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Update on sarcoidosis

Liu, Dianna; Birnbaum, Andrea D.

Current Opinion in Ophthalmology: November 2015 - Volume 26 - Issue 6 - p 512–516
doi: 10.1097/ICU.0000000000000207

Purpose of review Sarcoidosis is a multisystem inflammatory disease, characterized by the presence of noncaseating granulomas. Ocular inflammation is often the first manifestation of the disease, and uveitis can be the driving force for treatment. The goal of this review was to provide an update on the relationship between ocular and systemic disease, with a particular focus on cardiac sarcoidosis.

Recent findings Chest radiograph remains the best imaging tool for sarcoidosis, although newer modalities, such as whole-body PET scan, cardiac MRI, and chest computed tomography (CT), may provide additional valuable information in select populations. Ocular sarcoidosis is a marker for vascular endothelial dysfunction and increased arterial rigidity. Choroidal involvement is associated with an increased risk of cardiac disease requiring intervention. Cardiac disease continues to be underdiagnosed in patients with sarcoidosis, although it remains a leading cause of death.

Summary Sarcoidosis is a systemic disease, and ophthalmologists should continually assess patients for extraocular manifestations. Although no screening guidelines exist, baseline ECGs on asymptomatic patients might identify those at risk for adverse cardiac events. Patients with symptoms of cardiac disease, including palpitations, chest pain, and dyspnea, should have an evaluation by a cardiologist.

Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA

Correspondence to Andrea D. Birnbaum, MD, PhD, Assistant Professor of Ophthalmology, Northwestern University Feinberg School of Medicine, 645 North Michigan Avenue, Suite 440, Chicago, IL 60611, USA. E-mail:

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Sarcoidosis is a systemic granulomatous disease of unknown etiology. Ocular involvement has been reported in 12–23% of patients with biopsy-confirmed sarcoidosis in the USA [1], and uveitis is the most frequent manifestation. Sarcoidosis is a diagnosis of exclusion, although many clinicians assign a diagnosis of suspected or probable sarcoidosis to patients with characteristic ocular disease in lieu of biopsy. Intraocular inflammation is often the first clinical presentation of the disease. Ophthalmologists must continually monitor patients for systemic manifestations of pulmonary, cardiac, and neurologic involvement to reduce morbidity and mortality in this population. This review will highlight recent advances in the diagnosis and management of sarcoidosis.

Box 1

Box 1

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Sarcoidosis can be included on the differential of almost any presentation of uveitis. The clinical features most suggestive of sarcoidosis were defined by the International Workshop on Ocular Sarcoidosis in 2009 and included seven distinct findings: mutton-fat keratic precipitates, small granulomatous keratic precipitates, and/or iris nodules; nodules in the trabecular meshwork or tent-shaped peripheral anterior synechiae; vitreous snowballs; multiple chorioretinal peripheral lesions; nodular and/or segmental periphlebitis; optic disc nodule(s) and/or solitary choroidal nodule; bilaterality [2].

Clinical presentation may vary based on race, age, and other systemic conditions. African-American and Scandinavian populations have the highest risk of developing sarcoidosis [3]. The disease commonly presents at an earlier age in African-Americans, and the inflammation is more often granulomatous in nature [4]. A bimodal distribution has been described for the onset of sarcoidosis, and the vast majority of individuals presenting after age 50 is women [4,5][4,5]. Ocular manifestations may also be age dependent. One study showed that peripheral choroidal lesions are more common in older patients, whereas younger patients often have more central choroidal lesions [5]. Presumably unrelated systemic conditions may increase or decrease the likelihood of developing ocular inflammation. One group reported that although atopy is not a risk factor for sarcoidosis, patients with sarcoidosis and atopy are less likely to have ocular involvement [6].

In order to make a diagnosis of ocular sarcoidosis, three conditions must be met. First, the patient must have a clinical picture consistent with sarcoidosis. The International Workshop on Ocular Sarcoidosis (IWOS) criteria can be helpful in assessing the patient. Second, a tissue biopsy must demonstrate histologic evidence of noncaseating granulomas. Third, other causes of granulomatous inflammation must be excluded. Many patients with ocular disease consistent with sarcoidosis are unable to undergo biopsy or do not have an appropriate site for biopsy. In these cases, a diagnosis of probable or presumed ocular sarcoidosis is made based on clinical findings, laboratory testing and chest imaging results [2]. An exception to these strict criteria is Heerfordt's syndrome, which can be diagnosed based on the classic presentation of uveitis, enlarged parotid glands, and fever. Histologic confirmation is not required.

