Sarcoidosis 

Updated: Jun 20, 2019
Author: Nader Kamangar, MD, FACP, FCCP, FCCM; Chief Editor: Zab Mosenifar, MD, FACP, FCCP 

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 such 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.

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.

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]

Etiology

The cause of the disease is not known; however, both genetic and environmental factors seem to play a role.[24] 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.

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.[25] 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[26] (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.[27]

Age

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

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.[28]

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.[29]

 

Presentation

History

Presentation depends on the extent and severity of the organ involved. Approximately 5% of cases are asymptomatic and incidentally detected by chest radiography. Systemic complaints of fever, anorexia, and arthralgias occur in 45% of cases. Pulmonary complaints — 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. Although common in Scandinavian patients, it is uncommon in African-American and Japanese patients.

Physical Examination

Pulmonary findings

They are usually normal but may be significant for crackles. Exertional oxygen desaturation may also be found.

Chest radiography staging system

Stage 0 is normal chest radiography findings.

Stage I is bilateral hilar lymphadenopathy (BHL). See the image below.

Stage I sarcoidosis. Stage I sarcoidosis.

Stage II is BHL and infiltrates. See the image below.

Stage II sarcoidosis. Stage II sarcoidosis.

Stage III is infiltrates alone. See the image below.

Stage III sarcoidosis. Stage III sarcoidosis.

Stage IV is fibrosis.

Ocular manifestations

About 30-60% of sarcoidosis patients develop intraocular inflammatory signs, and bilateral granulomatous uveitis is the most common presentation.[30]

CD4/CD8 ratio of vitreous-infiltrating lymphocytes has high diagnostic value in ocular sarcoidosis, comparable to that of the CD4/CD8 ratio in bronchoalveolar lavage fluid (BALF) lymphocytosis for pulmonary sarcoidosis.[31]

International criteria for the diagnosis of ocular sarcoidosis have been determined from the results of the first International Workshop On Ocular Sarcoidosis.[32] Four levels of certainty for the diagnosis of ocular sarcoidosis (diagnostic criteria) are recommended in patients in whom other possible causes of uveitis had been excluded. Criteria are as follows:

  • Biopsy-supported diagnosis with a compatible uveitis was labeled as definite ocular sarcoidosis

  • If biopsy was not performed but chest the radiograph was positive, showing bilateral hilar lymphadenopathy (BHL) associated with a compatible uveitis, the condition was labeled as presumed ocular sarcoidosis

  • If biopsy was not performed and the chest radiograph did not show BHL but there were 3 intraocular signs and 2 positive laboratory tests, the condition was labeled as probable ocular sarcoidosis

  • If lung biopsy was performed and the result was negative but at least 4 signs and 2 positive laboratory investigations were present, the condition was labeled as possible ocular sarcoidosis

The consensus conference identified the following 7 signs in the diagnosis of intraocular sarcoidosis[33] :

  • Mutton-fat keratic precipitates (KPs)/small granulomatous KPs and/or iris nodules (Koeppe/Busacca)

  • Trabecular meshwork (TM) nodules and/or tent-shaped peripheral anterior synechiae (PAS)

  • Vitreous opacities displaying snowballs/strings of pearls

  • Multiple chorioretinal peripheral lesions (active and/or atrophic)

  • Nodular and/or segmental peri-phlebitis (+/- candlewax drippings) and/or retinal macroaneurysm in an inflamed eye

  • Optic disc nodule(s)/granuloma(s) and/or solitary choroidal nodule

  • Bilaterality

The laboratory investigations or investigational procedures judged to provide value in the diagnosis of ocular sarcoidosis in patients having the above intraocular signs included the following[33] :

  • Negative tuberculin skin test in a BCG-vaccinated patient or in a patient having had a positive tuberculin skin test previously

  • Elevated serum angiotensin-converting enzyme (ACE) levels and/or elevated serum lysozyme

  • Chest radiograph revealing BHL

  • Abnormal liver enzyme tests

  • Chest CT scan in patients with a negative chest radiograph result

Ocular involvement may lead to blindness if untreated.

Cardiac manifestations

Heart block and sudden death may occur.

