Chapter 152. Sarcoidosis

Sarcoidosis is a multisystem granulomatous disease of unknown cause. The lung is the most commonly affected organ, but the skin is frequently involved.1 The first descriptions of sarcoidosis in the late 1800s were limited to its skin manifestations.1 The term sarcoidosis is derived from Caesar Boeck's 1899 report of what he described as “multiple benign sarkoid of the skin,” because he believed the lesions resembled sarcomas but were benign.2

Sarcoidosis occurs worldwide and affects all ages and races. Disease onset is most often in the third decade of life, although a smaller second peak occurs in people older than 50 years.1 The prevalence rate is slightly higher in women.1 Sarcoidosis is more frequent away from the equator. The highest prevalence of sarcoidosis is found in Caucasians in Denmark, Sweden, and, in the United States, in persons of African descent.1 In the United States, the lifetime risk of sarcoidosis is 2.4% in African-Americans and 0.85% in Caucasians.3 The age-adjusted annual incidence rate of sarcoidosis in the United States is 35.5 per 100,000 for African-Americans and 10.9 per 100,000 for Caucasians.3 The frequency and severity of the disease also vary between different ethnicities and races. African-Americans tend to have more severe disease, whereas Caucasians are more likely to present with asymptomatic disease.4,5 African-Americans are also more likely to have extrapulmonary disease,6 require treatment,7 develop new organ involvement,8 and have a lower rate of clinical recovery than Caucasians.5,8 The disease is more common in life-long nonsmokers.9

The current understanding is that the development of sarcoidosis requires at least three major events: (1) exposure to antigen(s), (2) acquired cellular immunity directed against the antigen and mediated through antigen-presenting cells and antigen-specific T lymphocytes, and (3) the appearance of immune effector cells that promote a nonspecific inflammatory response.10 The identity of the putative antigen(s) of sarcoidosis is unknown.

Presumably, antigen-presenting cells such as macrophages recognize, process, and present the processed antigen to CD4+ T cells of the T helper 1 type (Fig. 152-1). The processed antigen is presented to these lymphocytes via HLA class II molecules on the antigen-presenting cells that have undergone enhanced expression from exposure to the sarcoidosis antigen and possibly interferon-γ (IFN-γ).10,11 These activated macrophages produce interleukin (IL)-12, which induces lymphocytes to shift toward a T helper 1 profile and causes T lymphocytes to secrete IFN-γ. These activated T cells release IL-2 and chemotactic factors that recruit monocytes and macrophages to the site of disease activity. IL-2 and other cytokines also expand various T-cell clones. IFN-γ further activates macrophages and transforms them into giant cells.11 Tumor necrosis factor (TNF), IL-2, and other cytokines may also be important in stimulating macrophages.12Figure 152-1 displays the major features of the presumed immunopathogenesis of sarcoidosis.

A variety of candidate antigens have been suggested as provocative agents for the cascade of immunologic events that eventuate in sarcoidosis. Infectious agents such as mycobacteria,13 Propioni-bacterium acnes,14 and Chlamydia15 have been associated with sarcoidosis. Mineral dusts, such as silica, iron,16 and titanium,17 also have been associated with sarcoidosis as have combustible wood products because the disease has been found more commonly in individuals who use wood stoves.18 Interestingly, firefighters have been found to be at greater risk of developing sarcoidosis.19

Genetics play a major role in determining susceptibility to sarcoidosis, as it is more common in relatives of an affected person than in individuals in the general population.20 Genes coding for HLA class II antigens are thought to be prime candidates for a role in the development of the disease because these molecules present exogenous peptides to CD4+ T-cell receptors. Numerous studies in various ethnic groups have shown a relationship of HLA antigens to the development of disease, protection from disease, good prognosis, poor prognosis, acute disease, chronic disease, and various phenotypic expressions of sarcoidosis.21

The interplay of antigenic and genetic factors suggests that there may be multiple causes of sarcoidosis. Patients may have to experience a specific interaction between one or several exposures and be genetically programmed to one or several abnormal immunologic responses. Each putative antigen may be associated with a specific HLA class II molecule and T-cell receptor.

