AUTHOR AND EDITOR INFORMATION

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
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Background

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.

For more information from eMedicine and Medscape, see the following:

• Novel Therapies for Sarcoidosis
• Mycobacterial Antigens May Be Important In Sarcoidosis Pathogenesis
• Sarcoidosis (pediatric focus)
• Sarcoidosis (ophthalmology focus)

Pathophysiology

The etiology of sarcoidosis is unknown, but several immune aberrations have been noted and are thought to play a role in its pathogenesis. Studies have shown an increase in B-cell activity with hypergammaglobulinemia noted in about one half of patients and in nonspecific immune-complex formation. Reduced delayed-type hypersensitivity responses are also found in many patients with sarcoidosis. Cutaneous anergy to tuberculin intradermal testing occurs in two thirds of patients. Immune dysregulation has been theorized to be due to a persistent antigen of low virulence that is poorly cleared by the immune system, leading to a chronic T cell of the Th1 subtype response, which results in granuloma formation. Medications that increase the Th1 response, such as interferon, have been reported to trigger or exacerbate sarcoidosis.¹ Recently, the gli-1 oncogene has been found to be highly expressed in persons with granulomatous skin diseases, including sarcoidosis.²

Proposed antigens fall into 3 categories that include infectious, environmental, and autoantigens. The most common infectious agents implicated are Mycobacterium tuberculosis, Mycoplasma species, Corynebacteria species, spirochetes, atypical mycobacteria, Propionibacterium acnes, Borrelia burgdorferi, herpes simplex virus, hepatitis C virus, Epstein-Barr virus, cytomegalovirus, coxsackievirus, rubella virus, Histoplasma species, Cryptococcus species, coccidioidomycosis, and sporotrichosis. Environmental antigens implicated include metals (eg, zirconium, aluminum, beryllium), organic dusts (eg, pine, pollen), and inorganic dusts (eg, clay, soil, talc). Heat shock protein has also been implicated.

Frequency

United States

The prevalence of sarcoidosis is 1-40 cases per 100,000 population. In whites, the annual incidence is 10-14 cases per 100,000 population, whereas in African Americans, especially women, the annual incidence is much higher, at 35.5-64 cases per 100,000 population.³

International

Sarcoidosis affects people worldwide. It is found in every country and every race, although the incidence varies dramatically. In Europe, the disease affects whites more commonly than other races, and it affects Western Europeans more than Eastern Europeans. Scandinavians have one of the highest incidence rates at 64 cases per 100,000 population, whereas, in Poland, the incidence is 3 cases per 100,000 population. The disease is rare in Eskimos, Southeast Asians, New Zealand Maoris, and native Canadian populations.

Mortality/Morbidity

The course of sarcoidosis is variable, ranging from self-limited acute disease to a chronic debilitating disease that may result in death. Spontaneous remissions occur in nearly two thirds of patients, but 10-30% of patients have a more chronic or progressive course.

• The mortality rate is 1-6%. Sarcoidosis can lead to death from severe involvement of lung parenchyma leading to pulmonary fibrosis and respiratory failure and from myocardial involvement leading to arrhythmias and cardiac failure.
• Other causes of significant morbidity and mortality include CNS involvement, blindness, pulmonary hemorrhage, renal insufficiency, hypopituitarism, and liver disease.

Race

In the United States, the disease is 10-17 times more common in African Americans than in whites.³ Whites present more commonly with earlier stage disease, usually bilateral hilar adenopathy (see Media File 2); African Americans present at an earlier age with later stage disease. African Americans also have a greater likelihood of developing extrathoracic disease, lupus pernio (see Physical), cystic bone lesions, chronic uveitis, chronic progressive disease, worse long-term prognosis, and a higher relapse rate. Lupus pernio also occurs with a higher frequency among Puerto Ricans than whites (see Media File 7). Erythema nodosum more commonly effects the Scandinavian population. Cardiac involvement is more common in Japan than in other countries.

Sex

Sarcoidosis affects both men and women, but it seems to be most prevalent among African American women. The incidence of sarcoidosis is highest in African American women followed in order by African American men, white women, and white men.

Age

Although sarcoidosis can appear at any age, a bimodal age distribution is seen, which peaks between ages 25-35 and 45-65 years.

