AUTHOR AND EDITOR INFORMATION

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• Miscellaneous
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INTRODUCTION

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Background

Sarcoidosis is a multisystem inflammatory disease of unknown etiology that predominantly affects the lungs and intrathoracic lymph nodes. Sarcoidosis is manifested by the presence of noncaseating granulomas (NCGs) in affected organ tissues.

A related Medscape CME course is Interstitial Lung Disease and Pulmonary Hypertension and a few of the related eMedicine articles include Sarcoidosis (emergency medicine focus), Sarcoidosis (dermatology focus), and Sarcoidosis (ophthalmology focus).

Pathophysiology

The cause of sarcoidosis is unknown. Efforts to identify a possible infectious etiology have been unsuccessful. Clinical sequelae result from the impact of NCGs on various organ tissues.

T cells play a central role in the development of sarcoidosis, as they likely propagate an excessive cellular immune reaction. For example, there is an accumulation of CD4 cells accompanied by the release of interleukin (IL)-2 at sites of disease activity. This may be manifest clinically by an inverted CD4/CD8 ratio. There also is an increased production of T_H1 cytokines, such as interferon. Moreover, both tumor necrosis factor (TNF) and TNF receptors are increased in this disease.

The importance of TNF in propagating inflammation in sarcoidosis has been demonstrated by the efficacy of anti-TNF agents, such as pentoxifylline¹ and infliximab,^{2, 3} in treating this disease. In addition to T cells, B cells also play a role. There is evidence of B cell hyperreactivity with immunoglobulin production. Antigen-presenting cells also accumulate at sites of involvement in sarcoidosis. Finally, levels of fibrinogenic cytokines (eg, transforming growth factor [TGF]–beta) are increased.

Frequency

United States

Incidence ranges from 5-40 cases per 100,000 population. The age-adjusted incidence for whites is 11 cases per 100,000 population. The incidence is considerably higher for African Americans, at 34 cases per 100,000 population.  The prevalence is 10 times greater for African Americans than for whites. Approximately 20% of patients who are African American reported an affected family member, while only 5% of whites in the United States who have sarcoidosis state they have family members also diagnosed with sarcoidosis.

International

Incidence is 20 cases per 100,000 population in Sweden and 1.3 cases per 100,000 population in Japan. Sarcoidosis occurs in China, Africa, India, and other developing countries. Although its incidence may be low, the disease remains hidden and often is misdiagnosed as tuberculosis.

Mortality/Morbidity

Data regarding mortality are lacking. Cardiac sarcoid is a major cause for mortality. However, in the US patients with sarcoidosis tend to die from the sarcoidosis because of the complications of end-stage lung disease (eg, respiratory failure, right heart failure).

• Functional impairment occurs in only 15-20% of patients and often resolves spontaneously. The overall mortality rate is less than 5% for untreated patients.
• The likelihood of regression for pulmonary disease correlates with the extent of parenchymal disease, as noted by chest radiography (CXR) stage.
• Cardiac disease is the most commonly reported cause of death in Europe and Japan, while pulmonary involvement most often accounts for mortality in the United States.

Race

See Frequency, United States.

Sex

Male-to-female ratio is approximately 2:1.

Age

Incidence peaks in persons aged 25-35 years. A second peak occurs for women aged 45-65 years.

CLINICAL

Section 3 of 11  

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• Follow-up
• Miscellaneous
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History

• Presentation depends on the extent and severity of the organ involved.
• • Approximately 5% of cases are asymptomatic and incidentally detected by CXR.
  • Systemic complaints, fever, anorexia, and arthralgias occur in 45% of cases.
  • Pulmonary, dyspnea on exertion, cough, chest pain, and hemoptysis (rare) occur in 50% of cases.
  • Löfgren syndrome
  • • Symptoms consist of fever, bilateral hilar lymphadenopathy (BHL), and polyarthralgias.
    • This presentation is associated with an excellent prognosis.
    • While common in Scandinavian patients, it is uncommon in African American and Japanese patients.