History

The diagnosis of sarcoidosis is often delayed for months to years because symptoms are nonspecific and can relate to involvement of any organ.22

Thirty to sixty percent of patients with pulmonary sarcoidosis are asymptomatic.23 Other than the lung, the skin, eye, liver, and peripheral lymph nodes are commonly involved. Consequently, sarcoidosis should be considered in a patient with skin lesions and concomitant pulmonary symptoms, eye complaints, right upper quadrant abdominal pain, or peripheral lymphadenopathy. In addition, the cytokines associated with the granulomatous inflammation of sarcoidosis may cause constitutional symptoms such as fever, night sweats, malaise, and weight loss.

Cutaneous lesions of sarcoidosis may occur before, coincident with, or after systemic involvement. Specific cutaneous lesions are usually asymptomatic. Pruritus and pain are rare. Cosmetic disfigurement is the most common complaint. Erythema nodosum associated with sarcoidosis is indistinguishable from erythema nodosum unassociated with sarcoidosis (see Chapter 70).

Cutaneous Lesions

Classically, lesions are divided into two categories: (1) specific and (2) nonspecific. Specific lesions have granulomas on biopsy. Nonspecific skin findings are reactive and do not exhibit sarcoidal granulomas.

Specific Lesions Skin

Specific sarcoidal lesions most often are found on the head and neck (Figs. 152-2, 152-3, and 152-4) but may occur symmetrically or asymmetrically on any part of the skin and mucosa. Almost all morphologies have been reported, including macules, papules, patches, plaques, and nodules. Alopecia occurs with scalp involvement, and nail changes also occur. Specific lesions of sarcoidosis may be scaly, telangiectatic, or atrophic. Despite the diversity in appearance, there are several clinical presentations that are classically associated with cutaneous sarcoidosis.

The most common presentation is the papular form (see Figs. 152-2, 152-3, and 152-4). These firm, 2–5-mm papules often have a translucent red-brown or yellow-brown appearance. The yellow-brown color has been likened to “apple jelly” and is accentuated with diascopy (Fig. 152-5). In addition to the color change, the underlying granulomas have a nodular quality that can also be appreciated with diascopy. The apple jelly appearance and nodules are not pathognomonic for sarcoidosis, as other granulatomous skin conditions, such as lupus vulgaris (see Chapter 184), may exhibit similar diascopic properties. Epidermal changes may or may not be present, but often the lesions have a waxy appearance, which reflects mild epidermal atrophy. Papular lesions occur most commonly on the face and neck, with a predilection for periorbital skin (see eFig. 152-5.1). Annular plaques (Fig. 152-6), nonannular plaques (Fig. 152-7 and see eFig. 152-7.1), and nodules (Fig. 152-8) may develop from these papular lesions and may or may not retain the classic translucent quality of the papules.

Lupus pernio describes the relatively symmetric, violaceous, indurated plaques and nodules that occur on the nose, earlobes, cheeks, and digits (Figs. 152-9, 152-10, and 152-11). This clinical variant of sarcoidosis is distinctive and has been associated with systemic involvement. Lupus pernio is associated with a higher prevalence of upper respiratory tract disease.24 Lupus pernio lesions may directly extend into the nasal sinus, leading to epistaxis, nasal crusting, and sinus bone involvement.

Angiolupoid lesions are pink papules and plaques with prominent telangiectasias that usually occur on the face (see eFig. 152-11.1) and may be a variant of lupus pernio, as both lesions usually appear on the face and can be violaceous.25,26 However, angiolupoid lesions tend to be less numerous than the papular and lupus pernio forms.26

Rarely, sarcoidosis can present as persistent subcutaneous nodules (Darier-Roussy sarcoid).27 The nodules may be tender or painless and preferentially occur on the extremities.

Scars

Cutaneous sarcoidosis occurs preferentially within scar tissue, at traumatized skin sites, and around embedded foreign material such as silica. Scars become inflamed and infiltrated with sarcoidal granulomas (Fig. 152-12). Inflammation of old scars (see eFig. 152-12.1) may parallel or precede systemic disease activity. Infiltrated scars may be tender or pruritic. Scar sarcoidosis may be the only cutaneous finding in a patient with systemic sarcoidosis; therefore, it is important to closely examine scar tissue in patients suspected of having the disease. The presence of sarcoidal granulomas surrounding foreign material does not establish the diagnosis of sarcoidosis, nor does foreign material in the presence of granulomas exclude the diagnosis.28 Other signs of systemic or cutaneous involvement are required to confirm the diagnosis.

