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Sarcoidosis is a multisystem granulomatous disease that can affect almost every organ in the body in people of all racial and ethnic groups.
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The cause of sarcoidosis remains unknown, but a number of recent studies have elucidated the immunologic basis for the disease pathogenesis with the macrophage playing a central role.
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Most patients with sarcoidosis present with respiratory symptoms, although some have generalized symptoms such as fever, fatigue, or weight loss.
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Many patients with sarcoidosis are asymptomatic at the time of diagnosis, and it is only recognized after an abnormal chest X-ray or laboratory test result. Uveitis may be the initial manifestation of the disease.
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Definitive diagnosis is made on biopsy; however, diagnosis if frequently based on clinical findings and chext X-ray or CT scan.
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Ophthalmic findings occur in as many as 50% of patients including anterior and posterior uveitis, retinal vasculitis, and optic nerve disease.
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Secondary glaucoma is a common cause of vision loss.
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Systemic corticosteroids and immunosuppressive agents, including the biologics, are used to treat the disease.
Sarcoidosis is a multisystem granulomatous disease that can affect almost every organ in the body in people of all racial and ethnic groups. The organs most commonly involved are the lungs, thoracic lymph nodes, and skin. The adrenal glands, which produce corticosteroids, are the only organs consistently spared by this disease. Sarcoidosis was initially described as a dermatologic disease by Hutchinson in 1869, and Boeck used the term sarkoid to describe the skin biopsies that had a histologic appearance similar to that of sarcomas. Uveitis was described in patients with sarcoidosis in the early 1900s, and in 1936 sarcoid uveitis associated with a facial nerve palsy and uveoparotid fever was termed Heerfordt’s syndrome. Although the cause of sarcoidosis remains unknown, it is important to make the diagnosis of sarcoidosis in patients with uveitis not only to allow appropriate therapy for the eye disease, but also to alert the physician to the possible systemic manifestations that may also require treatment.
Epidemiology
Epidemiologic studies of sarcoidosis are prone to considerable error because of variability in the criteria for diagnosis. Nevertheless, there are substantial differences in the yearly incidence rate in different parts of the world, from 0.2 per 100 000 in Japan and Spain to 64 per 100 000 in Sweden. , In one study, the age-adjusted annual incidence in African-Americans was 82 per 100 000 and in whites was eight per 100 000. More recently, the adjusted annual incidence of sarcoidosis among black Americans was 35.5 per 100 000, compared to 10.9 per 100 000 in white Americans. In addition, African-Americans with chronic sarcoidosis are more likely to develop ocular manifestations than are whites. There are conflicting data in the literature on whether sarcoidosis is more common in females. ,
Etiology
Although the cause of sarcoidosis remains unknown, a number of recent studies have elucidated the immunologic basis for the disease pathogenesis ( Fig. 22-1 ). The macrophage, acting as an antigen-presenting cell, is hypothesized to initiate the inflammatory response in sarcoidosis. Possibly in response to presentation of an unknown antigen, macrophages are thought to release cytokines such as TNF-α and interleukin (IL)-12 that cause the infiltration of T-helper lymphocytes. These lymphocytes will also release cytokines and recruit other inflammatory cells to the site of inflammation. In response to these events, granulomas are formed and immunoglobulins produced in large quantities by stimulated B lymphocytes and released into the circulation. The immunohistochemical staining of one eye with sarcoidosis showed granulomas in the choroid and anterior uvea composed of macrophages and T-helper cells.
The primary involvement of the lung in sarcoidosis suggests sensitization and a resultant immune response to an endogenous lung antigen or an inhaled infectious agent or other antigen. Frequent involvement of the eye and skin also supports this hypothesis. A number of epidemiologic studies have now reported associations between environmental exposure and sarcoidosis. Early studies suggested associations of sarcoidosis with exposure to tree pollen and smoke from wood-burning stoves in rural areas. Other environmental associations with sarcoidosis include mold and insecticides. Microbial triggers have also been described in sarcoidosis. The development of sarcoidosis has been associated with IFN-α treatment for hepatitis, although the association may be related to the underlying hepatitis C infection.
Additional data suggest that sarcoidosis is an abnormal immune response directed against one of many different antigens in a patient with a hereditary or acquired abnormality of the immune system. There does appear to be some genetic predilection to the disease. Sarcoidosis has been reported more commonly in monozygotic than in dizygotic twins. Furthermore, there have been associations between both class I antigens (HLA-B8) and class II antigens (HFA-DRB1). There are a number of immune defects in patients with sarcoidosis. Despite the inflammatory response seen in multiple tissues, delayed-type hypersensitivity is depressed, causing anergy on skin testing, and a generally depressed cellular immunity has been reported.
