Sarcoidosis

Updated: Feb 09, 2017
  • Author: Nader Kamangar, MD, FACP, FCCP, FCCM; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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Overview

Practice Essentials

Sarcoidosis is a multisystem inflammatory disease of unknown etiology that manifests as noncaseating granulomas, predominantly in the lungs and intrathoracic lymph nodes. The age-adjusted incidence is 11 cases per 100,000 population in whites but 34 cases per 100,000 population in African Americans. 

Signs and symptoms

The presentation in sarcoidosis varies with the extent and severity of organ involvement, as follows:

  • Asymptomatic (incidentally detected on chest imaging): Approximately 5% of cases
  • Systemic complaints (fever, anorexia): 45% of cases
  • Pulmonary complaints (dyspnea on exertion, cough, chest pain, and hemoptysis [rare]): 50% of cases
  • Löfgren syndrome (fever, bilateral hilar lymphadenopathy, and polyarthralgias): Common in Scandinavian patients, but uncommon in African-American and Japanese patients

Pulmonary findings on physical examination are as follows:

  • Usually normal
  • Crackles may be audible
  • Exertional oxygen desaturation may be present

Dermatologic manifestations may include the following:

  • Erythema nodosum
  • A lower-extremity panniculitis with painful, erythematous nodules (often with Löfgren syndrome)
  • Lupus pernio (the most specific associated cutaneous lesion)
  • Violaceous rash on the cheeks or nose (common)
  • Maculopapular plaques (uncommon)

Ocular involvement, which may lead to blindness if untreated, may manifest as follows:

  • Anterior or posterior granulomatous uveitis (most frequent)
  • Conjunctival lesions and scleral plaques

Other possible manifestations are as follows:

  • Osseous involvement
  • Heart failure from cardiomyopathy (rare)
  • Heart block and sudden death
  • Lymphocytic meningitis (rare)
  • Cranial nerve palsies and hypothalamic/pituitary dysfunction (rare)

See Clinical Presentation for more detail.

Diagnosis

Imaging studies for sarcoidosis are as follows:

  • Chest radiography: Central to the evaluation
  • Routine chest computed tomography (CT): Adds little to radiography
  • High-resolution CT (HRCT) scanning of the chest: May be helpful; identifies active alveolitis versus fibrosis, and findings correlate with biopsy yield
  • Gallium scans: Used infrequently; has low sensitivity and specificity, but may be helpful when the clinical picture remains confusing despite histologic evidence of noncaseating granulomas (eg, differentiating chronic hypersensitivity pneumonitis from sarcoidosis)

Staging of sarcoidosis is as follows:

  • Stage 0: Normal chest radiographic findings
  • Stage I: Bilateral hilar lymphadenopathy
  • Stage II: Bilateral hilar lymphadenopathy and infiltrates
  • Stage III: Infiltrates alone
  • Stage IV: Fibrosis

Pulmonary function tests and a carbon monoxide diffusion capacity test of the lungs for carbon monoxide (DLCO) are used routinely in evaluation and follow-up. Possible findings are as follows:

  • An isolated decrease in DLCO is the most common abnormality
  • 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. Impaired heart rate recovery during the first minute following exercise has been shown to be an independent predictor for cardiovascular and all-cause mortality, [1] and it may identify patients who are at high risk for ventricular arrhythmias and sudden death. [2]

All patients with sarcoidosis should have an annual electrocardiogram. Patients who report palpitations should have a thorough evaluation with at least Holter monitoring.

Diagnosis requires biopsy in most cases. Endobronchial biopsy via bronchoscopy is often done. The yield is high; results may be positive even in patients with normal chest radiographs. The central histologic finding is the presence of noncaseating granulomas with special stains negative for fungus and mycobacteria.

Routine laboratory evaluation is often unrevealing, but possible abnormalities include the following:

  • Hypercalcemia (about 10-13% of patients)
  • Hypercalciuria (about a third of patients)
  • Elevated alkaline phosphatase level
  • Elevated angiotensin-converting enzyme (ACE) levels

See Workup for more detail.

Management

Nonsteroidal anti-inflammatory drugs (NSAIDs) are indicated for the treatment of arthralgias and other rheumatic complaints. Patients with stage I sarcoidosis often require only occasional treatment with NSAIDs.

Treatment in patients with pulmonary involvement is as follows:

  • Asymptomatic patients may not require treatment
  • In patients with minimal symptoms, serial reevaluation is prudent
  • Treatment is indicated for patients with significant respiratory symptoms
  • Corticosteroids can produce small improvements in the functional vital capacity and in the radiographic appearance in patients with more severe stage II and III disease

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. For pulmonary disease, prednisone is generally given daily and then tapered over a 6-month course. High-dose inhaled corticosteroids may be an option, particularly in patients with endobronchial disease

Common indications for noncorticosteroid agents include the following:

  • Steroid-resistant disease
  • Intolerable adverse effects of steroids
  • Patient desire not to take corticosteroids

Noncorticosteroid agents include the following:

