Sarcoidosis
Key Points
Sarcoidosis is a multisystem inflammatory disease of unknown etiology characterized by noncaseating granulomas in the involved organs
The most common manifestation is pulmonary involvement, but extrapulmonary manifestations include the skin, central nervous system, peripheral nervous system, liver, kidney, musculoskeletal system, heart, salivary glands, the eye, and orbit
Sarcoid uveitis is the most common ophthalmic manifestation
Scar sarcoidosis is a rare circumscribed form of cutaneous sarcoidosis localized in scars
Sarcoidosis develops in genetically susceptible individuals through an alteration of the immune system in response to certain environmental, occupational, or infectious exposures
Eyelid lesions appear as yellowish to violaceous scaling, erythematous, firm small nodules, often associated with epiphora, pruritus, eyelid thickening, madarosis, and occasionally poliosis or trichiasis
Up to 30% of patients with clinical sarcoidosis will undergo spontaneous remission
Oral or intralesional corticosteroids are the initial treatment of choice for the management of sarcoid lesions of the eyelid
Sarcoidosis is thought to predominantly be a benign condition, but more than 40% of patients require treatment for many years
Sarcoidosis is a multisystem inflammatory disease of unknown etiology characterized by noncaseating granulomas in the involved organs. Signs and symptoms of the disease are not specific, and it may take months to years before the correct diagnosis is made.1 Sarcoidosis has a female predilection. Females also present at an earlier age and show a significantly higher frequency of eye, salivary gland, and skin involvement.2 The age at onset shows peak incidences in the 3rd and 5th decades of life, but it can also be seen in children and adults over the age of 60. The disease is more common in black individuals than white, with an incidence ratio of 2:1 to 7:13,4,5 and a prevalence ratio of 3:1 to 5:1.3 Serum angiotensin converting enzyme (ACE) has been used as a major biomarker for the diagnosis of sarcoidosis. ACE is produced by the epithelioid cells of the sarcoid granuloma,6 and serum ACE levels have been used as a reflection of the granuloma burden in this disease,7 with a sensitivity for the diagnosis between 41% and 100% and a specificity of 83% to 99%.8
The most common manifestation of sarcoidosis is pulmonary involvement but extrapulmonary manifestations include the skin, central nervous system, peripheral nervous system, liver, kidney, musculoskeletal system, heart, salivary glands, eye, and orbit.9 After the lungs, the skin is the second most common organ involved in sarcoidosis, seen in 12% to 35% of patients with systemic disease.10,11,12,13,14,15,16 Cutaneous lesions can be the presenting manifestation of the disease in about one-third of cases.17 Cutaneous features include maculopapular eruptions, lupus pernio, and erythema nodosum.12 Diagnosis is based on biopsy showing the presence of noncaseating granulomas, as well as the clinical features, raised inflammatory markers, elevated serum ACE, and hilar lymphadenopathy on chest radiography.
Ocular involvement has been reported in 11% to 60% of patients with sarcoidosis.10,18,19,20,21,22,23,24 Females are affected more than males in a ratio of 2:1.25 The occurrence of ocular involvement was reported to be 1.8 times greater in women than in men in one study26 but 1.25 times greater in men than in women in another.18
Ophthalmic manifestations can involve the anterior and posterior segments of the eye, and less commonly the orbit and lacrimal gland (Figure 111.1).18 Sarcoid uveitis is the most common ophthalmic manifestation, presenting with bilateral mutton-fat keratic precipitates, anterior cells and flare, iris nodules, anterior and posterior synechia, and increased intraocular pressure often associated with pain, photophobia, and conjunctival injection.20,27 Vitritis, vasculitis, choroidal lesions, and optic neuropathy characterize posterior segment involvement. Rare and atypical ophthalmic manifestations include limbal corneal nodules, retinal pigment epithelial detachments, and solitary choroidal granulomas.28
Granulomatous inflammation of the conjunctiva is the second most common ophthalmic finding in sarcoidosis,29 usually involving the palpebral surface (Figure 111.2), but less frequently the bulbar conjunctiva.30 Multiple translucent noncaseating conjunctival granulomas can occur as the first clinical signs.31 Lesions present as one or more white, discrete conjunctival deposits that may show redness and irritation.32 Occasionally they can present as follicular conjunctivitis33,34 or progress to conjunctival
scarring and symblepharon formation35,36 that may simulate a conjunctival tumor.37
scarring and symblepharon formation35,36 that may simulate a conjunctival tumor.37
 FIGURE 111.1 Lacrimal gland involvement with sarcoidosis. |
The age distribution of ocular sarcoidosis in adults is bimodal, with two peaks of incidence between 20 and 30 years and 50 to 60 years.23 The mean age at presentation of uveitis is 42 years (range 4-82),38 and ocular findings are reported to be higher and to occur at an earlier age in patients of African descent compared with Caucasians.39,40
Adnexal involvement is rarely associated with intraocular inflammation.12 In one study of 30 patients with adnexal sarcoidosis, only 3% had concomitant intraocular inflammation.41 The incidence of eyelid involvement in adnexal sarcoidosis may be as high as 17%.19,20,41 It is seen in adults at a mean age of 46 years (range 29-66), and with 58% occurring in males. Eyelid erythema and swelling may be the only sign,42,43 with lesions varying in size from small papules44 to large masses.45 Chronic eyelid nodules may cause eyelid deformities, with extensive scarring, entropion, trichiasis, madarosis, or symblepharon (Figure 111.3).46,47 Isolated eyelid structures such as the Müller muscle may be involved with granulomatous inflammation causing eyelid retraction.48