Clinical manifestations
Most patients with sarcoidosis present with respiratory symptoms, although some have generalized symptoms such as fever, fatigue, or weight loss. Many are asymptomatic at the time of diagnosis, and sarcoidosis is only recognized after an abnormal chest X-ray or laboratory test result. Sarcoid uveitis is diagnosed when ocular inflammation is found in a patient with extraocular findings diagnostic of sarcoidosis. The definitive diagnosis of sarcoidosis requires the demonstration of a noncaseating, granulomatous, noninfectious inflammatory process on biopsy; however, a number of laboratory and other diagnostic tests can strongly support the diagnosis. Two-thirds of patients with sarcoidosis have a remission within a decade after diagnosis with minimal health consequences; however, one-third have recurrent, progressive disease leading to significant organ damage.
Ophthalmic involvement occurred in 50% of patients with sarcoidosis in one report, but most series report eye findings in about 25% of patients. The common ocular findings in patients with sarcoidosis are listed in Table 22-1 . Of patients with chronic systemic sarcoidosis, 26% have ophthalmic involvement at some point during the course of their disease. Ocular disease is usually bilateral, but may be unilateral or markedly asymmetric. It is important to examine both the conjunctiva and the lacrimal gland in patients with possible sarcoidosis. The palpebral conjunctiva should be carefully scrutinized for sarcoid granulomas ( Fig. 22-2 ), which are seen in 7–17% of patients with ophthalmic involvement. The lacrimal gland, which is clinically involved in 7–26% of patients with ocular sarcoidosis, should also be examined for possible enlargement as a result of the disease. Although a positive conjunctival biopsy for sarcoidosis does not correlate with the presence of anterior uveitis in sarcoidosis, the demonstration of a noncaseating granuloma in the conjunctiva can be diagnostic.
| DIAGNOSTIC CRITERIA | |
| Suspected sarcoidosis | Hilar adenopathy, erythema nodosum, increased serum ACE level, positive lung or lacrimal or salivary gland gallium scan results, increased serum globulin level, increased serum or urinary calcium level, lymphadenopathy, decreased lung diffusing capacity |
| Definite sarcoidosis | Histologic confirmation of noncaseating granulomas |
| Associated findings | Uveitis, arthritis, neurologic signs and symptoms, anemia, decreased pulmonary function, lymphadenopathy |
| OCULAR FINDINGS | |
| Common | Acute nongranulomatous or chronic granulomatous iridocyclitis, vitritis, vitreal snowballs, macular edema, perivenous sheathing, small yellow choroidal, and retinal pigment epithelial patches of inflammation, optic disc swelling, retinal neovascularization |
| Rare | Large choroidal granulomas, subretinal neovascularization, optic neuropathy |
Anterior uveitis
Anterior uveitis is the most common ocular manifestation and occurs in almost two-thirds of patients with ocular sarcoidosis. From 53% to 60% of patients with ocular sarcoidosis will have a chronic granulomatous uveitis. Most of these patients will have mutton-fat keratic precipitates (KPs) that may be extremely large and dense, as shown in Figure 22-3 . Iris nodules, albeit characteristic for granulomatous inflammation, occur in only 11% of all patients with ocular sarcoidosis ( Fig. 22-4 ). Occasionally, an iris nodule can enlarge to the point where it resembles a tumor. Although the presence of other signs of inflammation and the yellow color of the lesion may be reassuring, only a reduction in the size of the lesion after corticosteroid therapy can prove that the nodule is inflammatory and not malignant.
