Chapter 54. Sarcoidosis

• Systemic disease due to noncaseating epithelioid granulomatous inflammation in affected organs.
• Most frequently affected organs are lung, lymph nodes, eyes, skin, joints, liver, muscles, central and peripheral nervous system, upper airway, heart, and kidneys.
• Clinically apparent organ involvement is typically restricted to a few organs, usually defined early in the course of disease.
• In the United States, sarcoidosis is more common and severe in blacks.
• Diagnosis requires a compatible clinical picture and a biopsy with typical noncaseating granulomas, excluding diseases that can cause similar granulomatous reactions.

Epidemiology

Sarcoidosis is found worldwide with a prevalence ranging from 10 to 80 cases per 100,000 in North America and Europe. Higher regional prevalence has been reported in Scandinavia and the southeast coastal United States. In the United States, one study from a Midwest city estimated that the lifetime risk of developing sarcoidosis was 2.7% in black women, 2.1% in black men, 1% in white women, and 0.8% in white men. Worldwide, there is a slight female predominance. Although all ages can be affected, most cases occur between the ages of 20 and 40 years, with a second peak incidence in women over age 60.

Genetics

A genetic predisposition to sarcoidosis is supported by familial clustering in approximately 5–10% of cases of sarcoidosis. A recent multicenter study on the etiology of sarcoidosis in the United States (A Case-Control Etiologic Study of Sarcoidosis [ACCESS]) suggests that the familial relative risk is approximately 5.0 among first-degree relatives, and this risk is higher in white families compared with black families.

The strongest associations between genotype and sarcoidosis risk have been identified within the major histocompatibility (MHC) locus on chromosome 6. Two recent genome-wide linkage analyses identified an association with the butyrophilin-like 2 gene (BTNL2) (located within the MHC locus) in both whites and blacks with sarcoidosis.

Etiology

The cause of sarcoidosis is uncertain. The genetic pattern of inheritance suggests that susceptibility to sarcoidosis is polygenic and interacts importantly with environmental factors. Geographic differences in disease prevalence and reports of time-space clustering of cases have also suggested that sarcoidosis may be associated with an environmental, likely microbial, exposure. The large, multicenter study ACCESS found no evidence for a single dominant environmental or occupational exposure associated with an increased risk of developing sarcoidosis. Multiple regression analyses found positive associations with modest odds ratios of approximately 1.5 for exposures to molds and mildews, insecticides, or musty odors at work. The ACCESS data supported a negative association of tobacco use or tobacco smoke exposure among sarcoidosis patients.

Since the first description of sarcoidosis, many experts have speculated that a potential microbial cause of sarcoidosis exists. Recent studies using polymerase chain reaction (PCR) have associated mycobacterial and propionibacterial organisms as possible etiologic factors for sarcoidosis. A recent meta-analysis concluded that 26% of sarcoidosis tissues contained mycobacterial nucleic acids, with an odds-ratio of 9- to 19-fold higher chance of finding mycobacterial nucleic acids in sarcoidosis compared with control tissues. Recently, a limited proteomic approach identified the mycobacterial catalase-peroxidase protein (mKatG) as a candidate pathogenic antigen. This and other studies from the United States and Europe have demonstrated immunologic responses to mKatG and other mycobacterial proteins in a subgroup of sarcoidosis patients, supporting a mycobacterial etiology of sarcoidosis. In Japan, a subgroup of sarcoidosis patients has been demonstrated to have immunologic responses to Propionibacterium acnes. No studies have demonstrated the presence of live organisms from sarcoidosis tissues, distinguishing sarcoidosis from active infections. How these microbial organisms trigger sarcoidosis remains unknown.

Pathophysiology

There are certain immunologic hallmarks of sarcoidosis regardless of the potential etiologic trigger. There is usually an accumulation of CD4+ dominant T cell infiltration at sites of granulomatous inflammation, with fewer CD8+ T cells usually surrounding the granulomas. These CD4+ T cells have biased expression of specific T cell receptor genes, consistent with oligoclonal expansion of antigen-specific T cells. The antigen-specific T cell response is highly polarized toward a T helper 1 response with expression of interferon-gamma (IFN-γ) and the Th1 immunomodulatory cytokines, interleukin-12 (IL-12), and IL-18. Along with Th1 cytokines, pro-inflammatory cytokines such as tumor necrosis factor (TNF), IL-1, IL-6, and a Th1-associated chemokines together orchestrate the local granulomatous response. Dysregulated expression of Th1 immunomodulatory cytokines has been hypothesized to central to the development of granulomatous inflammation in sarcoidosis.