The incidence rate of ventricular tachyarrhythmias requiring implantable cardioverter-defibrillator therapy is estimated to be 15% per year in those patients with cardiac involvement. Prophylactic implantable cardioverter-defibrillator implantation should be considered in patients with cardiac sarcoidosis.[34] Corticosteroid therapy may be effective for ventricular arrhythmias in the early stage, but it is less effective in the late stage.[35]

In one study, 90.4% of ECGs in cardiac sarcoidosis patients contained at least fragmented QRS or a bundle-branch block (specificity 0.633), compared with 36.7% of noncardiac cardiac sarcoidosis patients (P< .01). If patients with sarcoidosis have these ECG findings, further workup is indicated. The Japanese Ministry of Health and Welfare has used a right bundle-branch block and advanced A-V block as 2 of the clinical diagnostic criteria used for diagnosis of cardiac sarcoidosis.[36]

The diagnosis of cardiac involvement in systemic sarcoidosis has improved with the development of cardiac MRI. Both plasma A-type natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) can be elevated in cardiac sarcoidosis.[37]

Approximately 25% of patients may have noncaseating granulomas (NCGs) at autopsy, but less 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.

Other manifestations

Diabetes insipidus is the most frequently reported endocrine disorder, followed by hyperprolactinemia. Hormonal deficiencies associated with hypothalamic-pituitary sarcoidosis frequently include hypogonadism and diabetes insipidus.[38]

The enzyme 25-hydroxyvitamin D3 1α-hydroxylase (1α-hydroxylase) catalyzes the conversion of 25-hydroxyvitamin D3 to the active hormone calcitriol (1,25-dihydroxyvitamin D3). Under normal circumstances, calcitriol is synthesized in proximal renal tubules. Expression of 1 α-hydroxylase has been demonstrated in purified human alveolar macrophages. In one study, the 1 α-hydroxylase mRNA levels in bronchoalveolar lavage cells were 5-fold higher in sarcoidosis patients than in control patients.[39]

Quality of life, anxiety, and depression in sarcoidosis

Sarcoidosis is associated with fatigue and a high rate of psychiatric comorbidity. In one study, 44% of the subjects met the diagnostic criteria for at least one Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) axis I disorder. Specifically, 25% of subjects met the criteria for major depressive disorder, 6.3% for panic disorder, 6.3% for bipolar disorder, 5% for generalized anxiety disorder, and 1.3% for obsessive-compulsive disorder.[40]

One double-blind, randomized trial found that the treatment with dexmethylphenidate hydrochloride was associated with a significant improvement in sarcoidosis-associated fatigue.[41]

Complications

Sarcoidosis may initially manifest or be reactivated during or shortly after treatment with antiviral therapy in patients with chronic hepatitis C viral infection.[42]

 

DDx

 

Workup

Laboratory Studies

Serum markers such as serum amyloid A (SAA), soluble interleukin-2 receptor (sIL-2R), lysozyme, angiotensin-converting enzyme (ACE), and the glycoprotein KL-6 have been reported to be markers of sarcoidosis.[43]

Hypercalcemia or hypercalciuria may occur (noncaseating granulomas [NCGs] secrete 1,25 vitamin D). Hypercalcemia is seen in about 10-13% of patients, whereas hypercalciuria is 3 times more common.

Elevated 1, 25-dihydroxyvitamin D levels are associated with protracted treatment in sarcoidosis. In one study, serum 1, 25-dihydroxyvitamin D levels were associated with patients requiring repeated regimens of systemic immunosuppressive therapy or longer than 1 year of therapy. The majority (71%) of the patients with levels higher than 51 pg/mL required long-term immunosuppressive therapy.[44]

An elevated alkaline phosphatase level could suggest hepatic involvement. One study has shown that the severity of liver function test abnormalities is significantly related with the degree of fibrosis and extensiveness of the granulomatous inflammation in sarcoidosis.[45]

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.[46]

Air trapping is a common feature in sarcoidosis that can be supported with imaging studies and correlates with evidence of small airways disease on pulmonary function testing.[47]

Routine chest CT scanning adds little to diagnosis. High-resolution CT (HRCT) scanning of the chest may identify active alveolitis or fibrosis and correlates with yield of biopsy.

