Dermatologic Manifestations of Sarcoidosis 

Dermatologic manifestations are seen in 25% of patients with sarcoidosis. They usually accompany systemic involvement, but in some cases they may be the only manifestations of the disease. Sarcoidosis is characterized by noncaseating epithelioid granulomas that may affect any organ system.

Although Jonathan Hutchinson described the first case in 1869, the etiology of the disease is still unknown. The disease most commonly involves granuloma formation in the lungs. Other commonly involved organ systems include the lymph nodes (especially the intrathoracic nodes), the skin, the eyes, the liver, the heart, and the nervous, musculoskeletal, renal, and endocrine systems.

Cutaneous involvement is either specific or nonspecific. Histopathologically, specific lesions manifest as noncaseating granulomas, whereas nonspecific lesions do not reveal granulomas on histopathologic examination. Erythema nodosum (EN) (shown below) is the main nonspecific cutaneous disease. Lupus pernio, maculopapular, nodular, scar, plaque, angiolupoid, ichthyosiform, lichenoid, psoriasiform, and ulcerative lesions and subcutaneous nodules are examples of specific cutaneous disease.

Erythema nodosum

EN is a hypersensitivity reaction resulting from exposure to a variety of infections or inflammatory disorders. EN is usually an acute, self-limiting process and rarely requires treatment. Recurrences are uncommon. Tender, erythematous nodules are usually present on the extremities, most commonly on the anterior surface of the tibia. EN is more common in European, especially Scandinavian, women of childbearing age than in other people.

Löfgren syndrome

Löfgren syndrome is EN in conjunction with unilateral or bilateral hilar and/or right paratracheal lymphadenopathy, anterior uveitis, and/or polyarthritis. Other symptoms include fever, periarticular ankle inflammation, arthralgias, and pulmonary involvement.

Löfgren syndrome is usually an acute disease with an excellent prognosis, typically resolving spontaneously in 6-8 weeks. Pulmonologists, ophthalmologists, and rheumatologists often define this syndrome differently, describing varying combinations of arthritis, arthralgia, uveitis, EN, hilar adenopathy, and/or other clinical findings. (See the image below.)

Lupus pernio

Lupus pernio, first described by Besnier in 1889, is a striking manifestation of sarcoidal skin lesions. Lupus pernio is characterized by red to purple or violaceous, indurated plaques and nodules that usually affect the nose, cheeks, ears, and lips, but it can appear on the dorsa of the hands, and on the fingers, toes, and forehead. (See the images below.)

Lupus pernio is usually more common in black women with long-standing systemic, usually pulmonary, sarcoidosis than in other people. It is also commonly seen with chronic uveitis and bone cysts. The course is usually chronic, and severe cosmetic disfigurement may result. Lupus pernio, especially involving the nasal rim, has been associated with granulomatous involvement of the upper respiratory tract (50%) and lungs (75%).^[1]

Macular sarcoidosis

Macular or papular sarcoidosis is the most common lesion seen in cutaneous sarcoidosis, especially in black women. Granulomatous acne rosacea may mimic sarcoidosis clinically and histopathologically. Usually, lesions are asymptomatic, red-brown macules and papules commonly involving the face, the periorbital areas, the nasolabial folds, and/or the extensor surfaces. Lesions usually resolve without scarring, although scarring may occur. These lesions may also occur in acute sarcoidosis. (See the image below.)

Plaque sarcoidosis

Plaque sarcoidosis is characterized by round to oval, red-brown to purple, infiltrated plaques; the center of the plaque may be atrophic (see the image below). Some plaques may even appear scaly and can be confused with lesions of psoriasis or lichen planus.

