Ocular Sarcoidosis: A Review for the Postgraduates

Dr Vinaya Kumar Konana
Dr Kalpana Babu

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 populations2-4. 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 50-605. There is also a higher incidence of ocular involvement in women4. 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 Turkey1,6,7. 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.

Mechanism

Description

1

Dysregulation of the IL-23/IL-17 Pathway and Role of T Helper Cells

IL23R pleomorphism has been reported to be associated with increased susceptibility to sarcoidosis, more so ocular sarcoidosis

2

Microorganisms

Mycobacteria, Propionibacterium, Atopobium, Fusobacterium, Hepatitis C, Barr virus, herpes virus, and helicobacter pylori

3

Drug-induced sarcoidosis-like reaction

Ipilimumab, Nivolumab, Pembrolizumab, highly active antiretroviral therapy, Interferon-alpha, Interferon-beta, Etanercept, Adalimumab, and Infliximab BRAF inhibitors.[21]

Vemurafenib.[25]

4

Genetic predisposition

Monozygotic twins are more often concordant for the disease than dizygotic twins

Familial clustering occurs in in 5-16% of the patients

ACCESS study has revealed a familial risk of sarcoidosis to have an estimated odds ratio of 5.8 for siblings and 3.8 for first degree relative parents. [29]

HLA-DRB1 and HLA-DQB1 have been linked to sarcoidosis.[30,31]

Non-HLA genes associated with sarcoidosis are BTNL2, NOD2, NOTCH 4, RAS23 ANXA11.

Polymorphisms in genes encoding cytokines like transforming growth factor-beta, interleukin-8, and tumor necrosis factor-alpha and Toll-like receptor-4 have also been reported [16,17]. [38,39]

Genetic analyses also established that IL23R polymorphisms were associated with the susceptibility to sarcoidosis, especially ocular sarcoidosis.[11]

RAB23 and ANXA11 genes were associated with an increased risk of sarcoidosis- associated uveitis.[40]

5

Vascular Endothelial Damage

Uveitis in sarcoidosis patients has been hypothesized to be secondary to vascular dysfunction.

ocular involvement can be a biomarker of vascular damage, and choroidal involvement can predict an increased risk of cardiac disease

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 CCL2032-34.

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 21-4, 6,7

Figure 1: Slitlamp photograph showing A: Conjunctival granulomas in a
patient with pulmonary sarcoid B: Scleral nodule C: Keratic precipitates
in eyes granulomatous anterior uveitis D: large Koeppe nodules

Figure 2: Fundus photograph showing A: vitritis with snow banking
B: perivasculitis C: Peripheral chorioretinal punched out scars
D: multiple choroidal granuloma
Figure 3: Fundus photograph showing
A: disc edema B: Optic nerve granuloma

Eye lid

Granuloma, lagophthalmos (if associated with facial palsy)

Lacrimal gland

Keratoconjunctivitis sicca

Sclera

Scleritis/episcleritis

Conjunctiva

Conjunctival granuloma and nodules

Cornea

Band shape keratopathy

Pupillary abnormality

Horner syndrome, tonic pupils, and Argyll Robertson pupils

Anterior uveitis

Nongranulomatous anterior uveitis

Mutton Fat keratic precipitates

Iris and pupillary nodules

Increase in IOP

Tent shaped peripheral anterior synechiae

Nodules in trabecular meshwork (Berlin nodules)

Lens

cataract

Intermediate uveitis

Snowballs/strings of pearls vitreous opacities

Multifocal peripheral chorioretinal lesions (active and atrophic)

Retinal and choroidal lesions

Nodular and /or segmental periphlebitis (with or without candle wax exudate)

Choroidal granuloma

Hemorrhagic retinopathy with a branch or central retinal venous occlusions

Optic nerve

Optic disc nodules/ granuloma /optociliary shunts/ dilated collateral veins on the optic nerve head

Neurological manifestations

Cranial nerve palsies

Encephalopathy

Chiasmal syndromes

Motility disorders

Optic atrophy either due to direct sarcoid tissue infiltration or compression by cerebral mass.