Some studies have suggested that whole body F(18)-fluorodeoxyglucose positron emission tomography (FDG-PET) scanning appears to be of additional value to assess inflammatory activity in patients with persistent symptoms in the absence of signs of serological inflammatory activity and to detect extrathoracic lesions.[48] Whole-body FDG-PET scanning is of value in identifying occult and reversible granulomas in patients with sarcoidosis.[49, 50]

Prior to the ease and availability of bronchoscopy, gallium scanning was occasionally used 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 noncaseating granulomas (NCGs) (eg, differentiating chronic hypersensitivity pneumonitis from sarcoidosis).

Other Tests

Pulmonary function tests 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.

Patients with DLCO of less than 60% predicted and oxygen desaturation of less than 90% on the 6-minute walk test have a high likelihood of pulmonary hypertension and should undergo further evaluation for the presence of this disorder.[51] In one study, patients with a saturation of less than 90% during a 6-minute walk test were 12 times more likely to have pulmonary hypertension.[51]

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.

Attenuated heart rate recovery after exercise is thought to be a marker of reduced parasympathetic activity. 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, 52] Considering its prognostic significance, the heart rate recovery index may have clinical use in identifying patients with sarcoidosis who are at high risk for ventricular arrhythmias and sudden death.[2]

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 thorough evaluation.

Procedures

Diagnosis requires biopsy in most cases. 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 with whom one can ensure close follow-up.

Transbronchial biopsy via fiberoptic bronchoscopy has a high diagnostic yield. Results may be positive, even in the setting of normal chest radiography findings.

Standard transbronchial needle aspiration allows successful lymph node sampling in nearly all patients with sarcoidosis and is associated with high diagnostic yield regardless of disease stage.[53]

Endobronchial biopsy is performed during bronchoscopy and increases the yield of the procedure. In a study of 34 subjects, endobronchial biopsy findings were positive in 61.8% of patients with a yield comparable to transbronchial biopsy, which showed nonnecrotizing granulomas in 58.8% of subjects. The addition of endobronchial biopsy increased the yield of fiberoptic bronchoscopy by 20.6%.[54]

At least one study has shown that the diagnostic yield of endobronchial ultrasound-guided transbronchial needle aspiration for stage I and II sarcoidosis is even higher than standard transbronchial lung biopsy.[55]

In at least one study, the CD4/CD8 ratio and tumor necrosis factor (TNF)–α levels in induced sputum correlated with those in bronchoalveolar lavage fluid (BALF) and paralleled changes with treatment. Induced sputum may therefore be a surrogate for BALF for certain markers in patients with sarcoidosis.[56] In another study, the differential cell count in BALF demonstrated a significantly lower percentage of neutrophils and a significantly higher percentage of macrophages than in induced sputum. The profiles of T-cell subsets, however, showed the same pattern in both groups. A CD4/CD8 ratio of 2.5 or greater had a sensitivity of 100% and a specificity of 81.2%, with a positive predictive value of 81.2%, to distinguish sarcoidosis from nongranulomatous interstitial lung diseases.[57]

Histologic Findings

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

 

Treatment

Medical Care

Most patients (>75%) require only symptomatic therapy with NSAIDs. Approximately 10% of patients need treatment for extrapulmonary disease, while 15% of patients require treatment for persistent pulmonary disease.

Steroid treatment

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. In one study, treatment of acute exacerbations of pulmonary sarcoidosis with steroid doses as low as 20 mg of prednisone for a median of 21 days improved spirometry back to baseline and improved clinical symptoms.[58] Most patients who require long-term steroids can be treated using 10-15 mg of prednisone every other day.

Some data suggest that corticosteroid use may be associated with increased relapse rates. However, data suggest early treatment of stage II sarcoidosis with oral prednisolone for 3 months followed by inhaled budesonide for 15 months improves 5-year pulmonary function and reduces the need for future steroid treatment.[59]

High-dose inhaled corticosteroids may be an option, but conclusive data are lacking. Inhaled corticosteroids, in particular, can be used in patients with endobronchial disease.

Although corticosteroids are used for symptom relief and remain the mainstay of therapy, their efficacy in this disease is unclear. Since many patients' conditions improve spontaneously, showing a true benefit to therapy requires a careful control arm.