There is tremendous heterogeneity in the clinical manifestations of sarcoidosis. Pulmonary involvement is documented in >90% of patients. Nonpulmonary manifestations are present in many patients with or without pulmonary involvement (Table 54–1).

An initial diagnostic evaluation should consist of tests to evaluate the presence and extent of pulmonary involvement and screening for common extrathoracic involvement (Table 54–2). Specialized testing is indicated when symptoms or signs suggest extrapulmonary involvement.

Symptoms and Signs

Acute Sarcoidosis (Löfgren Syndrome)

This syndrome of acute sarcoidosis is characterized by erythema nodosum, bilateral hilar adenopathy, and often polyarthritis and uveitis (Figure 54–1). Löfgren syndrome is common among Scandinavians and Irish women but occurs in less than 5% of black patients with sarcoidosis. Acute sarcoidosis without erythema nodosum may also occur, often with disabling arthritis.

Pulmonary Sarcoidosis

The most common symptoms are progressive shortness of breath, nonproductive cough, and chest discomfort (Table 54–1). Chronic sputum production and hemoptysis are more frequent in advanced fibrocystic disease (chest radiograph stage IV, Figure 54–1). Typically, there are few physical findings of pulmonary sarcoidosis, with lung crackles heard in less than 10% of patients. Clubbing is rare. Airway obstruction is usually fixed (unresponsive to bronchodilators) and observed in a minority of patients. Bronchial hyperreactivity with occasional frank wheezing is found in 5–30% of patients.

Pulmonary hypertension or cor pulmonale is seen in >80% patients with advanced fibrocystic sarcoidosis with pulmonary fibrosis. Rarely, a granulomatous pulmonary vasculitis results in pulmonary hypertension with little evidence of interstitial lung disease. Dyspnea out of proportion to pulmonary function test results should prompt a search for pulmonary hypertension. Other causes of pulmonary hypertension, such as sleep disordered breathing or chronic thromboembolic disease, must be excluded. Severe pulmonary hypertension in patients with advanced lung disease is associated with higher rates of mortality while awaiting lung transplantation.

Ocular Manifestations

Uveitis is the most common eye lesion in sarcoidosis and may be the initial presenting manifestation. The uveitis is more commonly anterior, may be unilateral or bilateral, and is frequently associated with bilateral hilar adenopathy. Chronic uveitis occurs in as many as 20% of patients with chronic sarcoidosis and is more common in the black population. Granulomatous conjunctivitis appears as a granular or cobblestone-like appearance of the conjunctivae. Conjunctival nodules are also a common finding. Optic neuritis or retinitis may manifest dramatically with blindness. Severe chorioretinitis occurs uncommonly.

Chronic Cutaneous Sarcoidosis

Sarcoidosis commonly involves the skin (20–30%) and may be severe, especially in black patients. Cutaneous nodules, plaques and subcutaneous nodules, typically located around the hairline, eyelids, ears, nose, mouth, and extensor surfaces of the arms and legs, are common. Lupus pernio is a particularly disfiguring form of cutaneous sarcoidosis of the face with violaceous plaques and nodules covering the nose (Figure 54–2), nasal alae, malar areas, and around the eyes.

Hematologic Sarcoidosis

Peripheral lymph node enlargement occurs in 20–30% of patients as an early manifestation of sarcoidosis but then typically undergoes spontaneous remission. Persistent, bulky lymphadenopathy occurs less than 10% of the time. Splenomegaly, occasionally massive, occurs in less than 5% of cases and is often associated with hepatomegaly and hypercalcemia. Polyclonal hypergammaglobulinemia is present in 25% or more of patients. Anemia and peripheral lymphopenia are relatively common while leucopenia and thrombocytopenia are rare. A clinical association exists between sarcoidosis and common variable immunodeficiency (CVID); CVID should be suspected in patients with sarcoidosis who develop increased frequency of infections or hypogammaglobulinemia.

