Chapter 175 – Sarcoidosis
CLAUDE L. COWAN JR.
• A multisystem inflammatory disorder characterized histologically by the presence of noncaseating granulomas.
• Anterior and posterior uveitis.
• Bilateral hilar lymphadenopathy and/or pulmonary parenchymal disease.
• Cutaneous lesions.
• Neurological abnormalities, including optic neuropathy.
• Orbital and conjunctival infiltration.
Sarcoidosis is a systemic disorder characterized histologically by localized granuloma formation with a concomitant T-cell lymphopenia involving the peripheral blood. Its clinical features can be highly variable and may show considerable differences among individuals, geographical regions, and ethnic groups. The course of the disease demonstrates a similar variability—some patients have an acute, self-limited process, whereas others experience a progressive downhill course that results in severe disability or death. Ocular involvement is common and may precede clinical manifestations of systemic disease. Corticosteroids are the mainstay of treatment for both ocular and systemic disease and can be effective in the prevention of severe functional impairment.
EPIDEMIOLOGY AND PATHOGENESIS
The etiology of sarcoidosis remains unclear, but evidence suggests that it is an immunological response to some exogenous agent. The widespread distribution and diverse clinical presentations of sarcoidosis suggest that many causal agents exist. Bacteria and bacterial DNA fragments have been reported in sarcoid granulomas, but attempts to transmit sarcoid have not been successful.    Localized and regional granulomatous responses have been produced following inoculation of sarcoid material into experimental animals, but this has not been followed by the development of a systemic disorder compatible with the disease seen in humans.  Nevertheless, reports of “transmission” of sarcoidosis through organ transplantation suggest that a transmissible agent may be a factor in some patients.  Sarcoidosis incidence has shown an inverse secular trend with tuberculosis, but this finding remains unexplained. If sarcoid is triggered by an infectious agent, it is presumably widely distributed but of low virulence, such that clear time-space relationships have not been established in spite of scattered reports of local clustering.
Noninfectious agents, most notably pine products, have been linked to the development of sarcoidosis, but the geographical diversity that characterizes the distribution of sarcoid argues against a single or predominant causative agent. Familial clustering is well described, and although this is consistent with an infectious or environmental process, the greater prevalence among certain parent-offspring and sibling pairs suggests that genetically determined factors are at least as important as environmental ones.  The association of several human leukocyte antigen haplotypes with specific clinical courses and racial differences in susceptibility offer further evidence for the role of genetic factors in the development of sarcoidosis. Genetically programmed T-cell antigenic responsiveness may determine which environmental factors will precipitate a sarcoid reaction, with some threshold level of exposure being required to initiate the inflammatory response. More than one candidate gene has been found with increased frequency in individuals with sarcoidosis, raising the possibility that a synergistic response among two or more genes is required to confer disease risk.
Sarcoid is worldwide in distribution, and its prevalence varies widely from one region to another. The prevalence and incidence are probably underestimated, since the disease is often asymptomatic and may be suspected only on the basis of an abnormal chest x-ray. In addition, seasonal variations may affect the calculation of incidence rates. In Europe, there appears to be a north-south gradient, with the highest rates noted in Sweden, Norway, and Ireland. The incidence in the United States is highly associated with race, and the age-adjusted annual incidence is more than three times higher in blacks compared with whites. When stratified by age and race, the highest rate, 107/100,100, is found in African-American women aged 30–39. This is among the highest in the world. A similar predilection for blacks has not been confirmed throughout Africa but has been described in South Africa. The incidence of sarcoid peaks in the 20s and 30s, but presentations in early childhood and later in life are well described. The disease is reported to be more common in women, but some variability may occur based on age at presentation.
Ocular involvement by sarcoid is common and has been reported in up to 78% of patients. The wide range of reported prevalence reflects differences in study methodology, the demographics of the study population, and the length of follow-up, as well as the transient and asymptomatic nature of many findings.