Scalp

Alopecia occurs with involvement of the scalp and may be scarring or nonscarring (see eFig. 152-12.2).29–32 Biopsy shows noncaseating granulomas. Its reversibility is dependent on the degree of destruction of hair follicles.

Nails

Sarcoidosis may cause nail plate deformation and discoloration, but the incidence is very low.33 There may be clubbing, (Fig. 152-11) subungual hyperkeratosis, and even nail plate destruction. Nail manifestations may result from granulomas in the nail matrix or from involvement of adjacent bone.

Mucous Membranes

Sarcoidal granulomas may cause papules and plaques of the mucosal surfaces and tongue. Sarcoidosis is one cause of Mikulicz syndrome, the bilateral enlargement of the lacrimal (see eFig. 152-12.3), parotid, sublingual, and submandibular glands.

Additional Presentations

A myriad of additional clinical presentations have also been reported. These include ichthyosis,34 erythroderma,29 ulcerations (see eFigs. 152-12.4 and 152-12.5),35 morphea-form plaques,36 lichen niditus-like papules,37 folliculitis-like lesions,38 psoriasiform plaques,39 hypopigmented areas,40 gyrate erythema,41 verrucous lesions,38 faint erythema, penile (see eFig. 152-12.6) and vulvar lesions,42,43 palmar erythema,44 discoid lupus-like plaques,45 lower extremity edema,46 lesions mimicking tuberculoid leprosy (see eFig. 152-12.7) polymorphous light eruption,38 and pustular lesions.38

Nonspecific Lesions

Erythema nodosum (see Chapter 70) is the main nonspecific cutaneous manifestation of sarcoidosis (prevalence of approximately 17%). Erythema nodosum with bilateral hilar adenopathy, arthralgias, and fever is frequently the initial manifestation of sarcoidosis and is called Löfgren syndrome. These patients tend to have an acute form of sarcoidosis with eventual resolution.

Other nonspecific cutaneous manifestations of sarcoidosis are much less common. The neutrophilic dermatoses, Sweet disease and pyoderma gangrenosum, have been reported as nonspecific cutaneous sarcoid lesions. Most of the sarcoid patients with Sweet disease lesions or pyoderma gangrenosum have concomitant erythema nodosum.47 Nonspecific erythematous eruptions resembling viral exanthems or drug reactions without histologic evidence of granulomatous inflammation occur rarely with acute sarcoidosis. Additionally, patients with sarcoidosis may have pruritus without granulomatous infiltration, leading to prurigo nodules.25 Erythema multiforme had been regularly cited as a nonspecific cutaneous manifestation of sarcoidosis,38 but reports of histologically proven erythema multiforme with interface dermatitis associated with sarcoidosis are virtually nonexistent in the literature,25,38,48,49 and any association is probably coincidental. Erythroderma and lower extremity swelling have been described as both specific and nonspecific lesions of sarcoidosis.25,46,50,51

Related Clinical Findings

Lungs

The lung is the most common organ involved with sarcoidosis. Findings on pulmonary examination are usually absent. Patients with pulmonary sarcoidosis are often asymptomatic, with the disease detected on a screening chest radiograph. Common symptoms include dyspnea, cough, chest pain, and wheezing. The chest radiograph is abnormal in more than 90% of patients with sarcoidosis. Bilateral hilar adenopathy is noted in 50%–85% of cases (see eFig. 152-12.8). Pulmonary parenchymal infiltrates are seen in 25%–60% of cases.

Chest computed tomography (CT) reveals more thoracic disease than can be appreciated on the chest radiograph. CT is superior to the chest radiograph in detecting thoracic involvement with sarcoidosis, but there is insufficient evidence that CT has a clinical role in the management of pulmonary sarcoidosis.52

In sarcoidosis patients with normal lung parenchyma on chest radiograph, pulmonary function tests are abnormal in 20%–40% of cases. When the chest radiograph is abnormal, pulmonary function tests are abnormal in 50%–70% of cases.