Musculoskeletal Sarcoidosis

Systemic constitutional symptoms such as fever, malaise, and weight loss are seen in over 20% of patients and may be disabling. Arthralgias are common in active multisystem sarcoidosis, although joint radiographs are usually normal. Acute, often incapacitating polyarthritis involving the ankles, feet, knees, and wrists is commonly seen in patients with Löfgren syndrome; usually the polyarthritis regresses within weeks to several months with or without therapy. Persistent joint disease is found in less than 5% of patients with chronic sarcoidosis. Pain, swelling, and tenderness of the phalanges (sausage digit) of the hands and feet are most common.

Although random muscle biopsies in autopsy series often demonstrate muscle granulomas in patients with sarcoidosis, symptomatic myopathy with weakness and tenderness is uncommon. Rarely, sarcoidosis can present as a polymyositis with profound weakness and elevated serum creatine kinase and aldolase levels.

Radiographic skeletal findings are most typically noted as incidental findings and observed in <10% of all patients. These typically present as cystic and lytic lesions of varying sizes and may have associated sclerotic margins (Figure 54–3). Most commonly involved areas include bones of the skull, vertebrae, hands, and feet. The use of other imaging modalities (CT, MRI with gadolinium, technetium bone scan) has not been proven to be useful for judging the activity of such lesions or differentiating them from infection or malignancy.

Fibromyalgia may be associated with sarcoidosis and causes considerable morbidity in such patients. This cause of pain does not respond to immunosuppressive therapy.

Gastrointestinal Sarcoidosis

Although a liver biopsy demonstrates granulomatous inflammation in over 50% of patients, clinically significant liver involvement is documented in only 10–20% of patients and is rarely the sole manifestation of this disease. Active hepatic inflammation may be associated with fever, tender hepatomegaly, and pruritus. Characteristically, the serum alkaline phosphatase and γ-glutamyltransferase are elevated disproportionately higher than the transaminases or bilirubin. This is often part of a constellation of hepatic, spleen, and bone marrow involvement with or without hypercalcemia, sometimes referred to as “abdominal sarcoidosis.” Elevated serum liver function tests frequently revert to normal spontaneously or after treatment with glucocorticoids. Progressive cirrhosis may occur if severe, persistent granulomatous hepatitis is not treated.

Symptomatic gastrointestinal involvement in sarcoidosis is rare, and other causes, such as Crohn disease or ulcerative colitis, must be excluded.

Neurosarcoidosis

This manifestation occurs in 5–10% of patients with sarcoidosis. The most common manifestation is cranial neuropathy with bilateral or unilateral seventh nerve (Bell) palsy or less commonly, glossopharyngeal, auditory, oculomotor, or trigeminal palsies. The palsies may resolve spontaneously or with glucocorticoid therapy but may recur years later. Optic neuritis can result in blurred vision, field defects, and blindness. Other manifestations include mass lesions, aseptic meningitis, obstructive hydrocephalus, and hypothalamic-pituitary dysfunction. Seizures, headache, change in mental status, confusion, and diabetes insipidus can be initial manifestations of sarcoidosis. Spinal cord involvement is rare, but paraparesis, hemiparesis, and back and leg pains may occur. Peripheral neuropathies account for about 15% of cases of neurosarcoidosis, often presenting as mononeuritis multiplex or a primary sensory neuropathy. Recently, small fiber neuropathy has been associated with a pain syndrome in sarcoidosis; a few case reports suggest TNF inhibitors may be helpful in treating this debilitating condition.

Sarcoidosis of the Upper Respiratory Tract (SURT)

This manifestation occurs in 5–10% of patients, usually in those with long-standing disease. Severe nasal congestion and chronic sinusitis usually are unresponsive to decongestants and topical (intranasal) glucocorticoids. Chronic disease or surgical intervention may result in destruction of the nasal septum and a “saddle-nose” deformity. Laryngeal sarcoidosis may present with severe hoarseness, stridor, and acute respiratory failure secondary to upper airway obstruction. Often, SURT is associated with chronic skin lesions, particularly lupus pernio (see Figure 54–2).

