In recent years, the pathogenesis of sarcoidosis has been better understood. Sarcoid granulomas are composed of epithelioid cells, mononuclear cells, and CD4 T cells with a few CD8 T cells around the periphery. Bronchoalveolar lavage of sarcoidosis patients showed CD4/CD8 T-cell ratio more than 3–5:1 compared with a ratio of 2:1 in healthy people [6]. Similarly, CD4/CD8 ratios of vitreal and peripheral T lymphocytes were significantly higher in patients with ocular sarcoidosis than in patients without sarcoidosis [7]. In sarcoidosis, the granulomatous inflammation is associated with upregulation of cytokines such as interferon (IFN)-γ, interleukin (IL)-12, IL-18, and IL-27 produced by TH1 cells, consistent with TH1 cell polarization [8–11]. On the other hand, cytokines such as IL-4 and IL-5 produced by TH2 cells are downregulated [9–12].

Environmental factors are associated with increased risk of sarcoidosis. In the ACCESS study, occupational exposure to insecticides, pesticides, or mold and/or mildew and agricultural employment were associated with a 1.5-fold increase in sarcoidosis risk [13]. On the other hand, tobacco use was associated with decreased risk. The authors concluded that there was no single cause of sarcoidosis; rather, the disease is triggered by multiple factors. Genetic and host factors are important in the pathogenesis. Among siblings, all first-degree and second-degree relatives of sarcoidosis patients, the risk of developing sarcoidosis increased fivefold [13]. The genetic basis of sarcoidosis involves the class 2 human leukocyte antigens (HLAs) genes within the MHC locus on chromosome 6 [13, 14]. HLAs are cell surface proteins that are essential for immune recognition and function. In the ACCESS study, the HLA-DRB1*1101, RB1*0402, DRB1*1201, DRB1*1501, DRB3*0101, DPB1-V76, and DRB1*1401 were identified as risk factors for sarcoidosis [15, 16]. Among these HLA alleles, HLA-DRB1*0401 was associated with increased risk for ocular involvement. Genome-wide association studies identified polymorphisms in the BTNL2 gene within the MHC locus that are associated with increased risk of sarcoidosis. It is thought that these polymorphisms may influence T-lymphocyte activation and regulation [14].

The clinical and histopathological similarities to tuberculosis have raised questions about the role of mycobacterial organisms in the pathogenesis of sarcoidosis. Although histopathologic studies failed to reveal any microbial organisms, PCR studies showed a 10-fold to 20-fold greater likelihood of detecting mycobacterial DNA in tissues from patients with sarcoidosis than normal controls [17]. Mass spectrometry and protein immunoblotting experiments identified the mycobacterial catalase-peroxidase (mKatG) protein in almost half of patients with sarcoidosis [18]. The mKatG is a virulence factor for Mycobacterium tuberculosis and an enzyme that converts the prodrug isoniazid, an antituberculosis agent, to its active microbicidal form. The mKatG is an immunodominant T-cell antigen that causes increased lung and blood CD4 and CD8 T-cell responses in sarcoidosis patients [18–20].

Serum amyloid A (SAA), an amyloid precursor and acute-phase reactant, is both a component and innate regulator of granulomatous inflammation in sarcoidosis through Toll-like receptor-2 [21]. It is expressed at higher levels in sarcoidosis granulomas than in other granulomatous disorders [21]. Additionally, SAA induced granulomatous lung inflammation in animal models and stimulated the expression of cytokines such as IFN-γ, tumor necrosis factor (TNF), and IL-10 [21]. Based on these findings, Chen and Moller [22] proposed that the pathobiology of sarcoidosis is determined by aberrant innate response that results in the induction, misfolding, and aggregation of SAA. According to their hypothetical model [21, 22], in genetically susceptible patients, both etiologic triggers and environmental factors induce innate immune response that leads to expression of systemic and intracellular misfolded and/or aggregated SAA and hyperpolarized TH1 response. The misfolded and/or aggregation of SAA provides a nidus and template for further SAA aggregation in sarcoidosis granuloma. Additionally, SAA and SAA peptides released from granulomas stimulate macrophages and T cells, which results in further secretion of cytokines such as IFN-γ, TNF, IL-12, IL-18, and IL-27 by TH1 cells. Clearance of aggregated SAA and local pathogenic antigen and downregulation of TH1 cell response lead to remission, while inability to clear SAA and local pathogenic antigens leads to chronic inflammation and fibrosis.

The percentage of sarcoidosis patients with eye involvement varies widely, depending on racial origin, geographical location, and the diagnostic criteria used for ocular involvement. In a comparative analysis of 571 Finnish and 686 Japanese patients, Pientinalho et al. [23] reported that at presentation, 5 % of Finish patients had eye symptoms, while 41 % of Japanese patients had eye symptoms. In the ACCESS study, African-Americans and females experienced a higher percentage of ocular involvement [13].