The lesions most commonly occur on the extremities, face, scalp, back, and buttocks, and they may have an annular appearance (see the image below). The distribution is usually symmetrical. Angiolupoid sarcoidosis is a subtype that has a similar appearance but has large, telangiectatic vessels in addition to the characteristics mentioned above. This form of cutaneous involvement is usually chronic; most patients have the disease for more than 2 years. Lesions can heal with scarring, and, if plaques involve the scalp, they may lead to alopecia. Patients with plaque lesions usually have more severe systemic involvement.

Subcutaneous nodular sarcoidosis

Subcutaneous nodular sarcoidosis is also called Darier-Roussy sarcoidosis. Lesions are usually nontender, firm, oval, flesh-colored or violaceous nodules that are 0.5-2 cm in diameter. They are commonly found on the extremities or trunk. These lesions usually appear in the beginning of the disease. Patients with these lesions often have nonsevere systemic disease. In some patients, the nodules resolve spontaneously.^{[2, 3]}

Other lesions

Sarcoidosis is called the "great imitator" because it can have almost any morphology.^[4] Other rare lesions of cutaneous sarcoidosis are ichthyosiform,^[5] lichenoid, vasculitic,^[6] psoriasiform, erythrodermic, verrucous, papillomatous, and ulcerative lesions. (See the image below.)

Scar infiltration

Infiltration of scars may occur (see the image below). Scars from previous trauma, surgery, venipuncture, or tattoo may become infiltrated and show a red or purple color. These lesions may be tender.

Dermatologic conditions to consider in the differential diagnosis of sarcoidosis include the following:

• Cutaneous tuberculosis
• Drug eruptions
• Granuloma annulare
• Granuloma faciale
• Lamellar ichthyosis
• Leprosy
• Lichen planus
• Discoid lupus erythematosus
• Subacute cutaneous lupus erythematosus
• Lymphocytoma cutis
• Necrobiosis lipoidica
• Plaque psoriasis
• Syphilis
• Tinea corporis

B-cell lymphoma, foreign body reaction, and lichen planopilaris should also be considered in the differential diagnosis.

Kveim-Siltzbach test

The Kveim test is the most specific test for sarcoidosis. It is not commonly available because of difficulty in obtaining a validated antigen source, as well as a fear of transmitting infection. The Kveim test involves intradermal injection of tissue from the spleen or the lymph node of a patient with sarcoidosis. A biopsy sample is obtained from the area 4-6 weeks after injection and is histologically examined for noncaseating granuloma formation, which, if found, indicates a positive result.

Tuberculin skin test

Regarding the tuberculin skin test, patients with sarcoidosis have impaired delayed-type immune reactions. Two thirds of patients have cutaneous anergy to the tuberculin skin test.

The skin is the most easily accessible tissue for biopsy. Biopsy of all cutaneous lesions of sarcoidosis, except EN, is helpful because, histologically, EN is not specific for sarcoidosis. Obtaining a biopsy specimen is extremely important in confirming the diagnosis of sarcoidosis. Biopsy specimens need to be sent for histologic examination, and staining may need to be performed to rule out infectious causes of granuloma formation, including mycobacterial and deep fungal infections. Tissue culture may be appropriate in some clinical settings, especially if fungal or atypical mycobacterial infections are suspected. A biopsy sample of bronchial mucosa demonstrates the presence of noncaseating granulomas.

Typical sarcoid lesions are characterized by the presence of circumscribed granulomas of epithelioid cells with little or no necrosis. Granulomas are usually in the superficial dermis, but they may involve the thickness of the dermis and extend to the subcutaneous tissue. (See the image below.)

Islands of epithelioid cells may contain a few Langhans giant cells. Giant cells may contain asteroid or Schaumann bodies. Asteroid bodies are star-shaped eosinophilic structures. Schaumann bodies are round or oval, laminated structures that are usually calcified at the periphery. Granulomas are referred to as naked, because they only have a sparse lymphocytic infiltrate at the margins or granulomas. Fibrosis, if present, usually starts at the periphery and advances toward the center.