The best study addressing corticosteroids was the 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 thought to have an immediate indication for steroids were treated. 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 Table 1 below for detail).

Table 2. Results of Multicenter Trial Sponsored by the British Thoracic Society (Open Table in a new window)

Characteristics

Group La

Group Sb

P

Dyspnea score (range 1-4)

0.24

0.47

NS

Fibrosis score (range 0-16)

0.83

1.47

NS

FEV1c (% predicted)

95.9

86.9

0.05

VCd (% predicted)

99.8

90.8

0.02

DLCOe (% predicted)

84.3

77.7

NS

Weight gain (kg)

+3.26

+0.99

0.02

a Long-term steroids.

b Short bursts of steroids.

c Forced expiratory volume in 1 second.

d Ventilatory capacity.

e Diffusing capacity of lung for carbon monoxide.

Acthar gel (repository corticotropin injection) was used to treat pulmonary sarcoidosis in the 1950s. It was abandoned because of cost and toxicity compared with prednisone. More recently, it has been suggested as an alternative in patients who are on high-dose prednisone.[60, 61]

Nonsteroid treatment

Noncorticosteroid agents are being increasingly tried. 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.[62]

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.[3, 4]

Cyclophosphamide has been rarely used with modest success as a steroid-sparing treatment in patients with refractory sarcoidosis.[5, 6]

Azathioprine is another second-line therapy, which is best used as a steroid-sparing agent rather than as a single-drug treatment for sarcoidosis.[7]

Chlorambucil is an alkylating agent that may be beneficial in patients with progressive disease unresponsive to corticosteroids.[8]

Cyclosporine is a fungal cyclic polypeptide with lymphocyte-suppressive properties and may be of limited benefit in skin sarcoidosis or in progressive sarcoidosis resistant to conventional therapy.[9]

Infliximab[10, 11] and thalidomide[12, 13] have also 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.

In addition, long-term treatment with infliximab can be effective for extrapulmonary sarcoidosis, according to a retrospective study of 26 patients with biopsy-proven sarcoidosis.[14] In the study, sustained resolution or improvement occurred in 58.5% of organs, but disease activity progressed in 5.7% despite treatment. In 57.7% of patients, there were adverse events during an average duration of therapy of 46.2 months.[14] Improvement in pulmonary imaging findings was observed in patients with pulmonary sarcoid after initiation of infliximab treatment, but results at post-treatment were inconclusive. Infliximab treatment was well tolerated.[14]

Callejas-Rubio et al reported inconsistent results with tumor necrosis factor (TNF)–inhibitor therapy.[63] However, at least one study has shown treatment with adalimumab can reduce disease activity, as assessed by fluorodeoxyglucose positron emission tomography (FDG-PET) scanning.[64] Adalimumab has also been used successfully in sarcoidosis patients with refractory chronic noninfectious uveitis.[65]

Nontreatment and other issues

For pulmonary disease, asymptomatic pulmonary function testing and/or chest radiography abnormalities are not an indication for treatment. In patients with minimal symptoms, serial reevaluation is prudent. Significant respiratory symptoms associated with pulmonary function test and chest radiograph abnormalities likely require therapy. For such patients, treatment is indicated if objective evidence of recent deterioration in lung function exists. As mentioned above, corticosteroids can result in improvements in the functional vital capacity and in the radiographic appearance in patients with more severe stage II and III disease.

One 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 pulmonary function test results and a change in the chest radiograph.

For extrapulmonary sarcoidosis involving such critical organs as the heart, liver, eyes, kidneys, or central nervous system, medical intervention is indicated.

Topical corticosteroids are effective for ocular disease.

Surgical Care

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.[15] Patients with advanced sarcoidosis awaiting lung transplantation have a high mortality rate with a median survival of less than 2 years. Mortality is most closely linked to elevated right atrial pressure. In one retrospective cohort study, survival after transplantation determined by the Kaplan-Meier method was 62% at both 1 and 2 years, and a mere 50% at 3 years.[66]

Long-Term Monitoring

Monitor pulmonary function and chest radiography every 6-12 months.

Assess for progression or resolution.

Determine if previously uninvolved organs have become affected.

Annual slit-lamp eye examination and ECG are recommended.