Physical

• Pulmonary findings
• • They usually are normal but may be significant for crackles.
  • Exertional oxygen desaturation also may be found.
• CXR staging system
• • Stage 0 is normal CXR findings.
  • Stage I is BHL.
  • Stage II is BHL and infiltrates.
  • Stage III is infiltrates alone.
  • Stage IV is fibrosis.
• Dermatological manifestations
• • Erythema nodosum may occur.
  • • A lower extremity panniculitis with painful, erythematous nodules
    • Associated with Löfgren syndrome but may be seen in other conditions
  • Lupus pernio is the most specific associated cutaneous lesion.
• • Violaceous rash is often seen on the cheeks or nose.
  • Osseous involvement may be present.
  • Maculopapular plaques are possible.
• Ocular manifestations
• • Anterior or posterior granulomatous uveitis is most frequent.
  • Conjunctival lesions and scleral plaques may also be noted.
  • Ocular involvement may lead to blindness if untreated.
• Cardiac manifestations
• • Heart failure from cardiomyopathy rarely occurs.
  • Heart block and sudden death may occur.
  • Approximately 25% of patients may have NCGs at autopsy, but fewer than 5% have clinical cardiac disease.
• Neurologic manifestations (rare)
• • Cranial nerve palsies and hypothalamic/pituitary dysfunction may occur.
  • Lymphocytic meningitis is the most common neurologic manifestation.

Causes

• The cause of the disease is not known; however, both genetic and environmental factors seem to play a role. As yet, no bacterial, fungal, or viral antigen has been consistently isolated from the sarcoidosis lesions. Sarcoidosis is neither a malignant nor an autoimmune disease. An ongoing National Institutes of Health (NIH)–supported study is investigating genetic and acquired causes of sarcoidosis.
• The following have been suggested as possible candidates that might play a role in causing sarcoidosis.
• • Mycobacteria, such as Mycobacterium tuberculosis, and atypical pathogens have been suggested.
  • Fungi and viruses, particularly Mycoplasma, Chlamydia, and Epstein-Barr virus, have been unconvincingly implicated.

DIFFERENTIALS

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Other Problems to be Considered

Hilar infiltrates

Eosinophilic granuloma
Fungal infection
Lung cancer
Lymphoma
Tuberculosis

NCG on a biopsy

Berylliosis
Catscratch disease
Fungal infection
Hypersensitivity pneumonitis
Leprosy
Primary biliary cirrhosis
Tuberculosis

WORKUP

Section 5 of 11  

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Lab Studies

• Routine lab evaluation often is unrevealing.
• Hypercalcemia or hypercalciuria may occur (NCGs secrete 1,25 vitamin D). Hypercalcemia is seen in about 10-13% of patients, whereas hypercalciuria is 3 times more common.
• An elevated alkaline phosphatase level suggests hepatic involvement. Although liver involvement is common, it rarely is clinically relevant.
• Angiotensin converting enzyme (ACE) levels may be elevated.
• • NCGs secrete ACE, which may function as a cytokine.
  • Serum ACE levels are elevated in 60% of patients at the time of diagnosis.
  • Serum ACE levels may correlate with total body granuloma load.
  • Levels may be increased in fluid from bronchoalveolar lavage or in cerebrospinal fluid.
  • Sensitivity and specificity as a diagnostic test is limited (60 and 70%, respectively).
  • There is no clear prognostic value.
  • Serum ACE levels may decline in response to therapy.
  • Decisions on treatment should not be based on the ACE level alone.

Imaging Studies

• A chest radiograph is central to evaluation.
• Routine chest CT scan adds little.
• High-resolution CT (HRCT) scanning of the chest may be helpful.
• • It identifies active alveolitis versus fibrosis.
  • It correlates with yield of biopsy.
• Gallium scans may be performed.
• • There is little correlation with clinical status.
  • The scan has low sensitivity and specificity as a diagnostic test.
  • It is used infrequently. Prior to the ease and availability of bronchoscopy, gallium scanning was occasionally employed as a diagnostic test. It may still be helpful in a subset of patients in whom the clinical picture remains confusing despite histologic evidence of NCGs (eg, differentiating chronic hypersensitivity pneumonitis from sarcoidosis).
• The optimal imaging study for assessment of cardiac involvement is unclear. Some authors recommend the combined use of gallium and thallium scanning. However, the studies relying on this technique were small and were subject to significant bias. Moreover, even the criterion standard test for cardiac involvement, which is endomyocardial biopsy, is prone to sampling error, because sarcoidosis tends to be a patchy disease in cardiac tissue.