The diagnostic evaluation of a patient with suspected ocular sarcoidosis includes a combination of imaging and blood tests. Patients with ocular inflammation should undergo testing for tuberculosis and syphilis, as both of these infectious causes of uveitis can have a similar presentation as sarcoidosis. Serum angiotensin converting enzyme (ACE) and lysozyme are markers of granulomatous inflammation and can be elevated in patients with sarcoidosis. Testing for ACE reportedly has a sensitivity of 58–84% and specificity of 83–95%; testing for lysozyme has a sensitivity of 60–78% and a specificity of 76–95% [7–9][7–9][7–9].

A chest radiograph is the single best screening test for diagnosis of sarcoidosis, because over 90% of patients with sarcoidosis have pulmonary involvement. Alone, a chest radiograph has been found to be about 79% sensitive for sarcoidosis [10]. The combination of chest imaging with serum ACE and lysozyme levels can identify the vast majority of patients with ocular inflammation secondary to sarcoidosis [4]. In addition, the radiographic staging system for sarcoidosis is based on chest radiograph findings and may carry prognostic value [11]. Thin-cut, spiral computed tomography (CT) imaging is more sensitive and may have utility in patients with negative chest radiograph and a high clinical suspicion for sarcoidosis [4–12][4–12][4–12][4–12][4–12][4–12][4–12][4–12][4–12]. Distinctive CT patterns of parenchymal, mediastinal and hilar structures can aid in diagnosis [13]. Use of this test should be limited, though, as it subjects patients to high levels of radiation. In addition to disease staging, potential biopsy sites are often identified through these studies.

Dual-time point whole-body 18F-Fluorodeoxyglucose PET can identify sites with active inflammation and is often used to provide a systemic overview of disease activity and identify potential biopsy sites. This technology aids in management in patients with a known diagnosis of sarcoidosis, as any inflammatory condition can produce a false-positive result. Identification of extrapulmonary foci of inflammation will impact treatment decisions and overall prognosis. One report describes FDG uptake in an asymptomatic patient who was ultimately diagnosed with intermediate uveitis secondary to sarcoidosis [14]. Some studies have also looked at its efficacy in distinguishing between sarcoid and tuberculosis, although the results thus far are inconclusive [15].

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Numerous agents have been proposed as possible triggers of sarcoidosis and identified in patients with sarcoidosis. Organisms such as mycobacteria and propionibacteria are known to induce granulomatous inflammation and immunologic response consistent with sarcoidosis [16]. Propionibacterium acnes has been isolated in culture from biopsy samples of lymph nodes from patients with sarcoidosis [17]. Granulomatous inflammation can be induced in mice after inoculation with these bacteria [18]. Ocular tuberculosis has a clinical picture consistent with ocular sarcoidosis and may also serve as a trigger for the disease [19]. A polymerase chain reaction analysis of sarcoidosis tissue samples was positive for mycobacterium tuberculosis complex DNA in 16% of patients [20]. Reports of the coexistence or sequential development of sarcoidosis and tuberculosis increase the likelihood that the two entities are related in a subset of patients [21].

The use of TNF-α inhibitors has been linked to the development or recurrence of sarcoidosis. Verschueren et al.[22] described two cases of patients who were treated with etanercept for 6–12 months and subsequently developed biopsy-confirmed sarcoidosis. In both cases, the inflammation resolved after withdrawal of the medication [22]. An association also exists between lymphoma and sarcoidosis. Sarcoidosis-lymphoma syndrome describes the development of lymphoma in patients with chronic sarcoidosis [23], although in some cases the lymphoma precedes development of sarcoidosis [24].

