Introduction:

Sarcoidosis is a chronic multisystemic granulomatous disorder caused by an exaggerated cellular immune response to a variety of self or non-self-antigens in a genetically predisposed individual resulting in non-caseating granulomas. Ocular involvement occurs in 25-60% of systemic sarcoidosis at some point of time¹. In this article, we look at the emerging literature on epidemiology, pathogenesis, clinical profile, and management in ocular sarcoidosis.

Epidemiology:

Sarcoidosis has an overall incidence of 6-10 per 100,000. Although sarcoidosis occurs worldwide, it is predominant in certain ethnic and racial groups like the Afro-Caribbean, Scandinavian, and Irish populations^2-4. Highest incidence of ocular sarcoidosis is in the 20-40-year age group. Some studies show two peaks of incidence for ocular sarcoidosis the first at ages 20-30 and the second at ages 50-60^5. There is also a higher incidence of ocular involvement in women^4. The reported incidence of ocular sarcoidosis varies according to the geography, patient population, diagnostic criteria employed, and referral patterns of the reporting ophthalmologists. Earlier considered a disease of the developed world, in recent years, ocular sarcoidosis has increasingly been recognized from developing countries like India, Singapore, Thailand, Taiwan, Malaysia, Kuwait, Lebanon, and Turkey^1,6,7. This may be due to the increasing awareness of this disease and the availability of improved diagnostic modalities like computed tomography and trans-bronchial lymph node biopsies. Ocular involvement in ocular sarcoidosis can be as high as 90% and ocular involvement can precede systemic manifestations of sarcoidosis¹.

Pathogenesis:

Sarcoidosis is caused by antigenic stimulation. In genetically susceptible individuals, antigenic stimulation activates a cascade of immune reaction leading to sarcoidosis. Disease-modifying genes and the interplay of regulatory immune response mediated by regulatory cells and cytokines determine the severity of the disease. Presentation of antigen by the antigen-presenting cells leads to activation of CD4+ cells resulting in the release of cytokines and recruitment of immunocompetent cells and, compartmentalization at the site of resulting in the production of granuloma⁸. Sarcoidosis is a multisystem granulomatous disease of unknown etiology. Various factors implicated in the pathogenesis of sarcoidosis have been summarized in table 1 ^8-31.

Histopathology:

The classic sarcoid granuloma is made up of modified macrophages or epithelioid cells surrounded by a rim of lymphocytes and fibroblasts. Necrosis or caseation, which is usually seen with tuberculosis and fungal infections, is absent in sarcoid granulomas. Occasionally, small foci of fibrinoid necrosis may be present in sarcoidosis. Immunohistochemical studies demonstrate the presence of CD4+Tcells admixed with the epithelioid cells in the center of the cellular infiltrate. The compartmentalization of CD4+Tcells at sites of the disease leads to a markedly high CD4/CD8 ratio of more than 10. An elevated bronchoalveolar lavage (BAL) CD4/CD8 T-cell ratio greater than 3.5 predicts the diagnosis of sarcoidosis with 94% specificity and 53% sensitivity. This is also associated with a favorable prognosis. Histologic observations suggested that granuloma and fibrosis were associated with the activation of Th1 cells, monocytes, and macrophages, as well as the overproduction of IFN-γ, IL-2, TNF-α, IL-15, and CCL20^32-34.

Clinical Manifestations:

Patients may be asymptomatic or present with blurred vision, floaters, redness, or discomfort. Ocular involvement is usually a chronic disease and has an insidious onset. It can involve the lacrimal glands, orbit, eyelids, conjunctiva, uveal tract, and the optic nerve (Figure 1-3). The ocular findings in sarcoidosis are summarized in table 2^{1-4, 6,7}

Orbits, lacrimal gland and lacrimal sac:

Orbital involvement is usually primary, but rarely, sarcoidosis primarily affecting the paranasal sinuses can invade the orbit³⁶. Sarcoidosis coexisting with Graves’ disease has been reported^2,3. Sarcoidosis can involve the orbital adipose tissue, extraocular muscles, and optic nerve sheath, mimicking inflammatory disorders affecting the orbit^36,37.

