Management of chronic ocular sarcoidosis: challenges and solutions

Figures & data

Table 1 IWOS criteria for diagnosing ocular sarcoidosis: introducing seven clinical signs suggestive of ocular sarcoidosis, five laboratory investigations in suspected ocular sarcoidosis, and four levels of certainty

• Seven intraocular clinical sings of ocular sarcoidosis

1. Mutton-fat KPs/small granulomatous KPs and/or iris nodules (Koeppe/Busacca)

2. TM nodules and/or tent-shaped PAS

3. Vitreous opacities displaying snowballs/strings of pearls

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

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

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

7. Bilaterality

• Five laboratory investigations suggestive of ocular sarcoidosis

1. Negative tuberculin skin test in a BCG-vaccinated patient or in a patient having had a positive tuberculin skin test previously

2. Elevated serum ACE levels and/or elevated serum lysozyme

3. Chest X-ray revealing BHL

4. Abnormal liver-enzyme tests

5. Chest CT scan in patients with a negative chest X-ray result

• Four levels of certainty for the diagnosis of ocular sarcoidosis (diagnostic criteria) in patients in whom other possible causes of uveitis have been excluded

1. Definite: biopsy-supported diagnosis with a compatible uveitis

2. Presumed: biopsy not done, but chest X-ray positive showing BHL associated with a compatible uveitis

3. Probable: biopsy not done, no BHL on chest X-ray, but there were three of the above intraocular signs and two positive laboratory tests

4. Possible: lung biopsy negative, but at least four of the above signs and two positive laboratory investigations present

Abbreviations: ACE, angiotensin-converting enzyme; BHL, bilateral hilar lymphadenopathy; CT, computed tomography; IWOS, International Workshop on Ocular Sarcoidosis; KPs, keratic precipitates; PAS, peripheral anterior synechiae; TM, trabecular meshwork.

Table 2 Spectrum of ocular manifestations of sarcoidosis

Uveitis
Anterior	Iritis/iridocyclitis
	Iris nodules (Busacca, Koeppe)/granuloma
	Keratic precipitates
	Anterior and posterior synechiae
	Trabecular meshwork nodules/granulomas
Intermediate	Pars planitis
	Vitritis
	Snowballs, snowbanking, string of pearls
	Peripheral vasculitis
Posterior	Periphlebitis
	Choroidal granuloma
	Retinitis
	Multifocal choroiditis
	Chorioretinitis
	Acute posterior multifocal placoid
	pigment epitheliopathy (APMPPE)
	Serpiginous choroiditis
	Choroidal neovascularization
	Vaso-occlusive disease
	Vitreous hemorrhage
	Exudative retinal detachment
	Cystoid macular edema
Panuveitis	All three segments involved
Neurosarcoidosis	Optic neuritis
	Papilledema
	Optic nerve head granuloma
	Pupillary abnormalities
	Cranial neuropathy
	Increased intracranial pressure
	Nystagmus
	Hydrocephalus
	Visual hallucinations
	Visual field defects
Eyelids	Periorbital erythematous eyelid swelling
	Eyelid nodules/granulomas
	Entropion
	Trichiasis
	Madarosis
Conjunctiva	Conjunctival nodules
	Cicatricial conjunctival scarring
	Keratoconjunctivitis sicca (KCS)
	Conjunctival granulomas
	Follicular conjunctivitis
	Symblepharon
Sclera	Scleritis/episcleritis
Cornea	KCS
	Superficial punctate keratitis
	Band keratopathy
	Interstitial keratitis
	Peripheral ulcerative keratitis
Lacrimal system	Lacrimal gland inflammation/infiltration
	Nasolacrimal obstruction
	Dacryocystitis
Orbit	Ptosis
	Proptosis
	Globe displacement
	Extraocular muscle infiltration
	Extraocular muscle entrapment
	Optic nerve sheath involvement with
	optic nerve compression
Complications	Glaucoma
	Cataract
	Cystoid macular edema
	Epiretinal membrane
	Choroidal neovascularization
	Vitreous opacities
	Macular atrophy

Figure 1 Sarcoid-related panuveitis with vitreous haze and right-eye optic disk swelling.

Note: ×1.84 at 50° (TRC-50DX; Topcon Corporation, Tokyo, Japan).

Figure 2 Spectral-domain optical coherence tomography.

Note: Optic nerve-head granuloma, adjacent choroidal neovascular membrane with inner segment/outer segment (ellipsoid zone) disruption, and small amount of subretinal fluid in lung biopsy-proven sarcoidosis patient.