Eyes

The eyes are involved in one-fourth to three-fourths of sarcoidosis patients.53 Eye involvement with sarcoidosis is potentially vision threatening, and the patient may be asymptomatic. For this reason, every patient diagnosed with sarcoidosis requires an ophthalmologic examination.53 Redness, burning, itching, or dryness are the most common ocular symptoms when present. Any portion of the eye may be involved, and eye involvement may be the first manifestation of the disease.53 Uveitis is the most common ocular manifestation and can lead to cataracts and glaucoma. Other ocular manifestations include conjunctivitis, lacrimal gland involvement causing kerato-conjunctivitis sicca (dry eyes), and optic neuritis, which may rapidly lead to loss of vision. Heerfordt syndrome includes fever, parotid gland enlargement, facial palsy, and anterior uveitis.1

Liver

Hepatic involvement is common at disease onset but usually does not cause signs or symptoms.54 Although histologic evidence of hepatic sarcoidosis is present in more than one-half of sarcoidosis patients,55 signs of organ dysfunction due to hepatic sarcoidosis are far less common.54 Hepatomegaly, abdominal pain, and pruritus are present in only 15%–25% of patients with hepatic sarcoidosis. An increased serum alkaline phosphatase level occurs in approximately one-third of patients,56 but it is rarely associated with permanent hepatic dysfunction and therefore does not mandate treatment.54,56 Treatment is required in the rare patient with significant symptoms, evidence of synthetic dysfunction, or hyperbilirubinemia. Rarely, hepatic sarcoidosis may lead to a primary biliary cirrhosis-type picture, and portal hypertension may develop.57

Heart

Clinical evidence of cardiac involvement is found in only 5% of sarcoidosis patients,58 although myocardial granulomas have been found in approximately 25% of patients at autopsy.59 Most clinical problems are related to cardiac arrhythmias or left ventricular dysfunction.60,61 Sudden death may occur. Congestive heart failure may result when the myocardium is massively infiltrated with granulomas. Because of the potential lethal nature of heart involvement with sarcoidosis, an electrocardiogram is recommended for every patient diagnosed with the disease.1

Nervous System

Any portion of the central nervous system or peripheral nervous system may be affected by sarcoidosis. Neurosarcoidosis has a predilection for the base of the brain, and cranial neuropathies are the most common manifestation.62 The facial nerve is the cranial nerve most frequently involved.62 In fact, it is common for Bell palsy to be the first manifestation of sarcoidosis and resolve completely before other manifestations of the disease occur. Mass lesions may develop in the brain or spinal cord. Aseptic meningitis and peripheral neuropathy are other neurologic manifestations of sarcoidosis.63

Other Organs

The sinuses and upper airway are commonly involved with sarcoidosis, a condition known as SURT: sarcoidosis of the upper respiratory tract.64 Nasal SURT is often associated with lupus pernio skin lesions (see Fig. 152-9) and may cause epistaxis and severe nasal crusting. Sarcoidosis of the spleen is not rare.65 Sarcoidosis may also cause a disorder in calcium metabolism that results from activated sarcoidal macrophages demonstrating an increase in 1-α hydroxylase activity. This enzyme converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, the active form of the vitamin, an increase of which may result in hypercalcemia, hypercalciuria, and nephrolithiasis.66 Sarcoidosis may be associated with a reduction in any blood cell line. Leukopenia may result from bone marrow involvement or from splenic sequestration. Thrombocytopenia may result from bone marrow involvement, splenic sequestration, or from an idiopathic thrombocytopenic purpura-like syndrome related to the hypergammaglobulinemia often seen in patients with sarcoidosis.67

Box 152-1 lists clinical, imaging, and laboratory tests recommended when a diagnosis of sarcoidosis is entertained. These tests screen for involvement of various organs. A careful history and physical examination should be performed to detect signs and symptoms of organ involvement as well as to obtain a history suggesting another granulomatous disease (e.g., exposure to tuberculosis, endemic fungi, beryllium exposure).

Additional laboratory tests that assess disease activity are listed in the following sections. Although controversial, these tests are not routinely recommended because active granulomatous inflammation in sarcoidosis may remit spontaneously and therefore does not mandate treatment.