Anterior uveitis is the foremost cause of ocular morbidity and often presents early in the course of the disease or before the diagnosis is suspected. Although frequently unilateral at the onset, second eye involvement is common at some point during the course of the disease. The uveitis is characteristically granulomatous in nature and accompanied by medium to large “mutton fat” keratic precipitates. Multiple Busacca or Koeppe nodules are not uncommon, and they may achieve considerable size ( Fig. 175-1 ). Nodular deposits may occasionally be seen in the angle and, when extensive, can lead to increased intraocular pressure.
Figure 175-1 Typical appearance of chronic sarcoid uveitis. Note the multiple Busacca iris nodules and posterior synechiae.
A subacute presentation occurs most frequently, and patients may be relatively asymptomatic until the inflammation is well established. This can lead to the insidious development of anterior and posterior synechiae. Patients who experience a chronic course with multiple exacerbations are at high risk for secondary glaucoma or cataract. Cystoid macular edema may accompany anterior segment inflammation and can serve as a barometer of disease activity, since it often resolves when the inflammation subsides. However, protracted periods of inflammation may lead to chronic macular edema and loss of visual acuity. Acute anterior uveitis occurs relatively infrequently and is less often associated with severe sequelae because its symptomatic nature leads the patient to seek treatment.
Other manifestations of anterior segment sarcoid include conjunctival granulomas, scleritis and episcleritis, a nonspecific conjunctivitis, and interstitial keratitis. These infrequently cause significant ocular morbidity, but conjunctival inflammation occasionally resolves with symblepharon formation. Band keratopathy, though associated with sarcoidosis, is rarely a primary event and is more likely to be a complication of chronic uveitis.
Posterior segment involvement is reported to occur in nearly 30% of patients with ocular disease. This may be an underestimation due to the small size and peripheral location of many lesions and the generally asymptomatic nature of localized disease. Periphlebitis and vitritis are the most common manifestations of posterior uveitis in sarcoidosis. The involved venules are often mid-peripheral or peripheral in location and demonstrate short segments of perivascular cuffing with or without focal vascular narrowing ( Fig. 175-2 ). A cellular reaction in the anterior vitreous may accompany the periphlebitis, and when this is seen on anterior segment examination, it should prompt a careful examination of the peripheral retina. Severe vasculitis may be associated with extensive perivascular exudation, resulting in an appearance that has been likened to candle-wax drippings. Periphlebitis is occasionally complicated by retinal neovascularization, and these lesions can simulate the peripheral “sea fans” associated with sickle retinopathy. The report of multifocal arterial ectasias associated with sarcoidosis suggests that a clinically significant arteritis may occasionally accompany posterior segment inflammation.
The vitritis of sarcoidosis may be generalized and nonspecific or characterized by gray-white round opacities in the inferior vitreous. These “snowball” opacities can occur singly, in clusters, or in a linear array or strand, like a “string of pearls.” Veil-like vitreous condensations are not uncommon, and although they
Figure 175-2 Retinal periphlebitis involving the superior temporal arcade. Note the appearance of focal vascular narrowing associated with the phlebitic foci.
Figure 175-3 Multiple choroidal lesions simulating pneumocystis choroiditis. These lesions remained unchanged in spite of several courses of systemic corticosteroids.
may cause bothersome symptoms, vision remains good in the absence of severe clouding or macular edema. Retinitis associated with sarcoid may be difficult to distinguish from other causes of retinal inflammation. It can extend into the preretinal vitreous, leading to the appearance of vitreous snowballs.
Choroidal lesions vary considerably in their appearance and often mimic nonsarcoid choroidal disorders ( Fig. 175-3 ). Isolated tumefactions with or without subretinal fluid, clusters of yellow subretinal lesions, and scattered discrete peripheral white lesions occur in one or both eyes. The latter may increase in number over time and evolve into focal atrophic spots. Histologically, choroidal granulomas are seen less frequently than clinical descriptions suggest, since many of these lesions are actually located in the subpigment epithelial space. Fluorescein angiography may demonstrate nonfluorescence, hypofluorescence, early blocking with late staining, or hyperfluorescence throughout. If the eye is otherwise uninvolved, it is usually remarkably quiet. Vision loss may be associated with serous detachment of the macula, pigment epithelial dropout, or subretinal neovascularization.