Genetic factors are known to play a role in the development of sarcoidosis. Reports of familial sarcoidosis are common. The risk of developing sarcoidosis is four-fold higher in children of sarcoidosis patients and five times higher in siblings of sarcoidosis patients [3]. Several HLA-DR alleles have been associated with either an increase or decrease in the risk of sarcoidosis. In a Turkish population HLA DRB1*15 was found more frequently in sarcoid patients than controls [25]. The presence of the HLADRB1*11 impacted the clinical phenotype and was identified more frequently in patients without extra-pulmonary findings [25]. The allele DRB1*0401 was highly associated with sarcoidosis with ocular involvement [26].

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Ninety-five percent of sarcoidosis patients have lung or mediastinal lymph node involvement. Most never develop clinically significant disease that requires treatment [27]. Others develop severe disease with mortalities rates as high as 6% [28]. Deaths are typically attributed to respiratory, neurologic, and cardiovascular involvement [29]. Decreased lung function is common in advanced pulmonary disease and can lead to infection, pulmonary embolism, dyspnea, and infection. Aspergillus-related lung disease complicates management in 1–2% of patients [30]. Granulomatous inflammation of the heart can cause arrhythmias, heart failure, and sudden death.

Mortality rates have increased in the USA by 50.5% in women and 30% in men [31]. The reason for this is unclear can include increasing incidence or recognition of sarcoidosis, increasing severity, or an aging sarcoidosis population. In the Veteran population, sarcoidosis patients with a diagnosis of ocular inflammation had a lower 1-year mortality rate than those without ocular disease [32].

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Cardiac sarcoidosis

Cardiac sarcoidosis is an underdiagnosed and potentially fatal form of sarcoidosis. Clinical presentation includes heart block with arrhythmias, congestive heart failure, and pericardial abnormalities [33]. A recent case study attributed death to cardiac disease in 50% of patients [29]. Several autopsy studies suggest the clinical diagnosis is missed in over half of the patients who ultimately die from cardiac sarcoidosis [29,34–38][29,34–38][29,34–38][29,34–38][29,34–38][29,34–38].

Ophthalmologists can play a role in the diagnosis of patients with cardiac sarcoidosis. In addition to granulomatous inflammation and destruction of tissue, endothelial changes and arterial wall properties are also believed to play a role in the pathophysiology of both ocular and cardiac sarcoidosis [39]. A recent study looked at the relationship between ocular sarcoidosis and vascular function. Patients with pulmonary sarcoidosis and ocular inflammation [ocular sarcoidosis (OS), n = 28], pulmonary sarcoidosis without ocular involvement (WOS; n = 58), and healthy controls (n = 77) underwent three distinct tests of vascular function. The first was an evaluation of endothelial function that involved estimation of flow-mediated dilation in the brachial artery. The other measurements focused on arterial stiffness. One calculated arterial stiffness using the carotid-femoral pulse wave velocity. The second measured the augmentation index (Aix) of the central pressure waveform. All patients with sarcoidosis (OS and WOS) showed decreased endothelial function and increased arterial stiffness relative to the control group. In addition, the OS patients showed greater dysfunction than those patient WOS. This suggests that ocular inflammation is a marker of microcirculatory damage in sarcoidosis patients [40▪]. Another study from Japan identified the presence of multiple peripheral chorioretinal atrophic lesions as a risk factor for severe cardiac diseases requiring pacemaker implantation. In this study of 108 consecutive patients with ocular sarcoidosis, seven patients (6.5%) required implantation of a pacemaker. Six had multiple peripheral chorioretinal atrophic lesions, two had tent-shaped peripheral anterior synechiae or nodules in the angle, and two had vitreous snowballs. The median duration of ocular symptoms was 4.5 years prior to pacemaker implantation [41▪].

Although guidelines for evaluation of cardiac disease in patients with ocular sarcoidosis do not exist, at minimum, ophthalmologists must perform a complete review of systems on every patient to identify symptoms consistent with cardiac disease. This evaluation should be conducted at every visit. Some specialists recommend an electrocardiogram at least once on every patient [42] as ECG abnormalities can develop prior to adverse cardiac events [43▪]. Patients with evidence of cardiac disease should have an urgent evaluation with a cardiologist. Imaging modalities are used increasingly to aid in diagnosis and management. Echocardiograms can quantify left ventricular function, cardiac magnetic resonance imaging helps assess myocardial tissue, and 18FDG-PET/CT can identify sites of active inflammation.