 FIGURE 111.2 Sarcoid granulomatous inflammation of the upper eyelid palpebral conjunctiva. |
Scar sarcoidosis is a rare circumscribed form of cutaneous sarcoidosis localized in scars that have been described in patients with systemic sarcoidosis or patients with no evidence of systemic disease.45 However, Ingber and Klinken showed that scar sarcoidosis can be an early sign of systemic sarcoidosis.49 It is marked by inflammatory infiltrations and bruise-like, black and blue discoloration. Scar sarcoidosis has been described following herpes zoster infections50 and in previous scars caused by venipuncture, trauma, tattoos, and sites of previous laser surgery.51
Etiology and Pathogenesis
Sarcoidosis has long been recognized as a disease with a genetic background owing to its accumulated appearance in families and within twin pairs. One twin study showed an 80-fold increased risk for the development of sarcoidosis for the monozygotic twin of an affected individual.52 Several novel predisposing genes have been identified by genome-wide association studies, including several HLA class II alleles, tumor necrosis factor (TNF) and interleukin 23 receptor (IL23R) genes, the butyrophilin-like 2 (BTNL2) gene, and the Ras-related protein Rab-23 (RAB23) gene. A detailed discussion of the possible predisposing genetic associations with sarcoidosis is beyond the scope of this chapter and has been extensively discussed elsewhere.52
Sarcoidosis likely develops in genetically susceptible individuals through an alteration of the immune system in response to certain environmental, occupational, or
infectious exposures.53,54 A comparison of gene expression in normal lungs and lungs affected by sarcoidosis found an upregulation of T helper-1 (Th1) immune response genes in sarcoidosis and also of genes regulating macrophage-derived proteases matrix metalloprotease 12 and ADAM-like decysin-1.55 A study of gene expression in skin lesions and normal skin of patients with sarcoidosis and the skin of normal controls found that skin lesions showed a strong Th1 profile and expression of interleukin (IL)-23 and IL23R.56
infectious exposures.53,54 A comparison of gene expression in normal lungs and lungs affected by sarcoidosis found an upregulation of T helper-1 (Th1) immune response genes in sarcoidosis and also of genes regulating macrophage-derived proteases matrix metalloprotease 12 and ADAM-like decysin-1.55 A study of gene expression in skin lesions and normal skin of patients with sarcoidosis and the skin of normal controls found that skin lesions showed a strong Th1 profile and expression of interleukin (IL)-23 and IL23R.56
 FIGURE 111.3 Papular and nodular sarcoid lesions on the eyelids. |
It is believed that sarcoidosis is a granulomatous reaction to one or more inciting exogenous agents in genetically susceptible individuals.57 Epidemiologic studies support an environmental trigger with case clustering, transmissibility by organ transplantation, and an immune response typical for nonself antigens.58 Besides an environmental trigger and a genetically mediated immune response, additional genes and exposures can likely modify the risk for the development and severity of sarcoidosis.59 Such modifier exposures might include smoking, which is known to decrease the risk of sarcoidosis, and photocopier toner and certain insecticides, which can increase the risk.60,61
Granulomas are inflammatory responses consisting of mononuclear phagocytes and their derivatives.62 The inciting event involves the deposition of antigenic material, not yet identified, into tissues where it is phagocytosed or endocytosed by macrophages or dendritic cells,63 is transported to the cell surface, and activates CD41 T cells.64 The granuloma organizes through the elaboration and secretion of cytokines and chemokines.65 The ensuing immune response leads to clinical lesions of sarcoidosis characterized by elevated IFN-g, IL-2, and IL-12. TNF alpha is a critical cytokine in this process that enhances the recruitment of macrophages into the granuloma.66
Clinical Characteristics
Eyelid involvement in sarcoidosis is rare. Typically, the eyelid lesions appear as yellowish to violaceous scaling and erythematous, firm small nodules, often associated with epiphora, pruritis, eyelid thickening, madarosis, and occasionally poliosis or trichiasis.13,67, They may also appear as larger nodules,13,16,19,67,68,69,70,71 papular eruptions,16,44,68,69,70 lupus
pernio plaques,16,72 or swelling of the eyelids (Figure 111.3).44 Eyelid nodules very rarely ulcerate or become necrotic.72 Even rarer is destructive sarcoidosis affecting the full-thickness eyelid leading to tissue loss (Figure 111.4).46,47 Scar sarcoidosis may occasionally develop at the site of old injuries or tumor resections (Figure 111.5). Dry eyes reported in patients with eyelid sarcoidosis are attributed to infiltration of the lacrimal gland and destruction of the meibomian glands.
pernio plaques,16,72 or swelling of the eyelids (Figure 111.3).44 Eyelid nodules very rarely ulcerate or become necrotic.72 Even rarer is destructive sarcoidosis affecting the full-thickness eyelid leading to tissue loss (Figure 111.4).46,47 Scar sarcoidosis may occasionally develop at the site of old injuries or tumor resections (Figure 111.5). Dry eyes reported in patients with eyelid sarcoidosis are attributed to infiltration of the lacrimal gland and destruction of the meibomian glands.
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