The lacrimal gland is the most common organ in the orbit to be affected. Histopathologic studies of biopsy-proven orbital sarcoidosis revealed the main lacrimal gland involvement in 42-63% cases^38-40. Usually, patients with lacrimal gland involvement are asymptomatic, but if there is extensive involvement, it can lead to severe keratoconjunctivitis sicca. An enlarged lacrimal can present as a palpable mass, ptosis, diplopia, or proptosis (Figure 4). Nasolacrimal duct obstruction can occur as a consequence of granulomatous inflammation and lead to watery eyes⁴¹.

Eyelids and Conjunctiva:

Conjunctival granulomas are millet shaped to large cream to brown nodular lesions, which can occur in sarcoidosis^6,42. They are usually asymptomatic. Large conjunctival granulomas can rarely cause diplopia. conjunctival granulomas generally respond to topical steroids. Eyelid granulomas are also seen in sarcoidosis⁴³. Patients can also present with fullness of the lids.

Sclera

Sarcoidosis can rarely present as scleritis and episcleritis. It may present as anterior diffuse, anterior nodular, or posterior scleritis^44-47.

Optic Nerve Involvement

Optic nerve involvement is very rare in sarcoidosis. The optic nerve can be affected by various mechanisms which include inflammation of the optic nerve, compression or infiltration of the anterior visual pathway, secondary to retinal ischemia and choroidal inflammation, glaucoma, granuloma, or consequence of hydrocephalus. Patients with sarcoidosis may develop a unilateral or, occasionally, a bilateral retrobulbar optic neuropathy^44,49.

Pupillary involvement sarcoidosis

Patients with sarcoidosis can have the involvement of the pupil. Pupillary manifestations can be in the form of Horner syndrome, tonic pupils, or Argyll Robertson pupils^50-55.

Uveitis:

It is typically chronic bilateral uveitis and characterized by a granulomatous inflammatory reaction in the anterior segment which includes mutton fat keratic precipitates, iris nodules, trabecular meshwork nodules, and tent-shaped peripheral anterior synechiae; snowball and/or “string of pearls” opacities in the vitreous; and in the posterior segment, nodular periphlebitis, multiple peripheral active, or atrophic chorioretinal lesions, optic disc nodules/granuloma, and choroidal nodules⁵⁶. In acute onset sarcoidosis, non-granulomatous anterior uveitis may be seen.

International workshop on ocular sarcoidosis (IWOS) criteria laid down criteria for the diagnosis of ocular sarcoidosis in 2009⁵⁷. Validation studies of IWOS criteria revealed that the criteria except liver enzymes had high diagnostic value only in Japan, while a study with an international cohort involving 14 centers across the world had many limitations^58,59. Also, the international validation study revealed a low sensitivity of the category ‘possible ocular sarcoidosis’. The criteria of a negative tuberculin test in a BCG vaccinated patient or having had a positive purified protein derivative (PPD) skin test done previously was not applicable in all countries, as the BCG vaccination was not performed in many countries and many patients had not received tuberculin test previously. The international study also suggested the need for more than five systemic investigations in suspected patients with ocular sarcoidosis⁵⁹.

To overcome these limitations, the IWOS criteria was revised recently in 2019 which arrived at the following consensus:(1) Other causes of granulomatous uveitis must be ruled out (2) seven intraocular clinical signs suggestive of ocular sarcoidosis (3) eight results of systemic investigations in suspected ocular sarcoidosis, and (4) three categories of diagnostic criteria depending on biopsy results and combination of intraocular signs and results of systemic investigations⁶⁰.(Table 3)

Complications:

The most frequent complications include cystoid macular edema (76%), cataract (49%), glaucoma (36%), retinal ischemia (16%), and neovascularization (11%)⁶¹. Corneal band-shaped keratopathy occurs in longstanding cases of uveitis. Reports of inflammatory choroidal neovascular membranes (CNVM) have been described in sarcoidosis. Rarely, can CNVM be an initial manifestation of ocular sarcoidosis.

Investigations/Laboratory Tests

Laboratory, radiological and ocular investigations play a pivotal role in narrowing down to diagnosis of ocular sarcoidosis (figure 5-9). The investigative tools used in the diagnosis of ocular sarcoidosis have been summarized in table 4.

Differential Diagnosis of Ocular Sarcoidosis:

In addition to the clinical signs and laboratory tests indicative of sarcoidosis, exclusion of other entities that can be mistaken for sarcoidosis is equally important for the diagnosis of sarcoidosis. Granulomatous uveitis may be seen in tuberculosis, syphilis, Vogt-Koyanagi-Harada disease, toxoplasmosis, herpetic uveitis, and multiple sclerosis⁶². Chorioretinal granulomas may also be seen in tuberculosis, syphilis, Vogt-Koyanagi-Harada disease, birdshot retinochoroidopathy, and primary intraocular lymphoma.