CLINICAL

Section 3 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Because sarcoidosis can involve any organ system, the clinical presentation is often variable. Patients most commonly present in winter and early spring, which suggests a possible environmental trigger. The onset is usually insidious, and findings may be discovered on routine chest radiographs. Cutaneous involvement is seen in 25% of patients with sarcoidosis; it usually accompanies systemic involvement but may be the only site of involvement.

• General manifestations: One third of patients have constitutional symptoms, such as fever, fatigue, and weight loss.
• Pulmonary system: The lungs are affected in most patients. Symptoms occur in one third to one half of patients and most commonly include dyspnea, dry cough, and chest tightness or pain. The disease can progress to parenchymal infiltration and, ultimately, irreversible fibrosis.
• Lymphatic system: One third of patients with sarcoidosis have palpable lymph nodes that are moveable and nontender. Right paratracheal lymph node enlargement is most commonly seen, followed next by cervical nodes.
• Ocular involvement: Anterior uveitis is the most common finding, which may be associated with fever and parotid swelling (also called uveoparotid fever). Chronic uveitis, most commonly occurring in African Americans, can lead to adhesions, glaucoma, cataract formation, and blindness. Although uveitis is most common, any part of the eye may be affected.
• Neurosarcoidosis: Involvement of the nervous system occurs in fewer than 10% of patients; it may be lethal. The disease can affect any part of the nervous system. Seventh cranial nerve palsy is the most frequent finding. The pituitary gland and the hypothalamus may be involved.
• Myocardial involvement: Clinically apparent cardiac involvement occurs in 5% of patients in the United States.
• Other organs may be involved: Elevated liver function tests suggestive of hepatic dysfunction, arthritis, proximal muscle weakness, anemia, leukopenia, hypercalcemia, diabetes insipidus, and renal failure may be noted.

Physical

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) is the main nonspecific cutaneous disease (see Media File 1); lupus pernio, maculopapular, nodular, scar, plaque, angiolupoid, ichthyosiform, lichenoid, psoriasiform, and ulcerative lesions and subcutaneous nodules are examples of specific cutaneous disease.

• 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 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.
• 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, the cheeks, the ears, and the lips, but it can appear on the dorsa of the hands, the fingers, the toes, and the forehead.
  • 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%).⁴
• Macular or papular sarcoidosis is the most common lesion seen in cutaneous sarcoidosis, especially in African American 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.
• Plaque sarcoidosis is characterized by round-to-oval, red-brown to purple infiltrated plaques; the center of the plaque may be atrophic (see Media File 5).
• • Some plaques may even appear scaly and can be confused with lesions of psoriasis or lichen planus.
  • They most commonly occur on the extremities, the face, the scalp, the back, and the buttocks, and they may have an annular appearance. The distribution is usually symmetric.
  • 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 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 the trunk.
  • These lesions usually appear in the beginning of the disease. These patients often have nonsevere systemic disease. In some patients, the nodules resolve spontaneously.
• Infiltration of scars may occur (see Media File 9). Scars from previous trauma, surgery, venipuncture, or tattoo may become infiltrated and show a red or purple color. These lesions may be tender.
• Sarcoidosis is called the "great imitator" because it can have almost any morphology.⁵ Other rare lesions of cutaneous sarcoidosis are ichthyosiform,⁶ lichenoid, vasculitic,⁷ psoriasiform, erythrodermic, verrucous, papillomatous, and ulcerative lesions.

Causes

The exact etiology of sarcoidosis has not been clearly defined. Genetic as well as environmental factors are thought to play a role in the disease process. Sarcoidosis is thought to result from exposure of a genetically susceptible host to specific environmental agents that the immune system is unable to clear effectively.