Angiotensin-Converting Enzyme

The epithelioid cell of the sarcoidal granuloma secretes angiotensin-converting enzyme68; therefore, serum angiotensin-converting enzyme (SACE) levels reflect the total granuloma burden in sarcoidosis. Clinical data concerning SACE in sarcoidosis suggest that an elevated SACE level is insufficiently specific for the diagnosis of sarcoidosis to rest on it alone and insufficiently sensitive to exclude the diagnosis.69 However, SACE may be useful as an adjunct in the diagnosis of the disease. Because SACE reflects the total body granuloma burden, SACE levels may be useful to monitor the course of sarcoidosis. Initial SACE levels are not different between patients who deteriorate and those who improve70; thus, SACE levels should not be used as a basis for treatment decisions.

Gallium, Nuclear Magnetic, and Positron Emission Scans

The mechanism of gallium-67 uptake in sarcoidosis is not completely understood. It is thought that inflammatory processes cause hyperemia and increased capillary permeability of gallium. Gallium also accumulates in macrophages and, to a lesser extent, in T lymphocytes, which are major participants in the granulomatous inflammation of sarcoidosis. Sarcoidosis may cause gallium uptake in thoracic and extrathoracic sites, although typically not in areas of skin involvement. Gallium scanning has not been found to be useful for monitoring the clinical course of sarcoidosis, but it may have a role in identifying organs with sarcoid involvement (see Section “Panda and Lambda Sign on Gallium-67 Scan”). Recently, organ activity from sarcoidosis has been detected by gadolinium enhancement on nuclear magnetic imaging (MRI) and by fluorodeoxyglucose positron emission tomography (PET) scanning.71 These latter scanning techniques may be more sensitive than gallium-67 scanning in revealing granulomatous inflammation from sarcoidosis. In addition, they are less cumbersome tests in that the patient does not have to return 48–72 hours later for rescanning.

The epithelioid granuloma of sarcoidosis usually contains a compact collection of mononuclear phagocytes. The granulomas typically are surrounded by a paucity of lymphocytes (“naked granulomas”), but varying degrees of lymphocytic inflammation may be present (Fig. 152-13 and see eFig.152-13.1).68 Epithelioid cells, which are themselves transformed monocytes, are commonly present within the sarcoidal granuloma. Multinucleated giant cells of the Langhans type result from the fusion of epithelioid cells. Although central fibrinoid necrosis is not uncommon, gross necrosis is not a characteristic feature of sarcoid granulomas and suggests an alternative diagnosis, such as tuberculosis, fungal infection, or vasculitis.68 Mycobacterial and fungal diseases must always be considered as alternative diagnoses; therefore, stains and cultures for mycobacteria and fungi should be routinely performed on biopsy specimens. Box 152-2 lists the major pathologic differential diagnoses of sarcoidosis on skin biopsy.

A clinically important aspect of the pathology of sarcoidosis involves the development of fibrosis. Dense bands of fibroblasts may encase the ball-like granulomas. This fibrotic response can produce tissue destruction and organ dysfunction that is often irreversible.10 Currently available chemotherapeutic agents for sarcoidosis can effectively treat the granulomatous inflammatory response but not the fibrotic reaction.

The diagnosis of sarcoidosis requires a compatible clinical picture, histologic demonstration of noncaseating granulomas, and exclusion of other diseases capable of producing similar histology or clinical features.1 Because sarcoidosis is a diagnosis of exclusion, the diagnosis can never be confirmed with 100% certainty.72

Normally, the diagnosis of sarcoidosis requires a compatible clinical picture, histologic demonstration of noncaseating granulomas, and exclusion of other diseases capable of producing similar histology or clinical features (Fig. 152-14). Alternatively, the diagnosis can be assumed without biopsy when the clinical presentation is typical for the disease and is not explained by an alternative cause.

The presence of noncaseating granulomas in a single organ does not conclusively establish the diagnosis of sarcoidosis because sarcoidosis is, by definition, a systemic disease that should involve multiple organs.73 Isolated skin granulomas should not be assumed to represent sarcoidosis, and efforts must be made to exclude alternative diagnoses (see Box 152-2). Although a confirmed diagnosis of sarcoidosis requires proof of granulomatous involvement in at least two separate organs, histologic confirmation is usually not required in the second organ.74

Certain disease presentations are so specific for the diagnosis of sarcoidosis (e.g., Löfgren syndrome,75 Heerfordt syndrome, and asymptomatic bilateral hilar adenopathy) that the diagnosis may be accepted without a tissue biopsy.