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Class Summary

NSAIDs are indicated for arthralgias and other rheumatic complaints and not for significant pulmonary disease. Patients with stage I sarcoidosis require only occasional treatment with NSAIDs.

Naproxen (Aleve, Anaprox, Naprelan, Naprosyn)

Naproxen is used for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.

Flurbiprofen

Flurbiprofen may inhibit cyclo-oxygenase, which, in turn, inhibits prostaglandin biosynthesis. These effects may result in analgesic, antipyretic, and anti-inflammatory activities.

Ibuprofen (Motrin, Ibuprin, Advil, Addaprin, Neoprofen)

Ibuprofen and other NSAIDs are useful in the management of joint complaints. It inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.

Ketoprofen

Ketoprofen is indicated for relief of mild to moderate pain and inflammation. Small initial dosages are indicated in small and elderly patients and in those with renal or liver disease. It inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.

Indomethacin (Indocin)

Indomethacin inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis. It is rapidly absorbed and metabolism occurs in the liver by demethylation, deacetylation, and glucuronide conjugation.

Corticosteroids

Class Summary

Corticosteroids are the cornerstone of therapy. They have potent immunologic effects that ameliorate many signs and symptoms.

Prednisone (Rayos)

Prednisone is an immunosuppressant used for the treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocytes and antibody production. The response may be rapid but often is seen over 12-16 weeks.

Antimetabolites

Class Summary

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

Methotrexate (Folex PFS, Rheumatrex, Otrexup)

Methotrexate is an antimetabolite that interferes with folate metabolism. It is cell cycle specific. Actively proliferating cells are more susceptible to its effects.

Antimalarial agents

Class Summary

Antimalarial agents have previously been used for the treatment of rheumatoid arthritis. Literature supporting its use in sarcoidosis is limited to case series. They have a relatively benign adverse effect profile.

Hydroxychloroquine (Plaquenil)

Hydroxychloroquine may be most useful in the management of osseous involvement. It inhibits chemotaxis of eosinophils and locomotion of neutrophils and impairs complement-dependent antigen-antibody reactions.

Immunosuppressants

Class Summary

These agents may be of benefit in patients whose conditions have not responded to steroids or in patients unable to tolerate prednisone.

Chlorambucil (Leukeran)

Chlorambucil is a bifunctional slow-acting aromatic nitrogen mustard derivative that interferes with DNA replication, transcription, and nucleic acid function by alkylation. It alkylates and cross-links strands of DNA. Alkylation takes place through the formation of a highly reactive ethylenimonium radical. The probable mode of action involves cross-linkage of the ethylenimonium derivative between two strands of helical DNA and subsequent interference with replication. Chlorambucil is known chemically as 4-[bis(2chlorethyl)amino]benzene butanoic acid.

The dosage must be carefully adjusted according to the response of the patient and must be reduced as soon as an abrupt fall in the white blood cell count occurs.

Azathioprine (Azasan, Imuran)

Azathioprine is an imidazolyl derivative of 6-mercaptopurine. Many of its biological effects are similar to those of the parent compound. Both compounds are eliminated rapidly from blood and are oxidized or methylated in erythrocytes and the liver. No azathioprine or mercaptopurine is detectable in urine 8 hours after it is taken.

Azathioprine antagonizes purine metabolism and inhibits the synthesis of DNA, RNA, and proteins. The mechanism whereby azathioprine affects autoimmune diseases is unknown. It works primarily on T cells. It suppresses hypersensitivities of the cell-mediated type and causes variable alterations in antibody production. Immunosuppressive, delayed hypersensitivity, and cellular cytotoxicity tests are suppressed to a greater degree than antibody responses. It works very slowly; it may require 6-12 months of trial prior to effect. Up to 10% of patients may have idiosyncratic reactions disallowing use. Do not allow the WBC count to drop below 3000/μL or the lymphocyte count to drop below 1000/μL.

Azathioprine is available in a tablet form for oral administration or in 100-mg vials for intravenous injection.

Cyclophosphamide

Cyclophosphamide is a cyclic polypeptide that suppresses some humoral activity. It is chemically related to nitrogen mustards. It is activated in the liver to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none type reaction. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.

