Skin sarcoidosis

In the United States, chronic skin sarcoidosis is more common in African Americans than Caucasians. In ACCESS, where patients were evaluated within six months of diagnosis, 19.7 % (64/325) of African Americans had specific (granulomatous) sarcoidosis skin lesions compared to 13.0% (51/393) of Caucasians (chi-square = 5.5, p < 0.05) (25). 

The diagnosis of specific sarcoidosis skin lesions usually requires a confirmatory biopsy. On occasion, a clinical diagnosis of skin sarcoidosis may be made if the lesions are typical (e.g., lupus pernio or lesions present on scar tissue). Sarcoidosis is not the only cause of granulomatous inflammation of the skin, and other potential causes must be carefully excluded. Usually the diagnosis of skin sarcoidosis is not secure without evidence of extracutaneous granulomatous disease. 

The diagnosis of skin sarcoidosis tends to be made rapidly relative to other organ involvement with sarcoidosis because the skin lesions are evident and can be easily biopsied. In a cohort of ACCESS patients, the patients with skin sarcoidosis were diagnosed significantly faster than those with pulmonary sarcoidosis (30). Patents with nonspecific skin lesions such as erythema nodosum do not demonstrate granulomatous inflammation on biopsy. Therefore, skin biopsies should be avoided in these patients as the procedure has no value in their diagnosis. 

Because skin sarcoidosis is rarely associated with significant morbidity or mortality and may remit spontaneously, the decision to treat is based primarily on cosmetic concerns. 

Corticosteroids are the drug of choice for the treatment of skin sarcoidosis. Usually a dose of 20 to 40 mg of prednisone equivalent/day is used initially and the dose is tapered depending on the treatment effect and the development of corticosteroid side effects. 

Hydroxychloroquine/chloroquine are often useful for patients with skin sarcoidosis (41). Their side-effect profile is much better than that of corticosteroids. However their maximum effect is often not achieved for several months. Therefore, they are often started simultaneously with corticosteroids, and the corticosteroids are tapered over several months while the antimalarials take effect. They cannot be used in patients with G6PD deficiency. Either drug, especially chloroquine, may cause retinal damage (41). Patients on antimalarial agents must therefore have regular ophthalmologic examinations. 

Minocycline and doxycycline have been reported to be effective for skin sarcoidosis in case series (44). Therapy with these drugs for more than two years may be required for them to be effective (44). Although these data suggest that sarcoidosis may be caused by an infectious agent, the tetracyclines also modify the immune response by suppressing activity of macrophages and T lymphocytes (45). 

Kaplan (1960) observed that colchicine may produce objective improvement in the periarthritis associated with sarcoidosis (presence of noncaseat-ing granulomas in tissue), Colchicine is sometimes used in llte treatment of scleroderma (deposition of fibrous connective tissues in skin or other organs) it may assist in preventing attacks of Mediterranean fever and it is sometimes used as part of drug therapy for some renal (kidney) diseases. 

Patients with sarcoidosis are intolerant of vitamin D possibly even to the tiny amoimt present in a normal diet, and to that synthesised in their skin by sunlight. The intolerance may be due to overproduction of calcitriol (see above) by macrophages activated by interferon the overproduction is reversed by corticosteroid, which is also used in the treatment of severe hypervitaminosis D (see below). 

Fumaric acid esters are used to treat a variety of skin disorders, including psoriasis (1), cutaneous sarcoidosis (2), necrobiosis lipoidica diabeticorum (3), and disseminated granuloma annulare (4). 

Recognized in 1961 (KIO), these are now well described (B18) and mimic the syndrome of mixed cryoglobulinemia (see 6.13). Skin lesions in this condition are raised, painful, and edematous with or without necrosis. Biopsy always reveals arteritis with a mononuclear and neutro-phile infiltrate. There is in most cases a preceding history of rheumatoid arthritis, Sjogren s syndrome, syphilis, sarcoidosis or other hyperimmune states, and this will dominate the clinical findings. Rarely the protein interactions build up to a level presenting as a viscosity syndrome so that this group can overlap with 7.7.1 unless the serum is carefully examined. 

