusions, usually bilateral |
|
Reproductive |
Rare |
Case reports of endometrial, ovarian, epididymal, and testicular involvement No effect on fertility May subside during pregnancy and relapse postpartum |
Diagnosis
Sarcoidosis is most often suspected when hilar adenopathy is incidentally detected on chest x-ray. Bilateral hilar adenopathy is the most common abnormality. If sarcoidosis is suspected, a chest x-ray should be the first test if it has not already been done. The x-ray appearance tends to roughly predict the likelihood of spontaneous remission (see table Chest X-ray Staging of Sarcoidosis) in patients with only thoracic lymph node involvement. However, staging sarcoidosis by chest x-ray can be misleading; for example, extrapulmonary sarcoidosis, such as cardiac or neurologic sarcoidosis, can portend a poor prognosis in the absence of pulmonary involvement. Also, chest x-rays findings predict pulmonary function poorly, so that chest x-ray appearance may not accurately indicate the severity of pulmonary sarcoidosis.
Chest X-ray Staging of Sarcoidosis
A normal chest x-ray (stage 0) does not exclude the diagnosis of sarcoidosis, particularly when cardiac or neurologic involvement is suspected. A high-resolution CT is more sensitive for detecting hilar and mediastinal lymphadenopathy and parenchymal abnormalities. CT findings in more advanced stages (II to IV) include
Bilateral hilar adenopathy in stage I sarcoidosis.
Bilateral hilar adenopathy with interstitial opacities in stage II sarcoidosis.
Diffuse interstitial opacities without hilar adenopathy in stage III sarcoidosis.
Severe, diffuse fibrosis with hilar adenopathy and cystic changes of the upper lobes in stage IV sarcoidosis.
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 Differential Diagnosis of Sarcoidosis). Löfgren syndrome does not require confirmation by biopsy.
The diagnostic evaluation, therefore, requires the following:
Differential Diagnosis of Sarcoidosis
Type |
Specific Disorder |
|
Mycobacterial infection |
Atypical mycobacteria |
|
Fungal infection |
|
|
Other infections |
Cat-scratch disease (lymph nodes only) |
|
Rheumatologic disorders |
Juvenile idiopathic arthritis (juvenile rheumatoid arthritis) Kikuchi-Fujimoto disease (lymph nodes only) |
|
Hematologic cancer |
Castleman disease (a lymphoproliferative disorder associated with infection by HIV or human herpesvirus 8) Splenic lymphoma |
|
Hypersensitivity |
Metals encountered in occupational settings: 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 |
|
Other |
Foreign body aspiration or inoculation Granulomatous hepatitis Granulomatous lesion of unknown significance |
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. Endobronchial ultrasound–guided transbronchial needle aspiration (EBUS-TBNA) of a mediastinal or hilar lymph node has a reported diagnostic yield of about 90%. It is usually the diagnostic procedure of choice in patients with intrathoracic involvement.
Bronchoscopic transbronchial biopsy can be tried when EBUS-TBNA is nondiagnostic; if the bronchoscopic transbronchial biopsy is nondiagnostic, it can be tried a second time.
If EBUS-TBNA and bronchoscopic transbronchial biopsies are nondiagnostic or if bronchoscopy cannot be tolerated, mediastinoscopy can be done to biopsy mediastinal or hilar lymph nodes, or video-assisted thoracoscopic (VAT) lung biopsy or open-lung biopsy can be done to obtain lung tissue. If sarcoidosis is strongly suspected but a biopsy site is not evident based on examination or imaging findings, positron emission tomography (PET) scanning can help identify sites such as heart, bone, and brain.
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 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 (tuberculosis, coccidioidomycosis, histoplasmosis) antigens should be explored. Purified protein derivative (PPD) skin testing should be done early in the assessment along with anergy controls.
Disease severity assessment
Severity is assessed according to organ involvement so, for example, with only pulmonary involvement
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 in patients with more extensive lung involvement.