Other Tests

• Pulmonary function tests (PFTs) and a carbon monoxide diffusion capacity test of the lungs for carbon monoxide (DLCO) may be performed.
• • They are used routinely in evaluation and follow-up.
  • The most common abnormality is an isolated decrease in DLCO.
  • A restrictive pattern is seen in patients with more advanced pulmonary disease.
  • Approximately 15-20% of patients have obstruction.
• Cardiopulmonary exercise testing is a sensitive test for identifying and quantifying the extent of pulmonary involvement. Cardiopulmonary exercise testing also may suggest cardiac involvement that otherwise is not evident.
• In accordance with the position statement of the American Thoracic Society, all patients should have an annual ECG. If patients report palpitations, this should prompt a through evaluation with at least a Holter monitor.

Procedures

• Diagnosis requires biopsy in most cases.
• Some asymptomatic patients who do not require treatment and only have BHL may be monitored without a biopsy.
• Transbronchial biopsy (TBB) via fiberoptic bronchoscope is often done.
• • The yield is high.
  • Results may be positive, even in the setting of normal CXR findings.
• Endobronchial biopsy is done during bronchoscopy and increases the yield of the procedure.
• If therapy is to be given for sarcoidosis, tissue confirmation is essential. Watchful waiting is indicated only for patients who exhibit a classic presentation, are asymptomatic, and can ensure close follow-up.

Histologic Findings

The central histologic finding is the presence of NCGs with special stains negative for fungus and mycobacteria.

TREATMENT

Section 6 of 11  

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Medical Care

Few reliable studies on disease indications and optimal treatment exist. Most patients (>75%) require only symptomatic therapy (nonsteroidal anti-inflammatory drugs). Approximately 10% of patients need treatment for extrapulmonary disease, while 15% of patients require treatment for persistent pulmonary disease.

• Corticosteroids are the mainstay of therapy.
• • Generally, prednisone given daily and then tapered over a 6-month course is adequate for pulmonary disease. Earlier recommendations suggested an initial dose of 1 mg/kg/d of prednisone; however, more recent expert opinions endorse a lower dose (eg, 40 mg/d), which is tapered to every other day long-term therapy over several weeks. Most patients who require long-term steroids can be treated using 10-15 mg of prednisone every other day.
  • Data suggest that corticosteroid use may be associated with increased relapse rates.
  • Occasionally, certain patients cannot tolerate or do not respond to corticosteroids.
  • High-dose inhaled corticosteroids may be an option, but conclusive data are lacking.
• Noncorticosteroid agents are being used more frequently. Common indications for the initiation of such agents include steroid-resistant disease, intolerable adverse effects, or patient desire not to take corticosteroids.
• • Methotrexate (MTX) has been a successful alternative to prednisone and is a steroid-sparing agent.⁴
  • Chloroquine and hydroxychloroquine are antimalarial drugs with immunomodulating properties, which have been used for cutaneous lesions, hypercalcemia, neurological sarcoidosis, and bone lesions. Chloroquine has also been shown to be efficacious for the treatment and maintenance of chronic pulmonary sarcoidosis.^{5, 6}
  • Cyclophosphamide has been rarely used with modest success as a steroid-sparing treatment in patients with refractory sarcoidosis.^{7, 8}
  • Azathioprine is another second-line therapy, which is best used as a steroid-sparing agent rather than as a single-drug treatment for sarcoidosis.⁹
  • Chlorambucil is an alkylating agent that may be beneficial in patients with progressive disease unresponsive to corticosteroids or when corticosteroids are contraindicated.¹⁰
  • Cyclosporine is a fungal cyclic polypeptide with lymphocyte-suppressive properties that may be of limited benefit in skin sarcoidosis or in progressive sarcoid resistant to conventional therapy.¹¹
  • Infliximab^{2, 3} and thalidomide¹² have been used for refractory sarcoidosis, particularly for cutaneous disease. Infliximab appears to be an effective treatment for patients with systemic manifestations such as lupus pernio, uveitis, hepatic sarcoidosis, and neurosarcoidosis.
  • Tetracyclines have shown promise for the treatment of cutaneous sarcoidosis.¹³
• For pulmonary disease, asymptomatic PFT and/or CXR abnormalities are not an indication for treatment. In patients with minimal symptoms, serial reevaluation is prudent. Significant respiratory symptoms associated with PFT and CXR abnormalities likely require therapy. For such patients, treatment is indicated if objective evidence of recent deterioration in lung function exists. Corticosteroids can result in small improvements in the functional vital capacity and in the radiographic appearance in patients with more severe stage II and III disease.
• One recent study demonstrated an approach that may minimize the use of corticosteroids without harming the patient. This is accomplished by withholding therapy unless the patient shows at least a 15% decline in one spirometric measure associated with increasing symptoms or, if asymptomatic, withholding therapy unless the patient shows worsening PFTs and a change in CXR.
• For extrapulmonary sarcoidosis involving such critical organs as the heart, liver, eyes, kidneys, or central nervous system, corticosteroid therapy is indicated.
• Topical corticosteroids are effective for ocular disease.
• Inhaled corticosteroids are occasionally used, in particular in patients with endobronchial disease.