Cyclophosphamide is biotransformed by cytochrome P-450 system to hydroxylated intermediates that break down to active phosphoramide mustard and acrolein. The interaction of phosphoramide mustard with DNA is considered cytotoxic.

When used in autoimmune diseases, the mechanism of action is thought to involve immunosuppression due to destruction of immune cells via DNA cross-linking.

In high doses, it affects B cells by inhibiting clonal expansion and suppression of the production of immunoglobulins. With long-term low-dose therapy, it affects T-cell functions.

Cyclosporine (Gengraf, Neoral, Sandimmune)

Cyclosporine is an 11-amino acid cyclic peptide and natural product of fungi. It acts on T-cell replication and activity.

It is a specific modulator of T-cell function and an agent that depresses cell-mediated immune responses by inhibiting helper T-cell function. Preferential and reversible inhibition of T lymphocytes in the G0 or G1 phase of the cell cycle is suggested.

Cyclosporine binds to cyclophilin, an intracellular protein, which, in turn, prevents the formation of interleukin 2 and the subsequent recruitment of activated T cells.

It has about 30% bioavailability, but there is marked interindividual variability. It specifically inhibits T-lymphocyte function with minimal activity against B cells. Maximum suppression of T-lymphocyte proliferation requires that the drug be present during the first 24 hours of antigenic exposure.

Cyclosporine suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease) for a variety of organs.

Infliximab (Remicade)

Infliximab neutralizes cytokine TNF-alpha and inhibits its binding to the TNF-alpha receptor. Mix it in 250 mL of normal saline for infusion over 2 hours. It must be used with a low-protein-binding filter (1.2 micron or less). Infliximab is indicated to reduce the signs and symptoms of active ankylosing spondylitis

Thalidomide (Thalomid)

Thalidomide is an immunomodulatory agent that may suppress excessive production of TNF-alpha and may down-regulate selected cell-surface adhesion molecules involved in leukocyte migration.

 

Questions & Answers

Overview

What is sarcoidosis?

What is the presentation of sarcoidosis?

What pulmonary findings suggest sarcoidosis?

What are the dermatologic manifestations of sarcoidosis?

What are the ocular manifestations of sarcoidosis?

What are the less common manifestations of sarcoidosis?

What imaging studies are performed in the workup of sarcoidosis?

How is sarcoidosis staged?

What is the role of pulmonary function and carbon monoxide diffusion capacity testing in the workup of sarcoidosis?

What is the role of cardiopulmonary exercise testing in the workup of sarcoidosis?

What testing should be done annually for patients with sarcoidosis?

How is sarcoidosis diagnosed?

What is the role of routine lab testing in the workup of sarcoidosis?

What is the indication for NSAIDS in the management of sarcoidosis?

What is the treatment of sarcoidosis in patients with pulmonary involvement?

What is the treatment of extrapulmonary and pulmonary sarcoidosis?

What are indications for noncorticosteroid treatment of sarcoidosis?

What noncorticosteroid agents are used in the treatment of sarcoidosis?

When is lung transplantation indicated in the treatment of sarcoidosis?

What is sarcoidosis?

What is the pathogenesis of sarcoidosis?

Which antigen levels are higher in patients with sarcoidosis?

What is the role of plasmatic hypergammaglobulinemia in the pathophysiology of sarcoidosis?

What is the role of glycoprotein KL-6 and surfactant protein D (SP-D) in the pathophysiology of pulmonary sarcoidosis?

What is the role of Th17 cells in the pathogenesis of sarcoidosis?

What causes sarcoidosis?

What is the incidence of sarcoidosis in the US?

What is the global incidence of sarcoidosis?

Is sarcoidosis more common in males or females?

How does the incidence of sarcoidosis vary among age groups?

What is the prognosis of sarcoidosis?

What are the causes of mortality in sarcoidosis?

What is the incidence of functional impairment in patients with sarcoidosis?

What is the likelihood of regression for pulmonary disease in sarcoidosis?

What is the underlying cause of sarcoidosis-related mortality in the US?

Presentation

What are the symptoms of Löfgren syndrome in patients with sarcoidosis?

What are the variable presentations of sarcoidosis?

What are pulmonary findings suggestive of sarcoidosis?