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The first-line treatment for ocular sarcoidosis is corticosteroids. In the short term, they rapidly and effectively reduce inflammation to prevent structural and functional damage. Topical, intravitreal, and periocular corticosteroids (and less often systemic therapy) produce large spikes in intraocular pressure in susceptible patients. Some clinicians ‘challenge’ patients with topical corticosteroids for at least 2 weeks to assess the steroid response prior to a periocular or intravitreal injection. Patient with severe anterior disease or inflammation in the posterior segment may require systemic corticosteroids. The initial dose is typically 0.5 mg to 1.0 mg/kg/day, and the drug is tapered as quickly as possible.

In the long term, corticosteroids carry a significant side-effect profile and are associated with increased mortality rates [44]. In addition to the risk of infection, long-term systemic use of corticosteroids increases the risk of osteoporosis, diabetes mellitus, and obesity. Intravitreal fluocinolone acetonide implants provide effective local therapy for posterior and panuveitis, but all patients eventually require cataract surgery and one-third require filtering surgery [45]. The dexamethasone implant carries a lower risk of hypertension and cataract [46].

Patients with chronic ocular and extraocular disease who require continuous treatment with systemic corticosteroids should be transitioned to steroid-sparing agents to reduce morbidity or mortality. Immunosuppressive agents such as methotrexate, mycophenolate mofetil, and azathioprine are often used for long-term control of systemic and ocular inflammation. Higher doses are typically required to control ocular inflammation than isolated systemic disease.

Patients who are refractory to steroid-sparing agents often benefit from anti-TNF-α therapy [47]. TNF-α is released by macrophages and is thought to be involved in the development of granulomatous inflammation [48]. Hence, TNF-α inhibitors have been found to be effective treatment for some sarcoidosis. Infliximab, a monoclonal antibody directed against TNF-α, has been used for refractory skin, neurologic, hepatic, and pulmonary sarcoidosis [49–51][49–51][49–51]. Side-effects of infliximab include infection and cardiac failure and patients should be screened for risk of tuberculosis prior to start of therapy. Adalimumab is another TNF- α monoclonal antibody that has shown benefit in refractory pulmonary, ocular, and cutaneous sarcoidosis [52]. Etanercept is not effective in ocular sarcoidosis [53]. As mentioned previously, there is a concern that TNF-α antagonists, in particular etanercept, can also be a trigger for sarcoidosis. Rituximab is a monoclonal antibody to CD20 antibody that has shown some success in treatment of sarcoidosis [54,55][54,55].

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Sarcoidosis is a systemic granulomatous disease with genetic and environmental associations. Clinical diagnosis of ocular sarcoidosis is based on clinical criteria supported by chest imaging and blood test findings. Confirmation requires histologic evidence of noncaseating granulomatous inflammation and exclusion or treatment of infectious causes. Patients with ocular sarcoidosis who have compromised vascular function should be continually screened for cardiac symptoms with referral to cardiology when symptoms develop. Future research is needed to evaluate the utility of cardiac screening tests in patients with ocular sarcoidosis.

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Financial support and sponsorship

There was no financial support or sponsorship for this present research.

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Conflicts of interest

There are no conflicts of interest.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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The relationships between sarcoidosis with ocular disease, sarcoidosis without ocular disease, and vascular impairment were investigated. Vascular endothelial dysfunction was decreased and arterial stiffness was increased in patients with systemic sarcoidosis relative to subjects without sarcoidosis. This relationship was even more pronounced in patients with ocular manifestations of sarcoidosis, suggesting uveitis is associated with vascular dysfunction.

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A retrospective, cross-sectional study that compared the fundus findings in ocular sarcoidosis with severe cardiac sarcoidosis requiring a pacemaker. It concluded that peripheral chorioretinal atrophic lesions were associated with severe cardiac sarcoidosis.

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Prospective study aimed at identifying electrocardiographic signs associated with development of cardiac sarcoidosis. This study shows that there are electrocardiography abnormalities prior to the development of cardiac events.

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cardiac disease; sarcoidosis; uveitis

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