Surgical Care

For patients with advanced sarcoid-induced pulmonary fibrosis, lung transplantation remains the only hope for long-term survival.

Lung transplantation is a viable option for patients with stage IV sarcoidosis. Transplantation in such patients should be strongly considered when the forced vital capacity falls below 50% predicted and/or the forced expiratory volume in 1 second falls below 40% predicted.¹⁴

MEDICATION

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Because medical treatment focuses on anti-inflammatory therapies, corticosteroids remain the foundation of treatment.

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs are indicated for the treatment of arthralgias and other rheumatic complaints. Patients with stage I sarcoidosis often require only occasional treatment with NSAIDs.

Drug Category: Corticosteroids

The cornerstone of therapy; have potent immunologic effects that ameliorate many signs and symptoms.

Drug Category: Antimetabolites

Given the adverse side-effect profile of corticosteroids, methotrexate has recently received significant attention as either a corticosteroid alternative or a corticosteroid-sparing agent.

Drug Category: Antimalarial agents

Previously employed for the treatment of rheumatoid arthritis. Literature supporting its use in sarcoidosis is limited to case series. Has a relatively benign side-effect profile.

FOLLOW-UP

Section 8 of 11  

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Further Inpatient Care

• Monitor pulmonary function and CXR every 6-12 months.
• Assess for progression or resolution.
• Determine if previously uninvolved organs have become affected.

Further Outpatient Care

• Annual slit lamp eye examination and ECG are recommended.

Prognosis

Many patients do not require therapy, and their conditions will spontaneously improve. Markers for a poor prognosis include advanced CXR stage, extrapulmonary disease (predominantly cardiac and neurologic), and evidence of pulmonary hypertension. Multiple studies have demonstrated that the most important marker for prognosis is the initial CXR stage (see Table 2).

Table 1. Prognosis

Although corticosteroids are used for symptom relief and remain the mainstay of therapy, their efficacy in this disease is unclear. A meta-analysis suggests that corticosteroids have little impact on sarcoidosis. However, prior studies have been hampered by their uncontrolled nature, small sample size, and the variable natural history of the disease. Since many patients' conditions improve spontaneously, showing a true benefit to therapy requires a careful control arm.

The best study addressing corticosteroids was the recently completed multicenter trial from Britain sponsored by the British Thoracic Society. In this nonrandomized study, 55 patients were selectively observed or treated with corticosteroids. Additionally, patients who were felt to have an immediate indication for steroids were treated an observed. The trial required a 6-month run-in period to exclude patients who improved spontaneously. At the end of the trial, the groups treated with long-term steroids fared better on some measures than did the patients who were observed and treated with short bursts of steroids (see the table below for greater detail).