Table 3 Treatment options in sarcoidosis induced uveitis according to location of inflammation and severity

Corticosteroids
Topical (eyedrops)	Prednisolone acetate 1%
	Prednisolone sodium phosphate 0.5%
	Difluprednate 0.05%
	Dexamethasone 0.1%
	Rimexolone 1%
	Hydrocortisone acetate 1%
	Loteprednol 0.2% and 0.5%
	Fluorometholone 0.1% and 0.25%
	Betamethasone 1%
Periocular	Triamcinolone acetonide (20–40 mg)
Intraocular (implants)	Dexamethasone implant (0.7 mg)
	Triamcinolone acetonide (1–4 mg)
	Fluocinolone acetonide (0.19 mg and 0.59 mg)
Immunosuppressives*
Antimetabolites	Methotrexate 7.5–25 mg/week PO/SC/IM
	Azathioprine 1–4 mg/kg/day PO
	Mycophenolate mofetil 1–2 g/day PO
	Sulfasalazine
	Leflunomide 100 mg/day PO
Alkylating agents	Cyclophosphamide 1–3 mg/kg/day PO/IV
	Chlorambucil 0.1–0.2 mg/kg/day PO
Calcineurin inhibitors	Cyclosporine A 2.5–1 mg/kg/day PO
	Tacrolimus 0.15–0.3 mg/kg/day PO
	Sirolimus
Biologic agents
Anti-TNFα	Infliximab (3–5 mg/kg loading, then
	3–10 mg/kg every 4–8 weeks IV)
	Adalimumab (loading dose 80 mg, then 40 mg every 2 weeks SC)
	Golimumab (50 mg SC monthly)
Interleukin inhibitors	Certolizumab (50 mg SC monthly)
IL6-receptor antagonist	Toclizumab (4 mg/kg IV every 4 weeks)
	Anakinra (100 mg/day SC)
IL1-receptor antagonist	Daclizumab (1–2 mg/kg doses IV in 4-week intervals)
IL2-receptor antagonist
Others
Chimeric monoclonal antibody against CD20 on B-cell surface	Rituximab (1 g every 2 weeks IV)

Note:

* Recommended doses data from Jabs et al.⁹⁶

Abbreviations: PO, per os (oral); SC, subcutaneous; IM, intramuscular; IV, intravenous.

Table 4 Recent studies evaluating the use of adalimumab in sarcoid-associated uveitis

Study	Design	Etiology of uveitis	Outcome
Suhler et al^Citation77	Multicenter, open-label, prospective	31 patients, 6/31 (19.3%) sarcoidosis	6/6 clinical responders at 10 weeks, 3/6 secondary failure at 50 weeks
Taylor et al^Citation71	Double-blind, placebo-controlled, multinational, Phase III study	217 patients Sarcoidosis: 8/107 (7%) placebo group, 10/110 (9%) adalimumab group	Adalimumab found to be associated with a lower risk of uveitic flare or visual impairment and with more adverse events and serious adverse events than placebo
Airody et al^Citation72	Double-blind, placebo-controlled, multinational, Phase III study	226 patients Sarcoidosis: 14/111 (13%) placebo group, 18/115 (16%) adalimumab group	Adalimumab significantly reduced the risk of uveitic flare or loss of visual acuity in patients with inactive, uninfectious intermediate, posterior, or panuveitis
Riancho-Zarrabeitia et al^Citation78	Open-label, multicenter, retrospective study	17 patients with sarcoid uveitis (10 received adalimumab, 7 infliximab)	Anti-TNFα therapy effective in sarcoid uveitis patients refractory to conventional immunosuppressive therapy; infliximab and adalimumab allowed substantial reduction in prednisone dose, despite having failed standard therapy
Mercier et al^Citation79	Monocentric observational retrospective study	21 patients Sarcoidosis: 2/21 (9.5%)	Anti-TNFα therapy effective on macular edema with a statistically significant reduction of MMT at M3, M6, and M12; regarding sarcoidosis, difficult to interpret, because only two patients were involved
Erckens et al^Citation80	Prospective case series	26 sarcoidosis patients with refractory posterior uveitis	Intraocular inflammatory signs showed improvement in 22 patients (85%) and stabilization in four patients (15%); at 12 months, no recurrences were reported in those successfully treated

JabsDARosenbaumJTFosterCSGuidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panelAm J Ophthalmol200013049251311024423

 PubMed Web of Science ®Google Scholar

SuhlerEBLowderCYGoldsteinDAAdalimumab therapy for refractory uveitis: results of a multicentre, open-label, prospective trialBr J Ophthalmol20139748148623376607

 PubMed Web of Science ®Google Scholar

TaylorSRBankerASchlaenAIntraocular methotrexate can induce extended remission in some patients in noninfectious uveitisRetina2013332149215423615343

 PubMed Web of Science ®Google Scholar

AirodyAHeathGLightmanSGaleRNon-infectious uveitis: optimising the therapeutic responseDrugs201676273926645222

 PubMed Web of Science ®Google Scholar

Riancho-ZarrabeitiaLCalvo-RíoVBlancoRAnti-TNF-α therapy in refractory uveitis associated with sarcoidosis: multicenter study of 17 patientsSemin Arthritis Rheum20154536136826092330

 PubMed Web of Science ®Google Scholar

MercierAERibeiroEKorobelnikJFDelyferMNRougierMBEfficacy of anti-TNF-α therapy for the treatment of non-infectious uveitis: a retrospective study of 21 patientsOcul Immunol Inflamm Epub20161024

 Web of Science ®Google Scholar

ErckensRJMostardRLWijnenPASchoutenJSDrentMAdalimumab successful in sarcoidosis patients with refractory chronic non-infectious uveitisGraefes Arch Clin Exp Ophthalmol201225071372022119879

 PubMed Web of Science ®Google Scholar