  • Methotrexate (MTX) has been a successful alternative to prednisone
  • Chloroquine and hydroxychloroquine have been used for cutaneous lesions, hypercalcemia, neurologic sarcoidosis, and bone lesions
  • Chloroquine has been found effective for acute and maintenance treatment of chronic pulmonary sarcoidosis [3, 4]
  • Cyclophosphamide has been rarely used with modest success as a steroid-sparing treatment in patients with refractory sarcoidosis [5, 6]
  • Azathioprine is best used as a steroid-sparing agent [7]
  • Chlorambucil may be beneficial in patients with progressive disease unresponsive to corticosteroids or when corticosteroids are contraindicated [8]
  • Cyclosporine may be of limited benefit in skin sarcoidosis or in progressive sarcoid resistant to conventional therapy [9]
  • Infliximab [10, 11] and thalidomide [12, 13] have been used for refractory sarcoidosis, particularly for cutaneous disease, as well as for the long-term management of extrapulmonary sarcoidosis [14]
  • Infliximab appears to be an effective treatment for patients with systemic manifestations such as lupus pernio, uveitis, hepatic sarcoidosis, and neurosarcoidosis

For patients with advanced pulmonary fibrosis from sarcoidosis, lung transplantation remains the only hope for long-term survival. Indications for transplantation include either or both of the following [15] :

  • Forced vital capacity below 50% predicted
  • Forced expiratory volume in 1 second below 40% predicted

See Treatment and Medication for more detail.

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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. It is characterized by a seemingly exaggerated immune response against a difficult–to-discern antigen. [16]

Related Medscape articles include Acute Complications of Sarcoidosis, Dermatologic Manifestations of Sarcoidosis, and Ophthalmic Manifestations of Sarcoidosis.

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Pathophysiology

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 manifest clinically by an inverted CD4/CD8 ratio. Pulmonary sarcoidosis is frequently characterized by a CD4+/CD8+ ratio of at least 3.5 in bronchoalveolar lavage fluid (BALF), although up to 40% of the cases present a normal or even decreased ratio, thus limiting its diagnostic value. [17] Increased production of TH1 cytokines, such as interferon, is also a feature.

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 pentoxifylline [18] and infliximab, [10, 11] 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.

Soluble HLA class I antigens levels in serum and BALF are higher in patients with sarcoidosis. These levels tend to be significantly higher in active than in inactive stages and correlate with angiotensin-converting enzyme (ACE) levels. [19]

Active sarcoidosis has also been associated with plasmatic hypergammaglobulinemia. [20] B-cell accumulation has been shown in pulmonary lesions, and a beneficial effect with anti-CD20 monoclonal antibody therapy has been reported in select patients.

Glycoprotein KL-6 and surfactant protein D (SP-D) derived from alveolar type II cells and bronchiolar epithelial cells are significantly increased in pulmonary sarcoidosis and correlate with the percentage of lymphocytes in BALF, reflecting an inflammatory response in sarcoidosis. However, there is no significant correlation between KL-6 or SP-D levels and chest radiography findings, ACE levels, or CD4/CD8 ratio in BALF. [21] KL-6 has been shown to be predictive of increased pulmonary parenchymal infiltration. [22]

A study by Facco et al suggests that Th17 cells may play a role in the pathogenesis and progression of sarcoidosis; these cells were noted to be present in the blood, BALF samples, and lung tissue from patients with sarcoidosis, particularly in those with the active form of the disease. [23]

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Epidemiology

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. African Americans seem to experience more severe and chronic disease. [24] In African Americans, siblings and parents of sarcoidosis cases have about a 2.5-fold increased risk for developing the disease.

Working on the World Trade Center (WTC) debris pile after the September 11, 2001 terrorist attacks was associated with sarcoidosis [25] (odds ratio, 9.1; 95% confidence interval, 1.1-74.0), but WTC dust cloud exposure was not (odds ratio, 1.0; 95% confidence interval, 0.4-2.8).

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.

Race

See Frequency, United States and Mortality/Morbidity.

Sex

Male-to-female ratio is approximately 1:2. Morbidity, mortality, and extrapulmonary involvement are higher in affected females. [26]

Age

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

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Prognosis

Many patients do not require therapy, and their conditions spontaneously improve. Markers for a poor prognosis include advanced chest radiography 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 chest radiography stage (see Table 2 below).

In one study of patients with radiographic stage IV sarcoidosis, during an average follow-up of 7 years, pulmonary hypertension was observed in 30% of cases. Long-term oxygen therapy was required in 12%. Survival was 84% at 10 yrs. Cause of death in 11% patients included refractory pulmonary hypertension, acute and chronic respiratory insufficiency, and heart sarcoidosis. Seventy-five percent of fatalities are directly attributable to respiratory causes. [27]

Table 1. Prognosis (Open Table in a new window)

Stage Remission (%) Asymptomatic at 5 y (%) Chest Radiograph Clearing (%) Mortality (%)
Stage I 60-90 95 54 0
Stage II 40-70 58 31 11
Stage III 10-20 25 10 18
Stage IV 0 N/A 0 N/A

Data regarding mortality from sarcoidosis are scant. In the United States, deaths tend to result from 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 stage.

According to a study by Swigris et al, the rate of sarcoidosis-related mortality in the United States appears to have increased significantly from 1988-2007, particularly in black females aged 55 years or older. This study also confirmed findings from prior reports, indicating that the underlying cause of death in most patients with sarcoidosis was the disease itself. [28]

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