Recommended routine screening tests for extrapulmonary disease include
Cardiac magnetic resonance imaging (MRI) with and without gadolinium contrast, brain or spine MRI with or without gadolinium, bone scans, and electromyography may be appropriate in patients with cardiac, neurologic, or rheumatologic symptoms. PET scanning appears to be the most sensitive test for detecting bone and other extrapulmonary sarcoidosis. Abdominal CT with radiopaque contrast agents 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. Complete blood count may show anemia, eosinophilia, or leukopenia. Serum calcium should be measured to detect hypercalcemia. Blood urea nitrogen (BUN), creatinine, and liver function test results may be elevated in renal and hepatic sarcoidosis. Total protein may be elevated because of hypergammaglobulinemia. Elevated erythrocyte sedimentation rate is common but nonspecific. Measurement of calcium in a urine specimen collected over 24 hours is recommended to exclude hypercalciuria, even in patients with normal serum calcium levels. Elevated serum angiotensin-converting enzyme (ACE) levels also suggest sarcoidosis but are nonspecific and may be elevated in patients with various other conditions (eg, hyperthyroidism, Gaucher disease, silicosis, mycobacterial disease, fungal infections, hypersensitivity pneumonitis, lymphoma). However, angiotensisn-converting enzyme (ACE) levels may be useful for monitoring adherence with corticosteroid treatment. ACE levels plummet even when patients are taking low-dose corticosteroids.
Bronchoalveolar lavage (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 suggest the diagnosis in the proper clinical context. However, absence of these findings does not exclude sarcoidosis.
Whole-body gallium scanning has been largely replaced by PET scanning. If gallium scanning is available, it 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 remission is common, disease manifestations and severity are highly variable, and many patients require corticosteroids at some time during the course of their disease. Thus, serial monitoring for evidence of relapse is imperative. Almost two third of patients with sarcoidosis eventually achieve remission with few or no sequelae. In about 50% of patients who have spontaneous remission, remission occurs within the first 3 years after diagnosis; < 10% of these patients have relapses after 2 years. Patients who do not experience remission within 2 to 3 years 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, typically due to respiratory failure caused by pulmonary fibrosis, and less often due to pulmonary hemorrhage caused by aspergilloma. However, in Japan, infiltrative cardiomyopathy causing arrhythmias and heart failure is the most common cause of death.
Prognosis is worse for patients with extrapulmonary sarcoidosis and for blacks. Remission 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
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 chest x-rays, pulmonary function tests (including diffusing capacity), and markers of extrathoracic involvement (eg, routine renal and liver function testing, annual slit-lamp ophthalmologic examination). The frequency of follow-up testing is determined by the severity of disease.
Patients who require treatment regardless of stage include those with the following:
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Worsening symptoms
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Limitation of activity
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Markedly abnormal or deteriorating lung function
-
Worrisome x-ray changes (cavitation, fibrosis, conglomerate masses, signs of pulmonary hypertension)
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Heart, nervous system, or eye involvement
-
Renal or hepatic failure
-
Moderate to severe hypercalcemia
-
Disfiguring skin (lupus pernio) or joint disease
Nonsteroidal anti-inflammatory drugs (NSAIDS) are used to treat musculoskeletal discomfort.
Corticosteroids
Symptom management begins with corticosteroids. The presence of chest imagining abnormalities without significant symptoms or evidence of decline in organ function is not an indication for treatment. A standard protocol is prednisone 20 mg to 40 mg po once/day, depending on symptoms and severity of findings. Alternate-day regimens may be used: eg, prednisone 40 mg po once every other day. Although patients rarely require > 40 mg/day, higher doses may be needed to reduce complications in neurologic disease. Response usually occurs within 6 to 12 weeks, so symptoms and pulmonary function tests may be reassessed between 6 and 12 weeks. Chronic, insidious cases may respond more slowly. Corticosteroids are tapered to a maintenance dose (eg, prednisone 10 to 15 mg/day) after evidence of response and are continued for an additional 6 to 9 months 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 months. Corticosteroid treatment should be resumed for recurrence of symptoms and signs. Because angiotensin-converting enzyme (ACE) production is suppressed with low doses of corticosteroids, serial serum ACE levels may be useful in assessing adherence with corticosteroid treatment in patients who have elevated ACE levels.
Inhaled corticosteroids can relieve cough in patients with endobronchial involvement or with hyperreactive airways.
Topical corticosteroids may be useful in dermatologic, nasal sinus, and ocular disease.
Prophylaxis against Pneumocystis jirovecii pneumonia should be considered while patients are taking either > 20 mg prednisone daily or its equivalent for more than a month or immunosuppressants.