Sarcoid involves the optic nerve infrequently. Clinically, the nerve may show edema, infiltration, swelling associated with adjacent retinitis, or progressive atrophy. Retrobulbar or chiasmatic involvement can present with progressive vision loss in the face
Figure 175-4 Bilateral hilar adenopathy in a patient without pulmonary symptoms. Note the symmetry of the hilar node enlargement.
of a normal-appearing nerve. Visual field defects often accompany lesions of the visual pathways and may be indistinguishable from those caused by cerebrovascular accidents or mass lesions.
Dacryoadenitis is often initially suspected on the basis of swelling of the lateral aspect of the upper lids. Though frequently asymptomatic, it can cause pain, proptosis, and exposure keratopathy when severe. Infiltration of the lacrimal gland may also occasionally cause symptoms of keratoconjunctivitis sicca, even in the absence of overt dacryoadenopathy. Rarely, isolated orbital or extraocular muscle granulomas occur. They often lead to misdiagnosis, and the correct diagnosis typically is made only after orbital exploration and biopsy.
The diagnosis of sarcoidosis is based on the presence of a compatible clinical picture, supportive laboratory findings, and, in most cases, a confirmatory biopsy. Pulmonary involvement occurs at some point in the disease in nearly all cases. Bilateral hilar adenopathy, with or without parenchymal infiltrates, is the radiographical hallmark of the disease ( Fig. 175-4 ). One or more skin lesions occur in approximately 25% of patients, but they can be nonspecific and mimic other dermatological lesions. However, lupus pernio and erythema nodosum, when associated with hilar adenopathy, are sufficiently characteristic of this disorder to be considered supporting diagnostic criteria. Other nonocular extra-pulmonary manifestations, although compatible with sarcoidosis, are less reliable as diagnostic criteria. Nevertheless, in the appropriate clinical setting, plaque-like skin lesions, peripheral lymphadenopathy, Bell’s palsy, cardiac conduction abnormalities, and childhood arthritis should raise the index of suspicion for sarcoid. Symptoms associated with sarcoidosis are generally non-specific. Although cough, dyspnea, or chest pain may suggest the presence of pulmonary disease, other symptoms such as weight loss, malaise, fever, night sweats, or fatigue are nonlocalizing.
Laboratory tests, although not specific for sarcoidosis, may provide a high degree of correlation with disease activity. Serum angiotensin-converting enzyme (ACE) is elevated in approximately 60% of patients and correlates well with the degree of pulmonary involvement. Other tests, such as serum and urine calcium, erythrocyte sedimentation rate, immunoglobulin electrophoresis, liver function studies, and serum lysozyme, are less useful as predictors of sarcoid activity because of their lack of sensitivity or specificity. However, when used selectively, they can aid in making the diagnosis.
Figure 175-5 Conjunctival sarcoidosis. A, The patient shows numerous small, round nodular lesions and translucent cysts in the conjunctival fornix. B, A conjunctival biopsy reveals a discrete granuloma composed of epithelioid cells and surrounded by a rim of lymphocytes and plasms cells. Such granulomas may be found histologically even if no conjunctival nodules are seen clinically. (A-B, From Yanoff M, Fine BS. Ocular pathology. St Louis: Mosby; 2002.)
Gallium scanning is based on the tendency for 67 Ga to accumulate at sites of inflammation. It is especially useful in patients who have normal or equivocal chest radiographs but clinical or laboratory findings consistent with sarcoidosis. Bilateral hilar uptake combined with increased uptake in the parotids and orbits is highly characteristic of sarcoid. The greater sensitivity of chest computerized tomography in detecting intrathoracic adenopathy compared with standard radiographs makes it another useful adjunct in the evaluation of suspected pulmonary sarcoidoses. Gallium scanning combined with serum ACE provides increased sensitivity and specificity but should be considered as providing supportive rather than confirmatory evidence. Relative anergy to recall antigens occurs in sarcoidosis because of impaired recruitment of helper cells in the skin. Although testing for tuberculosis is commonly recommended, tests with other antigens, such as Trichophyton, Candida, and mumps, may be more useful in patients without known exposure to tuberculosis.