Cardiac Sarcoidosis

Although myocardial sarcoidosis is diagnosed in less than 10% of patients in the United States and Europe, autopsy series suggest that the histologic presence of sarcoidosis in the heart may be as high as 25%. In Japan, cardiac sarcoidosis occurs in nearly 50% of sarcoidosis patients. Arrhythmia, heart block, dilated cardiomyopathy, or sudden death can be the presenting clinical manifestations. Endomyocardial biopsies fail to demonstrate granulomatous inflammation in 80% of cases due to sampling inefficiencies in the setting of patchy inflammatory involvement and the lack of involvement of the right ventricle. A diagnosis of cardiac sarcoidosis can be inferred from a combination of biopsy-proven systemic sarcoidosis and a compatible myocardial imaging study, such as thallium or sestamibi scan, cardiac MRI with gadolinium enhancement, or cardiac positron emission tomography (PET) scan (Figure 54–4).

Salivary, Parotid, and Lacrimal Gland Sarcoidosis

Parotid or lacrimal gland enlargement or sicca syndrome can occasionally be the dominant clinical manifestations of sarcoidosis. Heerfordt syndrome, or uveoparotid fever, is an uncommon acute presentation of sarcoidosis manifesting as fever, parotid and lacrimal gland enlargement, uveitis, bilateral hilar adenopathy, and often cranial neuropathies.

Endocrine Abnormalities in Sarcoidosis

In patients with neurosarcoidosis, disturbances to the hypothalamic-pituitary axis may result in diabetes insipidus and other manifestations of hypopituitarism. There is a higher association of autoimmune thyroid disease and sarcoidosis compared to control populations. Pancreatic sarcoidosis manifesting as a mass is a rare manifestation and must be distinguished from cancer.

Renal Involvement in Sarcoidosis

Sarcoidosis may be associated with hypercalcemia, and more commonly, hypercalciuria. The abnormalities are caused by the increased conversion of inactive 25-OH vitamin D3 to the active 1,25(OH)2 vitamin D3 by epithelioid macrophages within tissue granulomas. Primary care physicians must be aware that a low serum 25-OH vitamin D level (the standard serum vitamin D test) usually does not represent vitamin D deficiency in sarcoidosis patients, but rather is a result from this increased conversion to active 1,25(OH)2 vitamin D. Vitamin D supplementation in this instance may precipitate hypercalcemic crisis in untreated sarcoidosis patients. Vitamin D supplementation should only be based on serum levels of active 1,25(OH)2 vitamin D (which requires special ordering) in patients with sarcoidosis. Nephrocalcinosis may cause renal failure in sarcoidosis. Direct granulomatous involvement of the kidneys causing chronic interstitial nephritis or membranous glomerulonephritis is rare.

Psychosocial Abnormalities

As many as 30–60% of patients with sarcoidosis report symptoms of depression. One study found this to be associated with female sex, lower socioeconomic status, poor access to health care and increased disease severity, but not race.

Laboratory Studies

Recommended initial studies for all patients with presumed or biopsy-proven sarcoidosis include the following:

• A comprehensive metabolic panel is useful to assess abnormalities of renal function, calcium level, and liver function.
• The complete blood cell count is usually either normal or demonstrates peripheral lymphopenia. Pancytopenia may be caused by hypersplenism or bone marrow infiltration with granulomas.

Imaging Studies

Chest radiographs are abnormal in 90% or more of patients with sarcoidosis and can be categorized by stage or type by international convention (Figure 54–1). Stage 0 indicates a normal chest radiograph (ie, seen in extrapulmonary sarcoidosis). Stage I shows bilateral hilar adenopathy. Stage II shows bilateral hilar adenopathy plus interstitial infiltrates. Stage III demonstrates interstitial infiltrates only. Stage IV demonstrates fibrocystic lung disease.

Uncommon findings associated with pulmonary sarcoidosis include large, well-defined nodular infiltrates, miliary disease, a pattern of patchy air space consolidation with air bronchograms, termed “alveolar sarcoidosis,” or the presence of mycetomas. Differential diagnoses include mycobacterial or fungal infection, malignancy, or granulomatosis with polyangiitis (formerly Wegener granulomatosis). Pleural effusions and pneumothoraces are unusual in sarcoidosis.

Chest CT typically demonstrates reticulonodular infiltrates that follow bronchovascular distribution. Occasionally, ground-glass infiltrates, well-defined nodules, mass-like infiltrates, alveolar consolidation, or honeycombing are seen. Pleural effusions are rarely secondary to sarcoidosis inflammation.