Alendronate or another bisphosphonate may be the treatment of choice for prevention of corticosteroid-induced osteoporosis. Using supplemental calcium or vitamin D risks hypercalcemia due to endogenous production of active vitamin D (1, 25 dihydroxy vitamin D) by sarcoidal granulomas. Serum and 24-hour urinary calcium measurements should be normal before starting such supplements.
Immunosuppressants
Immunosuppressants are often more effective in refractory cases. For example, immunosuppressive drugs have been used when:
Prior to adding other immunosuppressants, possible reasons for lack of clinical improvement, such as noncompliance, comorbid disease, and end-stage fibrosis should be considered.
Methotrexate is the most commonly used immunosuppressant. Patients should be given a 6-month trial of methotrexate 10 to 15 mg/week. Initially, methotrexate and corticosteroids are both given; over 6 to 8 weeks, the corticosteroid dose can be tapered and, in many cases, stopped. The maximal response to methotrexate, however, may take 6 to 12 months. In such cases, prednisone must be tapered more slowly. Serial blood counts and liver enzyme tests should be done every 1 to 2 weeks initially and then every 4 to 6 weeks once a stable dose is achieved. Folate (1 mg po once/day) is recommended for patients treated with methotrexate.
Other immunosuppressants include azathioprine, mycophenolate mofetil, cyclophosphamide, leflunomide, hydroxychloroquine, and infliximab. Infliximab, a tumor necrosis factor inhibitor, can be effective for treatment of chronic corticosteroid-dependent pulmonary sarcoidosis, refractory lupus pernio, and neurosarcoidosis. It is given intravenously 3 to 5 mg/kg once, again 2 weeks later, then once per month. It may take 3 to 6 months for maximal response.
Hydroxychloroquine 400 mg po once/day or 200 mg po bid can be effective for treating hypercalcemia, arthralgia, skin sarcoidosis, or enlarged uncomfortable or disfiguring peripheral lymph nodes. Ophthalmologic evaluation should be done before hydroxychloroquine is started and every 6 to 12 months during treatment to monitor for its ocular toxicity.
Relapse is common after stopping an immunosuppressant.
Other treatment considerations
Patients who have heart block or ventricular arrhythmias due to cardiac involvement should have an implantable cardiac defibrillator and pacemaker placed as well as drug therapy.
No available drugs have consistently prevented pulmonary fibrosis.
Treatment of sarcoidosis-associated pulmonary arterial hypertension is supportive with diuresis and supplemental oxygen. So far therapy with pulmonary vasodilators has not been found to be beneficial (1).
Organ transplantation is an option for patients with end-stage pulmonary, cardiac, or liver involvement, although disease may recur in the transplanted organ.
Treatment reference
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1. Vizza CD, Jansa P, Teal S, et al: Sildenafil dosed concomitantly with bosentan for adult pulmonary arterial hypertension in a randomized controlled trial. BMC Cardiovasc Disord17(1):239, 2017. doi: 10.1186/s12872-017-0674-3.
Key Points
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Systemic and extrapulmonary involvement are common with sarcoidosis, but > 90% of adult patients have pulmonary involvement.
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Obtain a chest imaging study but confirm the diagnosis by biopsy, usually endobronchial ultrasound-guided transbronchial needle aspiration of a mediastinal or hilar lymph node.
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Assess pulmonary severity with pulmonary function testing and exercise pulse oximetry.
-
Test for extrapulmonary involvement with ECG, slit-lamp examination, renal and hepatic function tests, and serum and urinary calcium testing.
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Treat patients with systemic corticosteroids when indicated (eg, severe symptoms, hypercalcemia, progressive decline in organ function, cardiac or neurologic involvement).
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Treat with immunosuppressants if patients cannot tolerate moderate doses of corticosteroids, sarcoidosis is resistant to corticosteroids, or if corticosteroids are required long term.
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
hydroxychloroquine |
PLAQUENIL |
cyclophosphamide |
CYTOXAN (LYOPHILIZED) |
mycophenolate |
CELLCEPT |
Methotrexate |
OTREXUP |
azathioprine |
IMURAN |
leflunomide |
ARAVA |
Alendronate |
FOSAMAX |
infliximab |
REMICADE |
prednisone |
RAYOS |
Sildenafil |
VIAGRA |
bosentan |
TRACLEER |