A confirmatory biopsy is usually sought, since some patients require chronic or high-dose corticosteroid therapy. Transbronchial biopsy provides ready access to pulmonary tissue, but conjunctiva, lacrimal glands, peripheral lymph nodes, skin, nasal mucosa, and minor salivary glands can also provide suitable biopsy sites. The lacrimal gland should not be considered a primary biopsy site if it is not easily accessible or appears entirely normal. Conjunctival biopsies, especially when granulomas are present ( Fig. 175-5 ), yield a high percentage of positive biopsies and are relatively easy to do. Analysis of bronchoalveolar lavage fluid is useful for establishing the diagnosis and staging disease activity. The presence of a
lymphocytosis associated with an increased helper-suppressor T-cell ratio is highly suggestive of the alveolitis of sarcoidosis.
The varied clinical presentations of ocular sarcoid and the features it shares with other diseases offer many opportunities for misdiagnosis. Findings likely to cause confusion with other disorders include iris nodules, intermediate uveitis, chorioretinitis, choroidal infiltrates, dacryoadenopathy, and peripheral neovascularization of the retina.
Iris nodules occur in several inflammatory conditions, including tuberculosis, syphilis, and leprosy. In addition, isolated or multinodular lesions may be seen with primary iris neoplasms, metastatic carcinoma, seeding from retinoblastoma, and leukemic infiltrates. Intermediate uveitis can be associated with Lyme disease and multiple sclerosis, or it may occur on an idiopathic basis, where it is known as pars planitis. Sarcoid is most likely to be confused with the latter when inferior preretinal infiltrates simulate the appearance of snowbanking.
Chorioretinitis is a feature of multiple disorders, among which histoplasmosis, tuberculosis, syphilis, and toxoplasmosis are most likely to be confused with sarcoid. Subretinal or choroidal infiltration occurs in a variety of conditions, including acute posterior multifocal placoid pigment epitheliopathy, birdshot choroidopathy, lymphoid hyperplasia, central serous choroidopathy, amelanotic melanoma, metastatic lesions, Harada’s disease, and pneumocystis choroiditis. Differentiating these disorders from sarcoid is often impossible on the basis of the fundus picture alone, and it often requires demonstration of other features of the disease in order to make the correct diagnosis.
Sarcoid-associated dacryoadenopathy and parotitis can mimic tuberculosis, Hodgkin’s disease, lymphoma, and brucellosis. In addition, isolated lacrimal gland enlargement may cause confusion with orbital pseudotumor or primary lacrimal gland tumors. Peripheral retinal neovascularization occurs relatively infrequently, but other causes of sea fan–like proliferations, such as sickle retinopathy, venous occlusive disease, and diabetic retinopathy, occur with sufficient frequency that sarcoid may be overlooked as a cause.
Infiltrative disease of the optic nerve, other inflammatory optic neuropathies, ischemic optic neuropathy, optic gliomas, optic disc edema, and optic nerve sheath meningiomas all have features that can be mimicked clinically or radiographically by sarcoidosis. Avoidance of misdiagnosis can be difficult when other signs of sarcoid are absent, but an appropriate index of suspicion may save patients from unnecessary investigations.
Sarcoidosis is a multisystem disorder that can involve virtually any organ. It is accompanied by abnormalities in cell-mediated and humoral immunity that lead to impaired responsiveness to recall antigens, depressed circulating T-cell levels, elevated globulin levels, and nonspecific elevation of antibody titers.
It involves the lungs and/or thoracic nodes in 90% of patients and is staged according to the severity of radiographical findings:
• Stage I consists of bilateral hilar adenopathy alone.
• Stage II adds parenchymal involvement.
• In stage III, parenchymal disease predominates without prominent hilar involvement.