Nuclear medicine studies, such as 67-gallium scanning and positron emission tomography using 18-fluorodeoxyglucose (FDG-PET), have been used to detect active inflammatory sites in sarcoidosis, potentially aiding in choosing sites for biopsy. FDG-PET uses less radiation exposure while offering better resolution and has largely replaced gallium scanning. Classic findings using gallium or PET scanning are uptake in the bilateral hilar and right paratracheal lymph node region (“lambda” sign) of the lungs, and uptake in the parotids or lacrimal and salivary glands (“panda” sign). The combination of signs (lambda-panda) is suggestive of sarcoidosis.

Joint radiographs may demonstrate “punched out” lesions with cystic changes and marked loss of trabeculae but without evidence of erosive chrondritis. Cystic lesions of the long bones, pelvis, sternum, skull, and vertebrae rarely occur (Figure 54–4).

MRI with gadolinium contrast enhancement has an important role in the evaluation of neurosarcoidosis, particularly in cases of suspected brain, cranial nerve, or spinal cord involvement.

Pulmonary Function Testing

Pulmonary function tests may show restrictive, obstructive, or combined impairment with a parallel reduction in diffusing capacity for carbon monoxide (DLCO). Resting gas exchange is usually preserved until extensive fibrocystic changes are evident, although oxygen desaturation with exercise occurs in less advanced disease.

Other Tests

A well-recognized feature of sarcoidosis is the impaired cutaneous response to common antigens that elicit delayed-type hypersensitivity reactions, seen in 30–70% of patients. Since anergy to purified protein derivative (PPD) testing is common in sarcoidosis, active tuberculosis must be strongly considered in any patient in whom a positive tuberculin skin test develops.

An electrocardiogram is routinely performed to screen for conduction abnormalities, which may signal the presence of early cardiac sarcoidosis. When cardiac sarcoidosis is suspected on the basis of symptoms or electrocardiographic abnormalities, Holter monitoring, and cardiac imaging is indicated. Two-dimensional echocardiography is useful as a screening tool but is insensitive to mild cardiac abnormalities. Radionuclide imaging with gated 201-thallium scanning, cardiac MRI, or cardiac PET are more sensitive studies to detect myocardial abnormalities related to sarcoidosis (Figure 54–4). Electrophysiologic testing may be indicated to exclude arrhythmias undetected by routine studies.

In patients with suspected neurosarcoidosis, MRI with gadolinium enhancement of the brain or spine is indicated. The characteristic inflammatory lesions by contrast MRI have a propensity for periventricular and leptomeningeal areas. These findings are nonspecific and can be produced by infectious (tuberculosis, fungal disease) or malignant (lymphoma, carcinomatosis) disease. A normal scan does not exclude neurosarcoidosis, particularly for cranial neuropathies, peripheral neuropathies, or in the presence of glucocorticoid therapy.

In neurosarcoidosis, the cerebrospinal fluid may demonstrate lymphocytic pleocytosis or elevated protein levels, providing supportive evidence of central nervous system or spinal cord inflammation. A diagnosis of neurosarcoidosis is usually confirmed by biopsy of a non–central nervous system site, generally by bronchoscopic or lymph node biopsy. Rarely, brain or spinal cord biopsy is needed to exclude infectious or malignant disease. In suspected cases of peripheral neuropathy or myopathy, electromyography or nerve conduction studies are often indicated.

Diagnostic Examinations

Identifying the extent of specific organ involvement requires a careful review of localizing symptoms in the setting of biopsy-confirmed granulomatous inflammation. Biopsy of the easiest, most accessible abnormal tissue site is used for confirmation of the diagnosis and to exclude infection, malignancy, or other diseases that have similar clinical manifestations. Biopsy by fiberoptic bronchoscopy is frequently used to diagnose pulmonary sarcoidosis because of its relative safety and high yield. Endobronchial or transbronchial needle aspiration biopsies may increase the yield further. Bronchoalveolar lavage fluid in sarcoidosis is typically characterized by increased proportions and numbers of activated CD4+ alveolar lymphocytes reflective of enhanced cell-mediated immune processes at sites of granuloma formation. These findings are not specific for sarcoidosis and do not predict clinical outcome.