How is sarcoidosis staged?

How common are intraocular inflammatory signs in patients with sarcoidosis?

Which findings are diagnostic for ocular sarcoidosis?

What are the IWOS diagnostic criteria for ocular sarcoidosis?

What are the 7 signs of intraocular sarcoidosis?

What is the possible outcome of untreated ocular sarcoidosis?

What are the cardiac symptoms of sarcoidosis?

What is the role of cardiac MRI in the diagnosis of sarcoidosis?

How common is the finding of noncaseating granulomas (NCGs) in patients with cardiac sarcoidosis?

What are the neurologic symptoms of sarcoidosis?

What are the endocrine manifestations of sarcoidosis?

What are the possible psychiatric comorbidities of sarcoidosis?

Which disorder is known to reactivate sarcoidosis?

DDX

What are the differential diagnoses for Sarcoidosis?

Workup

What is the role of serum markers in the workup of sarcoidosis?

How common are hypercalcemia and hypercalciuria in patients with sarcoidosis?

What is the significance of elevated serum 1, 25-dihydroxyvitamin D levels in patients with sarcoidosis?

Which lab finding suggests hepatic involvement in sarcoidosis?

What is the role of angiotensin-converting enzyme (ACE) measurement in the workup of sarcoidosis?

What is the role of imaging studies in the workup of sarcoidosis?

What is the significance of a finding of air trapping in the workup of sarcoidosis?

What is the role of CT scanning in the workup of sarcoidosis?

What is the role of FDG-PET scanning in the workup of sarcoidosis?

What is the role of gallium scanning in the workup of sarcoidosis?

What is the role of pulmonary function and carbon monoxide diffusion capacity testing in the workup of sarcoidosis?

Which patients with sarcoidosis have an increased risk for pulmonary hypertension?

What is the role of cardiopulmonary exercise testing in the workup of sarcoidosis?

What is the role of the heart rate recovery index in the workup of sarcoidosis?

What is the ATS recommendation for ECG screening in patients with sarcoidosis?

Which procedure is performed in the workup of sarcoidosis?

What is the role of transbronchial biopsy in the workup of sarcoidosis?

What is the role of endobronchial biopsy in the workup of sarcoidosis?

What is the diagnostic yield of endobronchial ultrasound-guided transbronchial needle aspiration for sarcoidosis?

What is the role of induced sputum analysis in the workup of sarcoidosis?

Which histologic findings support a diagnosis of sarcoidosis?

Treatment

What are the treatment options for sarcoidosis?

What is the mainstay of therapy for sarcoidosis?

How is steroid therapy administered in the treatment of sarcoidosis?

What is the efficacy of corticosteroids in the treatment of sarcoidosis?

How are inhaled corticosteroids used in the treatment of sarcoidosis?

What is the efficacy of corticosteroids in the treatment of sarcoidosis?

How effective is longer-term corticosteroid treatment vs short-burst therapy?

When is nonsteroidal therapy indicated in the treatment of sarcoidosis?

Which nonsteroidal agents are used in the treatment of sarcoidosis?

What is the role of infliximab in the treatment of extrapulmonary sarcoidosis?

What is the role of tumor necrosis factor (TNF)–inhibitor therapy in the treatment of sarcoidosis?

What are the indications for nontreatment in sarcoidosis?

Which treatment approach is effective in minimizing the use of corticosteroids in patients with sarcoidosis?

What are the indications for medical intervention in extrapulmonary sarcoidosis?

What is the treatment for ocular sarcoidosis?

What is the role of lung transplantation in the treatment of sarcoidosis?

What monitoring is needed for patients with sarcoidosis?

Medications

What are the goals of pharmacotherapy for sarcoidosis?

Which medications in the drug class Immunosuppressants are used in the treatment of Sarcoidosis?

Which medications in the drug class Antimalarial agents are used in the treatment of Sarcoidosis?

Which medications in the drug class Antimetabolites are used in the treatment of Sarcoidosis?

Which medications in the drug class Corticosteroids are used in the treatment of Sarcoidosis?

Which medications in the drug class Nonsteroidal anti-inflammatory drugs (NSAIDs) are used in the treatment of Sarcoidosis?