• Stage IV is a late stage characterized by pulmonary fibrosis.
Upper respiratory tract involvement can be overlooked, as its symptoms may suggest a nonspecific rhinitis. Complaints of nasal stuffiness or congestion warrant examination of the nasal mucosa in any patient who is suspected of having sarcoidosis. Cutaneous manifestations are common and include nodules, plaques, psoriasiform lesions, papules, ulcerations, and erythema nodosum ( Fig. 175-6 ). Lupus pernio, a plaque-like
Figure 175-6 Multiple cutaneous lesions involving the lid. Papules, umbilicated lesions, and plaques are evident in this patient.
lesion that involves the face, can be disfiguring and may be of prognostic value because of its association with chronic disease. Eyelid lesions mirror those seen elsewhere and should be considered part of the cutaneous disease.
Peripheral lymphadenopathy is common, but its nonspecificity makes it a poor stand-alone predictor of sarcoidosis. Occasionally, a sarcoid reaction is seen in regional lymph nodes that drain a carcinoma or lymphoma. This can lead to diagnostic confusion and a delay in reaching the correct diagnosis.
Cardiac involvement is apparent clinically in approximately 5% of patients, but its prevalence is reported to be as high as 27% in autopsy series. It is associated with conduction defects and ventricular arrhythmias and can cause sudden death from complete heart block or ventricular tachyarrhythmias. The association with heart block requires that caution be exercised when beta blockers are prescribed for patients who have glaucoma and sarcoidosis.
Neurosarcoidosis occurs in 5–10% of patients and may precede other manifestations of the disease by a year or more.  It has a predilection for the basal leptomeninges, and cranial nerve involvement is common ( Fig. 175-7 ). Hypothalamic and pituitary involvement can cause significant morbidity, and diffuse hemispheric disease may lead to seizures. Large lesions can mimic intracranial tumors and cause hemianopic or quadrantanopic field defects. Spinal tract lesions are unusual but may result in paralysis. Sarcoid retinitis is often seen with neurosarcoidosis.
Hepatic, splenic, and bone involvement causes symptomatic clinical disease in a minority of patients; however, subclinical liver disease is not uncommon, and liver biopsy for other indications may reveal a diagnosis of sarcoidosis. Hypercalcemia and/or hypercalciuria occur in up to 17% of individuals, and sarcoid is associated with an increased risk for nephrocalcinosis and nephrolithiasis compared with the general population.
Early-onset sarcoid that occurs in children younger than 4 years has a distinct clinical picture—the triad of rash, polyarthritis, and uveitis occurs commonly. The arthritis may initially be mono- or pauciarticular and may lead to a diagnosis of juvenile rheumatoid arthritis. These patients often have multisystem disease, and hepatosplenomegaly, parotid swelling, and cardiac abnormalities are not uncommon.
Sarcoidosis is defined by its histopathology. Characteristically, sarcoid tissue demonstrates granulomas with central nodules of
Figure 175-7 Enhancing lesions in a patient with progressive vision loss and seizures. Involvement of the frontal basal meninges and thalamus can be seen.
epithelioid cells surrounded by a mantle of lymphocytes and other mononuclear cells ( Figs. 175-5, B and 175-8 ). Although mild central necrosis may be seen, caseation is not a feature of sarcoidosis. Fibrosis can be associated with maturation of sarcoid granulomas and may lead to severe pulmonary dysfunction.
No known cure exists for sarcoidosis. Treatment is intended primarily to reduce the symptoms, lessen disability during periods of activity, and minimize the sequelae of inflammation. Corticosteroids remain the mainstay of treatment for ocular sarcoid, regardless of the site of involvement. Topical administration, when done with sufficient frequency, is effective for most patients who have anterior segment inflammation, but supplementation with periocular steroids may be required for patients who have severe or well-established disease. Occasionally, adequate control can be achieved only with systemic administration.
Chronic or recurrent anterior uveitis may require more aggressive therapy than would be suggested by the level of clinical inflammation. Progressive anterior and posterior synechiae can occur in patients who have frequent episodes of “silent” reactivation. The latter group of patients may be best served by long-term maintenance therapy, even in the absence of clinically active disease.