• Environmental influence
• • Numerous geographically localized outbreaks have been reported and suggest the possibility of an infectious agent or shared environmental exposure as the causative agents. Infectious organisms, such as mycobacteria, can induce granulomatous inflammation. Many organisms have been linked to sarcoidosis, including Mycoplasma species; Borrelia burgdorferi; Propionibacterium acnes; fungi, such as Histoplasma and Cryptococcus species; viruses, such as Epstein-Barr virus, cytomegalovirus, herpes simplex virus, hepatitis C virus,⁸ and rubella; and numerous other organisms.
  • Noninfectious agents, such as aluminum, zirconium, talc, pine tree pollen, and clay, have also been implicated.
• Genetic factors
• • Familial clustering of cases has been reported. Monozygotic twins are 2-4 times as likely to have the disease as dizygotic twins.⁹
  • Certain HLA associations have been demonstrated; the most common allele found in sarcoidosis is HLA-B8. Other associated alleles include HLA-A1 and HLA-DR3.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

B-cell lymphoma
Foreign body reaction
Lichen planopilaris

WORKUP

Section 5 of 11  

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Lab Studies

• CBC count with differential and platelets
• • Leukopenia and/or thrombocytopenia are frequent findings.
  • Eosinophilia occurs in 24% of patients, and anemia occurs in 5% of patients.
• Serum calcium and 24-hour urine calcium levels
• • Hypercalciuria has been found in 49% of patients in some studies, whereas 13% of patients had hypercalcemia.
  • Hypercalcemia occurs in sarcoidosis due to increased intestinal absorption of calcium that results from overproduction of a metabolite of vitamin D by pulmonary macrophages.
• Serum angiotensin-converting enzyme (ACE) level¹⁰
• • Serum ACE level is elevated in 60% of patients; therefore, this test is not sensitive in diagnosing sarcoidosis.
  • Serum ACE levels are helpful in monitoring disease activity and treatment response. ACE is derived from epithelioid cells of the granulomas, therefore, it reflects granuloma load in the patient.
• Serum chemistries, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, BUN, and creatinine levels: These levels may be elevated with hepatic and renal involvement.
• Other: Elevated liver function tests suggestive of hepatic dysfunction, elevated erythrocyte sedimentation rate, elevated anti-nuclear antibodies (30%), diabetes insipidus, and renal failure may be noted.

Imaging Studies

• Chest radiography
• • Radiographic involvement is seen in almost 90% of patients. Chest radiography is used in staging the disease.
  • Stage I disease shows bilateral hilar lymphadenopathy (BHL). Stage II disease shows BHL plus pulmonary infiltrates. Stage III disease shows pulmonary infiltrates without BHL (see Media File 3). Stage IV disease shows pulmonary fibrosis.
• CT of the thorax
• • CT of the thorax may demonstrate lymphadenopathy or granulomatous infiltration.
  • Other findings may include small nodules with a bronchovascular and subpleural distribution, thickened interlobular septae, honeycombing, bronchiectasis, and alveolar consolidation.
• Whole body gallium Ga 67 scanning
• • Two common findings seen in sarcoidosis are the lambda and panda patterns.
  • The lambda pattern is produced by uptake of the right paratracheal and bilateral hilar lymph nodes. The panda image is produced by symmetric uptake by the lacrimal and parotid glands.

Other Tests

• Kveim test
• • This 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 it is histologically examined for noncaseating granuloma formation, which, if found, indicates a positive result.
• Tuberculin skin test
• • Patients with sarcoidosis have impaired delayed-type immune reactions.
  • Two thirds of patients have cutaneous anergy to the tuberculin skin test.
• Pulmonary function test
• • The most common abnormalities found are defects in diffusing capacity and vital capacity.
  • Evidence of both restrictive abnormalities and obstructive abnormalities may be found.
• Bronchoalveolar lavage with a CD4/CD8 ratio: A CD4/CD8 ratio of more than 3.5 has a specificity of 94% for sarcoidosis.
• Electrocardiogram
• • An ECG should be performed to rule out unsuspected or asymptomatic arrhythmias or heart block.
  • Unsuspected ECG abnormalities may be seen in 10% or more of patients with systemic sarcoidosis, including Löfgren syndrome (see Physical).

Procedures

• Biopsy of tissue
• • 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.

Histologic Findings

Typical sarcoid lesions are characterized by the presence of circumscribed granulomas of epithelioid cells with little or no necrosis (see Media File 10). Granulomas are usually in the superficial dermis, but they may involve the thickness of the dermis and extend to the subcutaneous tissue. 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, which 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.

