Sarcoid-Associated Uveitis: Comparison of a Single-Centre Diagnostic System with the International Workshop on Ocular Sarcoidosis (IWOS) Diagnostic Criteria Ramandeep (Romi) Chhabra, Robyn Troutbeck, Rajitha Ajit, Nicholas Jones Manchester Royal Eye Hospital, Oxford Road, Manchester, M13 9WL, UK  

Introduction Sarcoidosis Multisystem disease with protean manifestations1 Ocular involvement reported in up to 60, usually as the initial manifestation IWOS: International Workshop on Ocular Sarcoidosis 20062 Aims: To help clinicians in suspecting sarcoidosis based on clinical signs To aid diagnosis by establishing relevant investigations To establish criteria for the diagnosis of ocular sarcoidosis 4 diagnostic categories of sarcoid-associated uveitis proposed Using 7 ocular clinical signs: and 5 laboratory investigations:

Laboratory Investigations Clinical Signs Mutton-fat/granulomatous KPs and/or iris nodules TM nodules and/or tent-shaped PAS Snowballs or strings of pearls in vitreous Multifocal peripheral chorioretinal lesions (active or atrophic) Nodular and/or segmental periphlebitis and/or macroaneurysm in an inflamed eye Optic disc nodule and/or solitary choroidal nodule Bilateral inflammation Laboratory Investigations Negative tuberculin skin test in a BCG- vaccinated patient or in a patient with previously (+)ve tuberculin test Raised serum ACE or lysozyme Chest X-ray : Bilateral hilar lymphadenopathy Abnormal Liver function tests Chest CT showing changes indicative of sarcoidosis (if CXR normal)

Sign 1a: Granulomatous KP

Sign 1b: Iris nodules

Sign 5a: Segmental periphlebitis

Sign 5b: Retinal artery macroaneurysm

Sign 6: Optic nerve head granuloma

Lab 3: Bilateral hilar lymphadenopathy

Lab 5: Peribronchial nodules on CT

“Barndoor” sarcoidosis: multifocal choroiditis, patchy periphlebitis, vitreous snowballs and papillitis

IWOS Sarcoid Classification Biopsy confirmation with compatible Uveitis Biopsy not done Bilateral Hilar lymphadenopathy + compatible Uveitis Presumed Ocular Sarcoidosis Hilar adenopathy (-)ve + 3 or more intraocular signs + 2 or more investigational tests Probable Ocular Sarcoidosis Biopsy negative Hilar adenopathy (-)ve + 4 or more intraocular signs + 2 or more investigational tests Possible Ocular Sarcoidosis Definite Ocular Sarcoidosis

Purpose To compare the IWOS diagnostic criteria for sarcoid-associated uveitis with the Manchester Uveitis Clinic (MUC) diagnostic system and to identify discrepancies.

Patients and methods MUC has prospectively entered patients into diagnostic database for 21yrs: 260 patients diagnosed with sarcoid-associated uveitis MUC Diagnostic Protocol for Ocular Sarcoidosis: Confirmed: Biopsy (+)ve or Kveim (+)ve with consistent uveitis Presumed: Raised ACE and/or hilar lymphadenopathy with consistent uveitis Possible: Uveitis strongly suggestive of sarcoid, with other diagnoses excluded, but ACE and CXR normal 100 randomly-selected MUC patients reviewed

Results Comparison of MUC and IWOS diagnostic systems 100 MUC records reviewed: Male 59:41 female Age range at presentation 11-90 (mean 52) Lab test MUC Kawaguchi* (IWOS) Raised ACE 78% 35% Abnormal CXR 54% 48% Clinical sign MUC Kawaguchi* (IWOS) KP (granulomatous) 62% (67%) 52% Snowballs 72% 69% C/R lesions 58% 76% Periphlebitis 39% 45% ON/single nodule 10% 6% Bilateral 91% 98%

Results Diagnosis MUC IWOS Matches Confirmed(MUC) Definite (IWOS) 26 25 Presumed 50 38 34 Possible (MUC) Probable (IWOS) 24 6 2 Possible (IWOS) N/A Unclassifiable 31 (Total) 100 61

Comparison of MUC and IWOS systems: Category: Confirmed/Definite MUC (Confirmed) 26 vs. IWOS (Definite) 25; Excellent correlation but: MUC “confirmed” classification permits (old) Kveim Biopsy +ve as a surrogate for tissue biopsy (not considered by IWOS) Category: Presumed Presumed: MUC 50 vs. IWOS 38 Of the 12 discordant patients (MUC+ve, IWOS –ve): All had uveitis compatible with sarcoid All had ACE levels >55 IU, but normal CXR Category: Possible/Probable MUC (Possible) 24 vs IWOS (Probable) 6; Of the 18 discordant patients (MUC+ve, IWOS –ve) the pattern of uveitis was highly suspicious of sarcoid and with no evidence of other causes But normal CXR, normal ACE Poor correlation at this level Category 4: IWOS possible: MUC no category

Results: Summary MUC vs. IWOS systems There was generally good correlation between the IWOS and MUC systems but: Using the IWOS system, 31/100 MUC patients were unclassifiable because: Despite each one exhibiting >2 IWOS eye signs: only 0 or 1 lab investigations were positive, and biopsies were not performed Under the MUC system, all 31 patients were classifiable Kawaguchi3 and colleagues found 81% positivity for TM nodules or Tent-shaped PAS, but these findings (although included by IWOS) do not have widespread support and the evidence base is poor Abnormal liver enzyme tests have been included as an indicator in the IWOS system, but the evidence base for this is weak IWOS includes 4 categories, which we feel is unnecessary

Conclusions Recommendations to amend the IWOS system: The MUC diagnostic system is clinically-orientated and simple The IWOS diagnostic system was designed to standardise nomenclature and to facilitate research, but in our view shows the following faults: ACE levels do not require quantification, but high levels (>100IU) have very high specificity for sarcoidosis The evidence base for the following IWOS indicators of sarcoid is inadequate: Raised liver enzymes Tent-shaped PAS Kveim biopsy +ve was not included as a tissue biopsy surrogate Four IWOS categories of diagnoses are superfluous; 3 should be sufficient Recommendations to amend the IWOS system: Permit ACE >100 to carry additional diagnostic weight Exclude raised liver enzymes and tent-shaped PAS as diagnostic indicators Include (historical) +ve Kveim biopsy as a surrogate for tissue biopsy Reduce categories to 3 by merging 3 and 4

References Jones N , Mochizuki M. Sarcoidosis: Epidemiology and clinical features. Ocu Imm & Inflam. 18(2), 72-79, 2010. Herbort Carl et al. International criteria for the diagnosis of ocular sarcoidosis: Results of the first International Workshop on Ocular Sarcoidosis (IWOS). Ocu Imm & Inflam, 17, 160-169, 2009. Kawaguchi T et al. Evaluation of characteristic ocular signs and systemic investigations in ocular sarcoidosis patients. Jpn J Ophthalmol 2007 Mar-Apr;51(2):121-6.

Choroidal Nodule