Posterior uveitis is managed primarily with periocular and/or systemic corticosteroids. Small segments of peripheral periphlebitis or mild vitritis may not require treatment, as the disease can wax and wane without progression. Choroidal infiltrates can be associated with serous elevation of the overlying retina and, rarely, subretinal neovascularization. Systemic steroids can clear choroidal lesions and any accompanying serous retinal detachment, but their effect is variable, and recurrences are not unusual. No clear evidence exists that steroid use prevents subretinal new vessel formation, but the association of prior inflammation with neovascularization in diseases such as presumed ocular histoplasmosis argues strongly for treating choroidal lesions when they involve the macula. Optic nerve involvement can be resistant to even high doses of oral steroids, and “pulsed” intravenous methylprednisolone may be required to achieve a response. Systemic cytotoxic agents are used to supplement steroid therapy for refractory disease or to allow a reduction in steroid dose. Regardless of the site of involvement, treatment should not be considered curative, and relapses should be anticipated.
Figure 175-8 Sarcoid granulomas replacing much of the ciliary body. Lighter-staining epithelioid granulomas are surrounded by darker-staining lymphocytes.
Indications for the treatment of systemic sarcoidosis include bothersome symptoms, organ dysfunction, and biochemical or radiographical deterioration. Oral corticosteroids remain the primary first-line therapy.    Inhaled steroids appear to be less effective for pulmonary disease, but they have been shown to be useful as maintenance therapy following an initial course of oral prednisone. High-dose intravenous methylprednisolone, when used in short 2- to 3-day pulses, can be a useful supplement to oral steroids. Steroid therapy has not been proved to provide long-term disease effect modification, but early treatment has been shown to improve 5-year pulmonary function in some patients with newly diagnosed stage II disease.  Cytotoxic drugs, and less frequently cyclosporin, can be useful for refractive disease or can be used as part of a steroid-sparing strategy. Methotrexate and azathioprine are the preferred cytotoxic agents due to their effectiveness and relative safety. However, like all such agents, they have the potential for hematological and gastrointestinal toxicity, as well as teratogenicity. These drugs may also be carcinogenic, although methotrexate appears to be less problematic in this regard.
Chloroquine and hydroxychloroquine can be very effective for pulmonary and cutaneous disease, but hydroxychloroquine is preferred due to its significantly lower risk for ocular toxicity. Thalidomide is reported to provide another alternative to systemic steroids for cutaneous sarcoid, but caution should be exercised when recommending this drug to women of child-bearing age. Ketoconazole has been useful in the management of hypercalcemia, and radiation therapy may be effective for some patients with refractory neurosarcoid. The successful use of tumor necrosis factor-a in one patient with advanced sarcoidosis suggests that selective manipulation of inflammation may have a future role in sarcoid management. 
COURSE AND OUTCOME
The overall prognosis for systemic and ocular sarcoid is good. Most patients recover without significant functional impairment.    Chronicity increases the risk for complications, as does delay in receiving appropriate therapy, but early recognition and treatment of patients who are prone to recurrences can improve their outlook. Systemic features associated with chronicity or poorer outcomes include central nervous system involvement, lupus pernio, nephrocalcinosis, stage III pulmonary disease, hepatosplenomegaly, and cardiac involvement. Clinical depression may occur in more than 50% of patients
and, as with other chronic conditions, can adversely affect adherence to therapy. Multisystem disease and pulmonary symptoms increase the risk for this complication. Black patients may be more likely to have symptomatic disease and ocular involvement, and they have higher rates of severe complications. However, a recent metaanalysis concluded that sarcoid mortality is largely independent of ethnicity. Most patients with sarcoidosis retain normal vision; bilateral vision loss to less than 20/200 is unusual. Chronic uveitis, cystoid macular edema, secondary glaucoma, and retina and optic nerve involvement are associated with poorer visual outcomes and represent difficult therapeutic challenges.
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