Mediastinoscopy or surgical lung biopsy (open-lung, thoracoscopic) should be considered in cases where lymphoma or other intrathoracic malignancy cannot be reasonably excluded. Biopsy of a skin nodule, superficial lymph node, nasal mucosa, conjunctiva, or salivary gland (lip biopsy) sometimes can establish a diagnosis. Biopsy of the liver or bone marrow is nonspecific and should be used to support a diagnosis of sarcoidosis only after malignancy, infectious granulomatous diseases, or other organ-specific diagnoses are excluded. In rare cases, biopsy of critical organs may be necessary to exclude malignancy, such as when sarcoidosis presents as a mass lesion in the brain. Biopsy confirmation of sarcoidosis is usually not necessary in Löfgren syndrome except in regions where histoplasmosis is endemic, and fungal infection must be excluded before initiating glucocorticoid therapy.

A diagnosis of sarcoidosis is based on a compatible clinical picture, histologic evidence of noncaseating granulomas, and the absence of other known causes of this pathologic response, such as tuberculosis, fungal diseases, and chronic beryllium disease.

There is consensus on the following indications for treatment (Table 54–3):

• Persistent, symptomatic, or progressive pulmonary disease.
• Threatened organ failure, such as severe ocular, central nervous system, or cardiac disease.
• Persistent hypercalcemia or renal or hepatic dysfunction.
• Posterior uveitis or anterior uveitis not responding to localized glucocorticoid therapy.
• Myopathy.
• Significant splenomegaly or evidence of hypersplenism such as thrombocytopenia.
• Severe fatigue and weight loss.
• Disfiguring skin disease or symptomatic lymphadenopathy.

There is consensus that patients with sarcoidosis and no evidence of end organ impairment (eg, normal pulmonary function tests with or without abnormal chest radiograph) with minimal respiratory symptoms should not be treated. Patients with limited cutaneous disease that is nondisfiguring can be considered for local intralesional glucocorticoid injections.

Medical

Currently, there are no medications approved by the US Food and Drug Administration for the treatment of sarcoidosis. Glucocorticoids remain the mainstay of treatment because of their effectiveness in reversing nonfibrotic organ impairment (at least over the short term), and relative safety.

Glucocorticoids

This class of drugs is the cornerstone of therapy for serious progressive pulmonary or extrapulmonary sarcoidosis (Table 54–3). Guidelines for when to initiate therapy with glucocorticoids and proper dosing have been formulated from extensive clinical experience without being subjected to prospective randomized control trials. Controversy exists regarding their overall effectiveness in altering the long-term course of the disease. However, clinical experience indicates that glucocorticoids provide prompt symptomatic relief and reverse organ dysfunction in almost all patients with active inflammation. The optimal dose and duration of glucocorticoid treatment have not been established by rigorous clinical studies. Topical glucocorticoids are usually ineffective except for specific cases of ocular sarcoidosis. Most studies find inhaled glucocorticoids for pulmonary sarcoidosis to be ineffective, and only a minority of patients with airway obstruction demonstrate meaningful responses to bronchodilators.

In general, initial treatment with glucocorticoids should be planned for a period of 8–12 months, except for Löfgren syndrome. One well-designed study by the British Thoracic Society demonstrated that in patients with active pulmonary sarcoidosis with interstitial infiltrates, a stable maintenance regimen of low-dose glucocorticoids is more effective at preserving lung function than symptomatic use of glucocorticoids followed by repeated tapering regimens.

For patients who require maintenance therapy for chronic sarcoidosis, glucocorticoid therapy often results in significant adverse effects such as weight gain, diabetes, and osteoporosis. Thus, when these adverse effects become intolerable, glucocorticoid-sparing drugs are often considered. However, all glucocorticoid-sparing drugs show variable effectiveness and have adverse risk profiles that warrant careful dosing and monitoring in the absence of controlled clinical comparison trials.

Glucocorticoid-Sparing Agents

Hydroxychloroquine

This agent is used for dominant skin, nasal mucosal, and sinus sarcoidosis but has not been consistently effective for pulmonary or systemic disease. Hypercalcemia and laryngeal, bone, and joint involvement have been reported to respond to hydroxychloroquine. Serial ophthalmologic evaluations should be performed every 6 months during hydroxychloroquine therapy. Chloroquine may have greater effectiveness but is rarely used because of the higher risk of ocular toxicity. When chloroquine is used for treatment recalcitrant mucosal or skin disease, it is given for 6 months followed by a 6-month drug holiday; ophthalmologic follow-up should be scheduled every 3 months.