Asymptomatic hilar adenopathy on chest radiograph almost always represents sarcoidosis.76 It has been suggested that histologic confirmation of sarcoidosis may not be required in asymptomatic patients with bilateral hilar adenopathy, provided the physical examination, complete blood cell count, and routine blood tests are all normal and there is no prior history of malignancy.23 In such cases, chest radiographs should be monitored at 3- to 6-month intervals, and a biopsy should be performed if there is significant change in the chest radiograph.23

Panda and Lambda Sign on Gallium-67 Scan

The presence of panda sign (bilateral lacrimal and parotid gland uptake) and lambda sign (bilateral hilar and right paratracheal uptake) on gallium-67 scanning is highly specific for sarcoidosis and may obviate the need for invasive diagnostic procedures. However, these signs are both positive in only a small percentage of sarcoidosis patients.

The granulomatous inflammation of sarcoidosis can remit spontaneously or with therapy. Therefore, the general prognosis of sarcoidosis is good.73 Pulmonary sarcoidosis resolves, improves, or stabilizes in 60% 90% of patients even without treatment.77 Remissions often occur within the first 6 months after diagnosis, although it may take 2–5 years.78 The prognosis is generally favorable for liver and peripheral lymph node sarcoidosis as well. The skin lesions may resolve with or without scarring or pigmentary changes.

Almost all severe impairment from sarcoidosis is the result of the development of fibrosis. As mentioned previously, this is probably the result of hyalinization of granulomatous inflammation. Presently it is unclear if this is the result of inadequate treatment or a host propensity for a brisk fibrotic response. Such cutaneous fibrosis may result in permanent scarring and disfigurement. Rarely, cutaneous lesions may ulcerate or destroy nearby bone or cartilage; this most commonly occurs in patients with lupus pernio.

Because sarcoidosis is a systemic disease, the prognosis is not solely related to pulmonary involvement. In the United States, three-fourths of sarcoidosis deaths result from pulmonary involvement. Sarcoidosis of the heart and central nervous system accounts for most of the remaining deaths.79

There is no current laboratory or radiologic test that can predict the outcome of sarcoidosis. Skin lesions are not a reliable indicator of prognosis, but several useful associations have been documented. Patients with cutaneous lesions are more likely to have chronic systemic sarcoidosis than sarcoidosis patients without skin involvement.80 Erythema nodosum with fever and arthralgias portends a good prognosis.81 Patients with Löfgren syndrome have a more than 80% rate of spontaneous remission, generally within 4–6 weeks.1 Lupus pernio indicates chronic disease and is associated with upper respiratory tract involvement, pulmonary fibrosis, and bony cysts.1Table 152-1 reviews various clinical features that are associated with the prognosis of sarcoidosis.

Because sarcoidosis often spontaneously remits and therapy may be associated with significant side effects, it is not mandatory to treat the disease.82 Treatment is indicated when there is evidence of progressive organ damage.82Table 152-2 shows suggested indications for treatment of various organs with sarcoidosis involvement. Tests of disease activity that are discussed in preceding sections are rarely used to determine the need for therapy. This is because the presence of active granulomatous inflammation from sarcoidosis does not imply that the disease will be progressive or lead to significant fibrosis and permanent organ damage.

Topical/Intralesional Therapy

Cutaneous sarcoidosis, including lupus pernio, may be improved with prolonged application (longer than 8 weeks) of class I topical steroids, but intralesional injections of triamcinolone are generally more effective. Topical tacrolimus reportedly has been effective for skin disease in several cases as well.83–85