The need for medical therapy varies based on the symptoms and the organ systems involved in each patient. Oral corticosteroids are usually the treatment of choice for patients with hypercalcemia and for those with symptomatic stage II and all stage III pulmonary disease, as well as for patients with neurologic, cardiac, or ocular involvement who are not responding to topical corticosteroids. The usual dose is 30-40 mg of prednisone daily for 2-3 months, with a gradual taper over 1 year to 10-20 mg every other day. Patients with severe disease may need prednisone doses up to 1 mg/kg/day.

As opposed to the more severe systemic involvement requiring oral therapy, Löfgren syndrome is usually an acute process that is self-limited and that resolves without immunosuppressive treatment in weeks. Symptomatic relief can be obtained using nonsteroidal anti-inflammatory drugs (NSAIDs).

Limited, nondisfiguring cutaneous involvement may be treated with topical or intralesional corticosteroids. Intralesional injections of 2-10 mg/mL^[7] of triamcinolone acetonide can be used at monthly intervals. More chronic skin lesions, such as plaques or lupus pernio, require more aggressive therapy because they can lead to permanent scarring.

If intralesional corticosteroids are not effective, other standard therapies include systemic corticosteroids, methotrexate,^{[8, 9, 10]} antimalarials (hydroxychloroquine^[11] and chloroquine).^[12] Infliximab is a promising option for patients with recalcitrant or disfiguring disease.^{[7, 13, 14]}

Other agents that have been used to treat cutaneous sarcoidosis include:

• Cyclosporine
• Chlorambucil^[15]
• Oral isotretinoin^[16]
• Allopurinol^[17]
• Minocycline^[18]
• Doxycycline
• Psoralen with ultraviolet A (UVA)
• Infliximab^[19]
• Etanercept
• Adalimumab^[20]
• Thalidomide^{[21, 22, 23]}
• Leflunomide
• Pentoxifylline
• Melatonin^[24]

One case report describes remission of sarcoidosis after the patient was placed on an angiotensin-converting enzyme (ACE) inhibitor.^[25] Another report describes improvement in 2 cases using photodynamic therapy with methyl aminolevulinate (Metvix).^[26]

In terms of nonpharmacologic therapy, radiation has been used in cases of treatment-resistant cutaneous lesions.^[27]

Surgical excision of small lesions or excision of larger lesions with skin grafting can be attempted. The risk of lesion recurrence and hypertrophic and keloidal scarring does exist. Laser surgery using carbon dioxide^[28] and pulsed dye laser has also been used in the treatment of disfiguring skin plaques and lupus pernio.^[7]

Inpatient care

Inpatient care is rarely needed for patients with cutaneous disease. However, in patients with respiratory insufficiency, hospitalization may be needed. Also, some patients may develop infections while on corticosteroids and/or immunosuppressive therapy that may result in hospitalization.

Consultations

Early involvement of other clinicians, such as an ophthalmologist, an internist, and a pulmonologist, for monitoring other organ systems that may be involved is recommended.

Long-Term Monitoring

Follow-up care should be frequent for the first 2 years after diagnosis. Patients with stage I disease can receive follow-up care twice yearly, whereas patients with more advanced lung disease should be seen more frequently. All patients should be monitored for at least 3 years after discontinuation of therapy.

During follow-up care, patients should have a history with a review of systems and should undergo physical examination, chest radiography, and pulmonary function tests to evaluate for active or insidiously progressive disease.

Ophthalmologic assessment is needed initially—generally annually in all patients and more frequently in those with ocular involvement. Therapeutic use of hydroxychloroquine (Plaquenil) may also warrant more frequent, detailed ophthalmologic examinations.

A large review by Ji et al of the Swedish Hospital Registry noted an elevated risk of skin cancer (especially squamous cell carcinoma), non-Hodgkin lymphoma, and leukemia in hospitalized patients with sarcoidosis, extending beyond the first year after hospitalization. Therefore, close follow up for malignancies is recommended.^[29]