Minocycline and Doxycycline (Synthetic Tetracycline Derivatives)

These agents have anti-inflammatory properties. The relatively safe side-effect profile of these medications make them a reasonable choice for non-threatening manifestations of sarcoidosis, such as skin lesions, but clinical experience suggests that these drugs usually are not effective in pulmonary or non-skin multiorgan sarcoidosis.

Cytotoxic Therapy

Methotrexate is usually the first cytotoxic therapy tried as a potent glucocorticoid-sparing drug. Studies suggest an approximate 60% response rate, which may take 4–6 months or longer for effect. Azathioprine and mycophenolate mofetil are alternative immunosuppressants that have been used in smaller series to treat severe extrapulmonary sarcoidosis and pulmonary sarcoidosis. These agents may require 2–3 months or more of therapy to demonstrate clinical effectiveness. Routine monitoring for renal, liver, and bone marrow toxicities are standard.

Biologic Agents

Laboratory experiments demonstrate that TNF plays an important role in granuloma formation. There is evidence supporting the effectiveness of select TNF inhibitors in sarcoidosis. A large, randomized multicenter prospective study found that a 24-week course of treatment with infliximab was associated with an improvement in lung function. A separate study also showed infliximab was associated in improvement in nonpulmonary sarcoidosis. The humanized TNF inhibitor adalimumab has not been studied by controlled clinical trials, but small case series suggest this therapy may also be beneficial in some patients with skin sarcoidosis and peripheral neuropathy. Etanercept, a TNF receptor antagonist, failed to show benefit in small clinical trials and cannot be recommended for sarcoidosis. All TNF inhibitors are associated with significant risk of severe infections, reactivation of latent tuberculosis, and potential risk for malignancy and autoimmune phenomena. Given these risks, anti-TNF agents are reserved for patients in need of potent glucocorticoid-sparing therapy and who have not tolerated a trial of cytotoxic therapy. The use of other biologic agents to treat sarcoidosis targeting T cells (alefacept), B cells (rituximab), and other cytokines such as IL-2 (basiliximab) are under study.

Surgical

Successful lung, heart-lung, and liver transplantations have been performed in a small number of patients with advanced organ insufficiency. Noncaseating granulomas may develop in the transplanted organs in some lung and heart transplant patients but do not seem to have a significant impact on overall survival.

Although sarcoidosis can potentially involve any part of the body, the extent of significant organ system involvement is usually evident within the first 2 years after diagnosis. The ACCESS study found that at 2-year follow-up, evidence for new organ system involvement developed in less than 25% of the study participants.

Studies suggest that approximately 50–70% of patients may undergo remission, which is usually evident within the first 2–3 years following diagnosis. Acute sarcoidosis (Löfgren syndrome) has a remission rate of greater than 70%. Monitoring of patients for several years after presumed remission is recommended to ensure stability of organ function. Patients with fibrocystic pulmonary sarcoidosis, lupus pernio, or nasal or sinus sarcoidosis, neurosarcoidosis, cardiac sarcoidosis or who have multisystem disease for greater than 2–3 years usually have unremitting, progressive (if not treated) disease. A waxing and waning course of sarcoidosis is unusual except in patients with ocular, neurologic, peripheral lymph node, or cutaneous involvement.

No biomarkers have been found to be useful in predicting outcomes or to assist in treatment decisions. Serum angiotensin-converting enzyme levels are elevated in 30–80% of patients with clinically active disease. The test has positive and negative predictive values of less than 70–80%, and serum angiotensin-converting enzyme levels do not predict clinical course. Thus, most clinicians agree this test is of limited usefulness in the management of sarcoidosis.

Major causes of death from sarcoidosis include respiratory insufficiency and cor pulmonale, massive hemoptysis, complications from cardiac sarcoidosis, neurosarcoidosis, or uremia from chronic renal failure. Several centers in the United States and Great Britain suggest that race is an important prognostic indicator, with blacks from Africa and West Indian patients more likely to have chronic persistent disease and suffer from increased morbidity and mortality. Hospital statistics suggest that sarcoidosis is the direct cause of death in 1–5% of persons admitted with this disease.

A patient should be considered for referral to a specialist in sarcoidosis in the following situations:

• Uncertainty of the diagnosis or clinical course.
• Uncertainty whether treatment is indicated.
• Disease that is not responding as expected to therapy.
• Severe extrapulmonary involvement, such as cardiac, neurologic, skin, or sinus involvement.
• Unsure about the use of glucocorticoid-sparing or alternative medications.