Nasolacrimal drainage system

Nasolacrimal duct obstruction

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 reported2,3. Sarcoidosis can involve the orbital adipose tissue, extraocular muscles, and optic nerve sheath, mimicking inflammatory disorders affecting the orbit36,37.

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% cases38-40. 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.

Figure 4: External photograph showing preseptal mass
superonasally to the right upper eyelid (a), conjunctival
granulomas (black arrows) (b), and CT orbits
showing ill-defined, heterogenous lesion in the superior
and nasal orbit near the lacrimal sac regions (c,d)

Eyelids and Conjunctiva:

Conjunctival granulomas are millet shaped to large cream to brown nodular lesions, which can occur in sarcoidosis6,42. 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 scleritis44-47.

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 neuropathy44,49.

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 pupils50-55.

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 limitations58,59. 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)

I Other causes of granulomatous uveitis must be ruled out

II. Intraocular signs suggestive of ocular sarcoidosis

1. Mutton-fat keratic precipitates (large or small) and/or iris nodules at pupillary margin (Koeppe) or in stroma (Busacca)

2. Trabecular meshwork nodules and/or tent-shaped peripheral anterior synechia

3. Snowballs/strings of pearls vitreous opacities

4. Multiple chorioretinal peripheral lesions (active and/or atrophic)

5. Nodular and/or segmental periphlebitis (candle-wax drippings) and/or macroaneurysm in an inflamed eye

6. Optic-disc nodule(s)/granuloma(s) and/or solitary choroidal nodule

7. Bilaterality (assessed by ophthalmological examination including ocular imaging showing subclinical inflammation)

III. Systemic investigations result in suspected ocular sarcoidosis

1. Bilateral hilar lymphadenopathy by chest X-ray and/or chest computed CT scan

2. Negative tuberculin test in a BCG-vaccinated patient or interferon-gamma releasing assays

3. Elevated serum angiotensin converting-enzyme

4. Elevated serum lysozyme

5. Elevated CD4/CD8 ratio (>3.5) in bronchoalveolar lavage fluid

6. Abnormal accumulation of 67-gallium scintigraphy or 18F-fluorodesoxyglucose positron emission tomography imaging

7. Lymphopenia

8. Parenchymal lung changes consistent with sarcoidosis, as determined by pneumologists or radiologists

Diagnostic criteria of ocular sarcoidosis

• Definite ocular sarcoidosis: diagnosis supported by biopsy with compatible uveitis

• Presumed ocular sarcoidosis: diagnosis not supported by biopsy, but bilateral hilar lymphadenopathy present with two intraocular signs

• Probable ocular sarcoidosis: diagnosis not supported by biopsy and bilateral hilar lymphadenopathy absent, but three intraocular signs and two systemic investigations selected from two to eight are present

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.

Figure 5: A: Chest X-Ray showing bilateral hilar lymphadenopathy
in a patient with sarcoidosis B: Coronal high resolution computerized
tomography (HRCT) scan showing fissural nodules in ocular
sarcoidosis (yellow arrow) C: Coronal HRCT scans showing symmetrical
hilar lymph node enlargement in ocular sarcoidosis (yellow arrows)
Figure 6: A: Fundus Fluorescein angiography showing disc leakage in
a eyes with posterior uveitis with multiple sarcoid choroidal
granulomas B: Indocyanine green angiography showing multiple
hypocyanascent choroidal granulomas which is appreciated better than
Fluorescein angiography
Figure 7: A: Fundus photo showing choroidal neovascular
membrane (CNVM) adjacent to the disc with subretinal fluid at
the macula, B: fundus fluorescein angiogram showing hot disc
with dye leakage from the CNVM
Figure 8: A: fundus photo of a patient with ocular sarcoidosis
showing multiple choroidal granuloma B: Optical
coherence tomography over the lesion shows homogenous
lesion at the level of choroid with increased transmission suggestive
of choroidal granuloma
Figure 9: Conjunctival biopsy showing chronic granulomatous
inflammation comprising of lymphocytes and macrophages