Systemic Corticosteroids

In general, corticosteroids are the drug of choice for the treatment of sarcoidosis. The recommended initial dose for pulmonary sarcoidosis is 20–40 mg of prednisone equivalent/day.1,82 Cardiac and neurologic sarcoidosis may require higher initial doses, up to 60–80 mg of prednisone equivalent/day.1 The corticosteroid dose can often be tapered to 0.1–0.2 mg/kg of prednisone equivalent/day over a few months.1,82 It is unusual for patients with pulmonary sarcoidosis to require a maintenance corticosteroid dose of more than 15 mg of prednisone equivalent/day, although more may be required for sarcoidosis of the skin, heart, or nervous system. An attempt should be made to taper the corticosteroid dose within 9–12 months of the initiation of therapy.82 Cardiac sarcoidosis may be an exception to this rule if the patient has had previous life-threatening manifestations of cardiac involvement. If life-threatening arrhythmias have occurred, placement of an internal defibrillator is indicated.60,86,87

Immunosuppressive Medications

If the patient cannot be successfully weaned from corticosteroids, adjunctive immunosuppressive medications can be used.82 Most of these are inadequate as monotherapy but are effective as corticosteroid-sparing agents. The appropriate doses for sarcoidosis are listed in Table 152-3 and discussed in the following sections.

Methotrexate

After corticosteroids, methotrexate is the next most studied agent for sarcoidosis. It is usually corticosteroid sparing, and corticosteroids can be discontinued in one-fourth of cases.88 The drug requires careful monitoring of liver function tests and blood cell counts. Folic acid may be given in conjunction with methotrexate. Approximately 10% of sarcoidosis patients taking methotrexate develop cirrhosis, even if their liver function tests are normal.89 Therefore routine liver biopsies should be considered after 2 g of total therapy (usually after 2 years).89 Low-dose methotrexate, 10–25 mg a week, is used for the treatment of cutaneous sarcoidosis.90 Cutaneous improvement may be noted within 1 month, but maximal therapeutic benefit often does not occur until at least 6 months after the initiation of treatment.

Hydroxychloroquine/Chloroquine

Antimalarial drugs are useful for skin and joint sarcoidosis, and hypercalcemia.91,92 Antimalarial agents are not highly effective for pulmonary disease, often take several months to be effective, and cannot be used in patients with glucose-6 phosphodiesterase deficiency. Either drug, especially chloroquine, can cause retinal damage.93 Patients taking antimalarial agents must therefore have regular ophthalmologic examinations.

Cyclophosphamide

Cyclophosphamide is effective for many forms of sarcoidosis. However, because of its significant side-effect profile, including its carcinogenic potential, it is usually only used for severe or potentially life-threatening disease.

Tetracycline Derivatives

Minocycline and doxycycline have been reported to improve skin sarcoidosis in case series. These drugs may take more than 2 years to be effective.94 Although the efficacy of these drugs suggests that sarcoidosis may be caused by an infectious agent, the tetracyclines also modify the immune response by suppressing activity of macrophages and T lymphocytes.95

Tumor Necrosis Factor Antagonists

TNF is a cytokine that is secreted in macrophages associated with sarcoidal granulomas.9 Antagonists of TNF have been shown to be useful for the treatment of sarcoidosis. Pentoxifylline,96 thalidomide,97 and infliximab98 have been the most studied. Infliximab appears to be particularly useful for the treatment of lupus pernio,99 and it may be superior to other TNF antagonists, as a study of etanercept failed to show benefit for sarcoidal uveitis.100 A tuberculin skin test is required before the use of TNF antagonists, and patients taking the drugs must be monitored closely for the development of tuberculosis. Adalimumab has also been reported to treat sarcoidosis effectively.101

Other Agents

Azathioprine,102 mycophenolate mofetil,103 leflunomide,104 and cyclosporine105 have been reported to be useful for the treatment of systemic sarcoidosis in case reports or small case series. Allopurinol,106 isotretinoin,107 and fumaric acid esters108 have been reported to be effective for sarcoidal skin disease. Resolution of sarcoidal skin manifestations after phototherapy and photodynamic therapy has also been described.109

Surgical Treatment

Electrodesiccation, pulse dye laser therapy, carbon dioxide laser therapy, and reconstructive surgical procedures have all been used successfully to improve the cosmetic disfigurement of cutaneous sarcoidosis, but these interventions do not have any effect on disease progression.

As the cause of sarcoidosis remains unknown, prevention is currently impossible.

Several clinical photographs were contributed by Lawrence Lieblich, M.D.