Treatment:

There are no standardized therapies for ocular sarcoidosis-associated uveitis. The mainstay of treatment is corticosteroids and is given via topical, periocular, or systemic routes.

Topical Corticosteroids:

When the inflammation is confined to the anterior segment, topical steroids can be used.

Local Corticosteroids:

Periocular injections or intravitreal injections of steroids may be useful in unilateral disease in the absence of a systemic disease. Intravitreal steroids or a sustained steroid drug delivery device like dexamethasone implants (Ozurdex, FDA approval—2010), is very useful in treating cystoid macular edema⁶³.A fluocinolone acetonide implant called Retisert (Bausch & Lomb) was approved by the FDA in 2005, for the treatment of chronic non-infectious uveitis affecting the posterior segment. However, it is not used nowadays, as it is associated with serious adverse events like glaucoma (glaucoma with 34% of filtering surgery at 4 years) and cataract(s)⁶⁴.

Systemic Steroids:

Systemic corticosteroids should be used in cases with optic neuropathy, macular edema with visual acuity <20/200, or occlusive retinal vasculitis with retinal ischemia. In addition, systemic therapy is used in patients who are resistant, and/or intolerant to local treatment, and/or have active systemic disease requiring treatment. In the acute phase, pulse intravenous corticosteroids are recommended in case of severe disease. Mean initial dose of prednisone/prednisolone is 0.5-1.0 mg/kg/day, to a maximum dose of 80 mg/day. Oral prednisolone has to be slowly tapered over a period of 3-6 months.

Immunosuppressive Agents:

For corticosteroid resistant or steroid intolerant cases, steroid sparing immunosuppressive agents like methotrexate, mycophenolate mofetil, azathioprine, and cyclosporine are effective^65,66 Study by Baughman et al.⁶⁵ reported that both methotrexate and azathioprine were efficient in the treatment of ocular sarcoidosis, but discontinuation rate was higher with azathioprine (methotrexate- 3.8% and azathioprine – 19.1% ).

Anti-TNF-α Treatment

Anti TNF-αagents have been used for the treatment of refractory cases of ocular sarcoidosis.

Adalimumab (ADA) has been approved by the FDA for the treatment of non-infectious anterior uveitis in patients with inadequate response to corticosteroids, corticosteroid dependence, or contraindication for use of corticosteroids based on VISUAL 1 and 2 trials^67,68.

Other Biologics

Reports of treatment with rituximab in aggressive cases of sarcoid have been reported in literature⁶⁹.Silpa-Archa, et al. reported that one case out of 17 cases studied had multidrug-resistant ocular sarcoidosis improved with tocilizumab therapy with no major side effects⁷⁰. Janus kinase inhibitors like tofacitinib or ruxolitinib have been used in patients with systemic sarcoidosis without ocular involvement and has been found to be effective^71-73.The treatment algorithm has been outlined in Figure 10 ⁷⁴.

Figure 10: Algorithm for the treatment of patients with ocular sarcoidosis. The algorithm has been adopted from Seve P, et al.⁷⁴ ADA: adalimumab; AU: anterior uveitis; AZA: azathioprine; CI: contraindication; CS: corticosteroids; IFX: infliximab; IVMP: intravenous methylprednisolone pulse; JAKi: Janus kinase inhibitor; LFN: leflunomide; ME: macular edema; MMF: mycophenolate mofetil; MTX: methotrexate; ON optic neuritis; ORV: occlusive retinal vasculitis; RTX: rituximab; TCZ: tocilizumab; TNFi: tumor necrosis factor inhibitor; VA: visual acuity

Treatment of Complications

Neovascularization may regress with systemic anti-inflammatory treatment, anti-vascular endothelial growth factors, and in some cases may require laser treatment. Associated complications like cataract and glaucoma may need to be treated appropriately to prevent visual morbidity.

Conclusion:

Sarcoidosis has been increasingly diagnosed in recent years, due to increased awareness of the disease and better availability of diagnostic modalities. Ocular evaluations contribute in making a diagnosis of systemic sarcoid. Early diagnosis and appropriate, adequate treatment reduces the visual morbidity in ocular sarcoidosis.

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