Investigations

A

Laboratory investigations

Tuberculin Test

Serum Angiotensin-Converting Enzyme and Lysozyme Level

Abnormal Liver Enzyme Tests

Lymphopenia

Serum Interleukin 2 Receptor

Krebs von den Lungen-6

Serum calcium level

Micro Ribonucleic Acid

B

Radiological investigations

Chest radiograph

High-resolution computerized tomography scan

Gallium Citrate Scanning

18F-Fluorodesoxyglucose Positron Emission Tomography

C

Biopsy

Transbronchial lymph node biopsy

Conjunctival granuloma biopsy

D

Bronchoalveolar Lavage Fluid analysis

E

Ocular investigations

Fluorescein angiography

Indocyanine green angiography

Optical Coherence Tomography

Optical Coherence Tomography Angiography

Aqueous CD4/CD8 Ratio

Vitreous CD4+/CD8+ Ratio

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 effective65,66 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 trials67,68.

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 effective71-73.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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Dr Vinaya Kumar Konana
Department of Vitreoretina, Vittala International Institute of Ophthalmology, Bengaluru, dr.vini69@gmail.com
Dr Vinaya Kumar Konana is currently working as a consultant, Department of Vitreoretina at Vittala international Institute of ophthalmology, Bengaluru. He has completed his MBBS from Vijayanagara Institute of Medical Sciences, Bellary in 2011 and post-graduation from Sankara Eye Hospital, Guntur, Andhra Pradesh in 2016. He completed his fellowship in vitreoretina surgery under Rajiv Gandhi University of Health Sciences from Sankara Eye Hospital, Bengaluru in 2018. Post fellowship he did one year of senior residency in Sankara Eye Hospital, Guntur in the department of vitreoretina. He has worked as an observer in department of Uveitis and Ocular Inflammation at Prabha Eye Clinic and Research Centre and Vittala international Institute of Ophthalmology. He has won travel grant award at USICON 2019 and Best of IJO Award for the year 2019. He has 28 publications in national and international journals and presentations in state and national conferences. He is very passionate about teaching and research. Apart from vitreoretinal surgeries, he is interested in the fields of ocular inflammation, retinopathy of prematurity, retinal imaging and ocular photography.
Dr Kalpana Babu
Department of Uvea and Ocular Inflammation, Prabha Eye Clinic & Research Centre & Vittala International Institute of Ophthalmology, Bengaluru, kalpanababumurthy@gmail.com
Dr.Kalpana Babu Murthy heads the department of Uveitis & Ocular Inflammation at Prabha Eye Clinic & Research Centre and Vittala International Institute of Ophthalmology, Bangalore. She is currently the vice president of the Uveitis Society of India and secretary of the Global Ocular Inflammation Workshops Society. She is an elected member of the International uveitis study group, national academy of medical sciences and a past member(Treasurer) of the executive board of the International Ocular Inflammation Society. She has received the Dr.Narsing A Rao best paper award(2004), MM Joshi overall best paper award(2005), Indian Journal of Ophthalmology-Gold award(2009), Asia pacific academy of Ophthalmology travel grant(Sydney2011), College of ophthalmologists of Hongkong & Hongkong ophthalmological society travel grant(2012) and APAO achievement award(2018). She has received the prestigious Col.Rangachari award by the All India Ophthalmic Society for the best research work done in India in 2018-19. She has 90 publications in peer reviewed journals, written 8 chapters for books on uveitis and 10 publications in non peer reviewed journals. She is reviewer for several peer reviewed ophthalmology journals & has been an invited speaker for 96 national & 52 international meetings. She has successfully organized many national and international meetings in uveitis including the Ist assembly of international ocular inflammation societies in Goa in 2011. She has participated in several multicenter drug & clinical trials in uveitis as a principal investigator. Her areas of interest include ocular tuberculosis, sarcoidosis, viral and HIV related ophthalmic diseases. She is also a cataract surgeon trained in complicated cataract and femtosecond cataract surgeries.
Published on 12th October 2020
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