TREATMENT

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Medical Care

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 neurologic, cardiac, or ocular involvement not responding to topical corticosteroids; hypercalcemia; and symptomatic stage II and all stage III pulmonary disease. 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/d. As opposed to the more severe systemic involvement requiring oral therapy, Löfgren syndrome is usually an acute process, which is self-limited and 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 2-5 mg/mL of triamcinolone acetonide can be used at monthly intervals. More chronic skin lesions, such as plaques or lupus pernio, need more aggressive therapy because they can lead to permanent scars. If intralesional corticosteroids are not effective, other standard therapies include systemic corticosteroids, methotrexate,^{11, 12, 13} and antimalarials (hydroxychloroquine¹⁴ and chloroquine) can be used.¹⁵ 
• Other agents that have been used to treat cutaneous sarcoidosis include cyclosporine, chlorambucil,¹⁶ oral isotretinoin,¹⁷ allopurinol,¹⁸ minocycline,¹⁹ doxycycline, psoralen with UVA, infliximab,²⁰ etanercept, adalimumab,²¹ thalidomide,^{22, 23, 24} leflunomide, pentoxifylline, and melatonin.²⁵
• One case report describes remission of sarcoidosis after the patient was placed on an ACE inhibitor.²⁶
• Radiation has also been used to treat treatment-resistant cutaneous lesions.²⁷

Surgical Care

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 dioxide²⁸ and pulsed dye laser has also been used in the treatment of disfiguring skin plaques and lupus pernio.

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.

Diet

No specific diet is recommended.

Activity

Activity is not restricted, unless the lungs are affected, in which case the patient's activity may be limited by shortness of breath.

MEDICATION

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The most commonly used medications in the treatment of cutaneous sarcoidosis are corticosteroids (eg, topical, intralesional, oral), methotrexate, azathioprine, and hydroxychloroquine. Case reports have described improvement with minocycline, isotretinoin, thalidomide, and infliximab.

Drug Category: Corticosteroids

These agents are effective in stopping symptoms of disease. They are usually not indicated in cutaneous disease unless the patient has chronic, disfiguring lesions (eg, plaques, lupus pernio).

Drug Category: Cytotoxic agents

These agents can decrease the dose of corticosteroid needed to control the disease. These agents can also be used for patients refractory to or those who cannot tolerate the adverse effects of systemic corticosteroids.

Drug Category: Antimalarials

These agents may have immunomodulatory effects.

Drug Category: Immunomodulatory agents

These agents regulate key factors of the immune system.

Drug Category: Tumor necrosis factor inhibitors

These agents inhibit tumor necrosis factor activity.

FOLLOW-UP

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Further 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.

Further Outpatient Care

• 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 review of systems, 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.

Prognosis

• The course of the disease is variable, but spontaneous remission occurs in 50% of patients, while another one third of patients have eventual improvement. About 10-30% of patients have chronic or progressive disease.
• The mortality rate is 1-6%. In the United States, mortality is most commonly due to respiratory failure from pulmonary involvement, cardiac involvement, or neurosarcoidosis. Complications of therapy are additional causes of morbidity and mortality.
• Adverse prognostic factors include African American race, chronic cutaneous lesions, chronic uveitis, age at onset older than 40 years, cystic bone lesions, neurosarcoidosis, myocardial involvement, and stage III or IV pulmonary disease.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Misdiagnosis is a pitfall.
• Toxicity from therapy, especially in an uninformed or unreliable patient.
• Failure to recognize systemic or ocular involvement is a pitfall.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Erythema nodosum.
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Media file 2:  Bilateral hilar lymphadenopathy.
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Media file 3:  Stage III pulmonary disease with pulmonary infiltrates.
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Media file 4:  Periocular papules and plaques.
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Media file 5:  Plaque sarcoidosis.
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Media file 6:  Erythematous papules on the knee.
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Media file 7:  Lupus pernio with nodules on the nasal tip and sidewall.
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Media file 8:  Annular sarcoidosis.
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Media file 9:  Sarcoidosis with infiltration of a scar.
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Media file 10:  Histopathologic features of sarcoidosis showing the hallmark noncaseating granulomas.
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Media file 11:  Cutaneous sarcoidosis. Violaceous papules or nodules of lupus pernio.
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REFERENCES

Section 11 of 11

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24. Rousseau L, Beylot-Barry M, Doutre MS, Beylot C. Cutaneous sarcoidosis successfully treated with low doses of thalidomide. Arch Dermatol. Aug 1998;134(8):1045-6. [Medline].
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Article Last Updated: May 12, 2008