This chronic form of anterior inflammation generally occurs in patients with sarcoidosis in the fourth to sixth decades and results in secondary damage to the eye, including cataract and glaucoma. The incidence of both of these complications is difficult to estimate from the literature because there is an increasing incidence of both cataracts and glaucoma with increased duration of the chronic inflammation. The prevalence of cataracts in patients with chronic sarcoid uveitis is 8–17%, and the prevalence of glaucoma varies from 11% to 23%. Both pupillary block and trabecular meshwork damage can cause glaucoma in these patients and may exist simultaneously. In contrast, chronic inflammation will occasionally lead to hypotony and phthisis. ,
Acute iridocyclitis of limited duration associated with small fine KPs occurs in 15–45% of patients with ocular sarcoidosis. Even among patients with chronic systemic sarcoidosis, those with anterior iridocyclitis frequently have one attack early in the course of their disease and no further recurrences. Some will develop a pattern of acute recurrent uveitis without granulomatous signs. Therefore, although granulomatous uveitis is the more common presentation of ocular sarcoidosis, even a patient with recurrent anterior iritis may have sarcoidosis as an underlying cause. We have followed several patients with recurrent anterior uveitis who developed mild vitritis years later, along with systemic manifestations of sarcoidosis. As will be discussed later, there is currently little proof that the lesions of acute iritis in patients with sarcoidosis are due to the same pathologic process that is responsible for the noncaseating granulomas of the thorax.
Posterior segment findings
Inflammation of the vitreous, retina, and choroid is less common but more visually disabling than inflammation in the anterior segment, and occurs in 6–33% of patients with sarcoidosis. Many of these patients will also have anterior inflammation. The presence of clumps of cells and proteinaceous debris called snowballs in the vitreous should suggest the diagnosis of sarcoidosis. Often these snowballs are located inferiorly and lie on the retinal surface anterior to the equator. The classic ‘candle wax dripping’ ( en taches de bougie ) along the retinal veins is not frequently seen ( Fig. 22-5 ), but many patients with posterior inflammation will have perivenous sheathing. , In contrast, periarterial sheathing is rarely observed. Small areas of peripheral venous occlusion have been reported, but large vein occlusions are uncommon. Deep yellow choroidal lesions consistent with Dalen–Fuchs nodules and mottling of the pigment epithelium occur in 36% of these patients ( Fig. 22-6 ) and are more common than true elevated choroidal granulomas. These smaller lesions are probably small choroidal granulomas that evolve and lead to secondary pigment epithelial alterations. They are similar in appearance and histologic findings to the Dalen–Fuchs nodules of sympathetic ophthalmia, although the lesions may be somewhat larger in sarcoidosis than in sympathetic ophthalmia. Large granulomas of the choroid can also occur and may resemble choroidal tumors. , These appear as yellow-white or yellow-gray discrete elevated masses. Large granulomas can have overlying serous retinal detachments and will cause decreased acuity if they involve the fovea ( Fig. 22-7 ). These lesions will block fluorescence in the early stages of a fluorescein angiogram and will stain in the late phase. If the lesions occur under the macula, one needs to be concerned about the development of a submacular neovascular net extending from the granuloma.
Chronic cystoid macular edema is usually the cause of decreased acuity in patients with posterior uveitis and sarcoidosis. However, the vitreous opacities can occasionally be sufficiently dense in this disease to contribute to a decrease in visual acuity. Nevertheless, we have been surprised that visual acuity is only minimally affected in most uveitis patients with even dense vitreous opacity as long as the macula and optic nerve are uninvolved. Neovascularization of the optic disc occurs in approximately 15% of patients with posterior uveitis related to sarcoidosis. In our experience, prompt steroid therapy will frequently lead to an involution of these vessels, which implies that the ischemic stimulus that promoted the neovascularization is reversible and related to the inflammation. If there is significant peripheral vascular ischemia or neovascularization, therapy with antiinflammatory drugs may not be adequate and photocoagulation may be indicated.
In contrast to retinal neovascularization, subretinal neovascularization in sarcoidosis is much less common and does not respond to medical therapy. Case reports usually describe a peripapillary or macular subretinal neovascular membrane ( Fig. 22-8 ). It is likely that choroidal inflammation with secondary retinal pigment epithelial damage leads to breaks in Bruch’s membrane that permit the development of the neovascular net. The natural course of these vascular abnormalities is not well defined, but they probably have a prognosis similar to that for subretinal membranes as a result of other causes.
Optic disc swelling occurs in 39% of patients with posterior uveitis, but is usually mild and not associated with visual dysfunction. The optic disc may also be hyperemic. Papilledema can occur due to sarcoid granulomas that invade the optic nerve, but it is probably not the common cause of disc swelling as the swelling follows a course that parallels the severity of the posterior uveitis. After the disc edema resolves, a peripapillary fibrous ring may remain ( Fig. 22-9 ). Retrobulbar neuritis without intraocular signs of inflammation has also been reported and is presumably related to direct involvement of the optic nerve by granulomatous inflammation.
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