Both chloroquine and hydroxychloroquine (Plaquenil ) have been reported as beneficial in treating sarcoidosis (218). In a randomized trial of chronic pulmonary disease, Baltzan et al. demonstrated that chloroquine slowed the progression of the disease (219). The antunalarials are associated with a higher rate of response for extrathoracic disease such as skin (218,220-223) and hyper-calcemic manifestations. These dmgs have not been studied in other ILDs. 

The frequency of chronic skin lesions in sarcoidosis ranges from 9% to 37% in various series (25-27). In A Case Control Etiology of Sarcoidosis study (ACCESS) sponsored by the National Institute of Health, chronic skin involvement was second in frequency [113/718 (15.7%)] only to lung involvement (28). Although cutaneous involvement may occur at any stage of the disease, it is most often present at the onset (25). 

Erythema nodosum, a nongranulomatous inflammatory skin lesion that occurs in approximately 10% of sarcoidosis patients (Fig. 5) (28). It is more common in women than men (28) and is also common in Europeans, Puerto Ricans, and Mexicans, particularly in women of childbearing age of these ethnicities (29). 

Data from ACCESS suggest that granulomatous skin involvement develops more commonly than other new organ involvement within the first two years of the diagnosis of sarcoidosis [13/215 (6%)] (30). Although not subjected to statistical analysis, these ACCESS data suggested that new onset skin involvement was more common in African Americans than Caucasians [10/93 (10.7%) versus 3/117 (2.6%)]. 

Cutaneous sarcoidosis lesions are divided into two categories specific and nonspecific. Specific lesions reveal granulomatous inflammation on biopsy. Nonspecific skin findings are reactive inflammatory lesions that do not exhibit sarcoidal granulomas. 

Despite the diversity in appearance, there are several clinical presentations that are typical for cutaneous sarcoidosis. The most common presentation is the papular form. These lesions are firm, 2 to 5 mm papules, and often have a translucent red-brown or yellow-brown qipearance (31). The yellow-brown color has been likened to apple jelly (31). Papular lesions occur most commonly on the face and neck with a predilection for periorbital skin. 

Another distinctive specific sarcoidosis skin lesion is lupus pernio, relatively symmetric, violaceous, indurated plaque-like and nodular sarcoidal lesions occurring on the nose, ear lobes, cheeks, and digits (Figs. 6 and 7). Lupus pernio... 

Figure 8 (See color insert.) Sarcoidosis skin lesions in a tattoo.

Cutaneous sarcoidosis may occur within scar tissue (33), tattoos (Fig. 8) (34), at traumatized skin sites, and around imbedded foreign material such as silica. Scar sarcoidosis may be the only cutaneous finding in a patient with systemic sarcoidosis therefore, it is important to closely examine scar... 

Erythema nodosum is the main nonspecific cutaneous manifestation of sarcoidosis. They present as violaceous to erythematous tender nodules on the extremities. In general, nonspecific sarcoidosis skin lesions are associated with an acute form of sarcoidosis that has a good prognosis where eventual resolution of the disease is common (39). 

Tumor necrosis factor alpha (TNF-a) is a cytokine that is secreted by macrophages associated with sarcoid granulomas (46). Antagonists of TNF-a including thalidomide (47), and infliximab (48) have been shown to be useful for the treatment of cutaneous sarcoidosis. Infliximab appears to be particularly useful for the treatment of lupus pernio (48). The use of infliximab is limited by its high cost and the need for intravenous administration. Fatal cases of tuberculosis have been associated with infliximab administration (49). Therefore, a tuberculin skin test is required prior to its use, and patients on the drug must be monitored closely for the development of tuberculosis. 

The reported incidence of hypercalcemia in sarcoidosis has varied from 2% to 63% in various series (180). These disparate findings may be attributable to differences in sunlight exposure, dietary calcium, skin color, and genetic factors of the populations studied. ACCESS found that a disorder in calcium metabolism from sarcoidosis was more common in men than women [17/268 (6.3%) versus 10/468 (2.1%), chi-square 7.38, p < 0.01], Caucasians compared to African Americans [20/393 (5.1%) versus 6/325 (1.8%), chi-square 223, p < 0.0001], and those diagnosed >age 40 years compared to <40 years [22/401 (5.5%) versus 5/335 (1.5%), chi-square 7.15, p < 0.01] (2). 

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