Sarcoidosis can involve any part of the eye, including the eyelid, orbit, lacrimal gland, conjunctiva, intraocular structures, and optic nerve. The most common ocular finding is granulomatous uveitis, affecting 20–70 % of patients [24]. Smith and Foster [25] reviewed their experience with 43 ocular sarcoidosis patients and found that anterior uveitis was the most common ocular finding (73 %), followed by vitritis (62 %), retinal and choroidal lesions (34 %), and ocular adnexal and orbital lesions (10 %). In a review of 379 patients with systemic sarcoidosis, Demirci and Christianson [26] reported that 8 % had orbital and adnexal involvement. Orbital manifestations of sarcoidosis are palpable periocular mass (89 %), proptosis (42 %), discomfort (31 %), ptosis (27 %), restricted ocular motility (23 %), dry eye (19 %), diplopia (15 %), and decreased vision (12 %) [27]. Patients with orbital sarcoidosis usually don’t develop intraocular inflammation. In a review of 20 patients with orbital sarcoid, Marvrikakis and Rootman [28] reported that anterior uveitis was present in 10 % of the patients. In the literature, the intraocular involvement ranged from 0 to 23 % of the patients with orbital sarcoidosis [26, 27]. In the orbit and adnexa, sarcoidosis most commonly affects the lacrimal gland (42 %), followed by the orbital tissue (39 %), eyelid (12 %), and lacrimal sac (8 %) [27]. In some studies, up to 60 % of patients develop lacrimal gland involvement [29]. The lacrimal gland involvement can present as enlargement of the gland or dry eyes. When sarcoidosis affects the extralacrimal orbital tissue, it presents as diffuse involvement or discrete mass. The discrete mass mostly affects the inferior quadrant [27]. Rarely, sarcoidosis can affect extraocular muscles, which could be symptomatic or asymptomatic [28]. When symptomatic, sarcoidosis presents with painful, external ophthalmoplegia, painless diplopia, or ptosis [28, 30–33]. The other rare orbital presentation is the dural involvement of the optic nerve sheath [28, 34]. Orbital and adnexal sarcoidosis can be the initial sign of the systemic disease, develop in patients with known systemic disease, or affect only orbital and adnexal tissue without developing systemic disease. The term “sarcoidal reaction” or “orbital sarcoid” is used for patients with orbital involvement alone and no systemic sarcoidosis [28]. In a review of 18 patents with orbital sarcoid, Mavrikakis and Rootman [28] reported that systemic sarcoidosis was discovered in half of the patients, while the other half showed no evidence of systemic disease during the mean follow-up of 5 years. In a review of 30 patients with orbital and adnexal sarcoidosis, Demirci and Christianson [26] found that 37 % of patients had known systemic disease, orbital and adnexal involvement was the initial manifestation of systemic disease in 34 % of the patients, and 29 % of patients had disease limited to the region. Using Kaplan-Meier estimates, systemic sarcoidosis was expected in 8 % of the patients who presented with only orbital and adnexal disease by 5 years [26]. No clinical feature was found to be significantly predictive of systemic disease in univariate or multivariate analyses [26].

Imaging of orbital sarcoidosis demonstrates homogenous or lobular enlargement of the lacrimal gland which molds to the eye or diffuse homogeneous involvement of orbital soft tissue. The involved tissue shows enhancement with contrast in computed tomography or gadolinium in magnetic resonance imaging. On histopathological examination, noncaseating granulomatous inflammation is the hallmark pathologic feature. The granulomata are predominantly composed of epithelioid histiocytes with scattered giant cells and foci of necrosis. Granulomata are usually surrounded by a paucity of lymphoid cells and fibrosis, the so-called naked granulomata.

The diagnosis of orbital sarcoidosis is usually based on clinical and radiologic findings; however, biopsy is required to confirm the diagnosis histopathologically and to exclude other possible diseases. However, even in cases with typical histopathologic findings, other causes of granulomatous inflammation should be ruled out. An international workshop in 2006 provided consensus and established criteria for the clinical diagnosis of ocular sarcoidosis [8]. However, there are no established criteria for clinical diagnosis of orbital sarcoidosis. A complete medical evaluation should be part of the work-up; the orbital specialist should have a high level of suspicion and low threshold for referral to an internist or pulmonologist in the context of findings suspicious for the disease. Skin lesions including erythema nodosum, lupus pernio, lesions along scars, tattoos and prior trauma sites, parotid enlargement, lymphadenopathy, hepatosplenomegaly, neurological signs especially for cranial nerve VII palsy, and normal lung examination are usual clinical findings in suspected cases [35]. Basic laboratory tests ordered in suspected sarcoidosis cases include chest-ray, complete blood count, renal function, serum calcium, liver function tests, tuberculin skin test, 24-h urine test for calcium levels, pulmonary function test, total immunoglobulins, and electrocardiogram. Elevated serum angiotensin-converting enzyme (ACE) level is associated with active sarcoidosis and has 60–73 % sensitivity in diagnosing sarcoidosis [36–38]. However, some recent studies showed no association between elevated ACE levels on ocular presentation [39]. Conjunctival biopsy has been reported to be helpful for the diagnosis of systemic sarcoidosis [40–42], but biopsy of clinically or radiologically involved tissue has a much higher diagnostic yield for sarcoidosis or diseases in the differential diagnosis.