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Failure to assume the diagnosis of sarcoidosis if lymphoma is a clinical concern

MULTIMEDIA

Section 10 of 11  

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• Multimedia
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Media file 1:  Stage I sarcoidosis.
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Media type:  X-RAY

Media file 2:  Stage II sarcoidosis.
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Media type:  X-RAY

Media file 3:  Stage III sarcoidosis.
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Media type:  X-RAY

Media file 4:  Noncaseating granuloma.
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Media type:  Photo

REFERENCES

Section 11 of 11

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1. Zabel P, Entzian P, Dalhoff K, Schlaak M. Pentoxifylline in treatment of sarcoidosis. Am J Respir Crit Care Med. May 1997;155(5):1665-9. [Medline].
2. Doty JD, Mazur JE, Judson MA. Treatment of sarcoidosis with infliximab. Chest. Mar 2005;127(3):1064-71. [Medline].
3. Yee AM, Pochapin MB. Treatment of complicated sarcoidosis with infliximab anti-tumor necrosis factor-alpha therapy. Ann Intern Med. Jul 3 2001;135(1):27-31. [Medline].
4. Lower EE, Baughman RP. Prolonged use of methotrexate for sarcoidosis. Arch Intern Med. 1995;155:846-851. [Medline].
5. Baltzan M, Mehta S, Kirkham TH, Cosio MG. Randomized trial of prolonged chloroquine therapy in advanced pulmonary sarcoidosis. Am J Respir Crit Care Med. Jul 1999;160(1):192-7. [Medline].
6. Zic JA, Horowitz DH, Arzubiaga C, King LE Jr. Treatment of cutaneous sarcoidosis with chloroquine. Review of the literature. Arch Dermatol. Jul 1991;127(7):1034-40. [Medline].
7. Demeter SL. Myocardial sarcoidosis unresponsive to steroids. Treatment with cyclophosphamide. Chest. July 1988;94:202-3. [Medline].
8. Doty JD, Mazur JE, Judson MA. Treatment of corticosteroid-resistant neurosarcoidosis with a short-course cyclophosphamide regimen. Chest. Nov 2003;124(5):2023-6. [Medline].
9. Müller-Quernheim J, Kienast K, Held M, Pfeifer S, Costabel U. Treatment of chronic sarcoidosis with an azathioprine/prednisolone regimen. Eur Respir J. Nov 1999;14(5):1117-22. [Medline].
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11. York EL, Kovithavongs T, Man SF, Rebuck AS, Sproule BJ. Cyclosporine and chronic sarcoidosis. Chest. Oct 1990;98(4):1026-9. [Medline].
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13. Bachelez H, Senet P, Cadranel J, Kaoukhov A, Dubertret L. The use of tetracyclines for the treatment of sarcoidosis. Arch Dermatol. Jan 2001;137(1):69-73. [Medline].
14. Nathan SD. Lung transplantation: disease-specific considerations for referral. Chest. Mar 2005;127(3):1006-16. [Medline].
15. Alberts C, van der Mark TW, Jansen HM. Inhaled budesonide in pulmonary sarcoidosis: a double-blind, placebo-controlled study. Dutch Study Group on Pulmonary Sarcoidosis. Eur Respir J. May 1995;8(5):682-8. [Medline].
16. Baughman RP, Iannuzzi MC, Lower EE, Moller DR, Balkissoon RC, Winget DB, et al. Use of fluticasone in acute symptomatic pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. Oct 2002;19(3):198-204. [Medline].
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18. Devaney K, Goodman ZD, Epstein MS, Zimmerman HJ, Ishak KG. Hepatic sarcoidosis. Clinicopathologic features in 100 patients. Am J Surg Pathol. Dec 1993;17(12):1272-80. [Medline].
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20. Hunninghake GW. Goal of the treatment for sarcoidosis. Minimize harm for the patient. Am J Respir Crit Care Med. Nov 1997;156(5):1369-70. [Medline].
21. Hunninghake GW, Gilbert S, Pueringer R, Dayton C, Floerchinger C, Helmers R, et al. Outcome of the treatment for sarcoidosis. Am J Respir Crit Care Med. Apr 1994;149(4 Pt 1):893-8. [Medline].
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Article Last Updated: Jul 25, 2008