T he American Thoracic Society, the European Respiratory Society, and the World Association of Sarcoidosis and Other Granulomatous Diseases have defined sarcoidosis as a multisystem disease of unknown causes characterized by granuloma formation and with a predilection for pulmonary involvement. They further note that “the presence of non-caseating granulomata in a single organ…does not establish the diagnosis of sarcoidosis,” and that the diagnosis of sarcoidosis requires a compatible clinical syndrome. Sarcoidosis is present worldwide. In the United States, the incidence has been estimated at 5.9/100,000 population/year for men and 6.3/100,000 population/year for women. In the United States, sarcoidosis is more common among African Americans than whites. The cumulative lifetime risk has been estimated at 0.85% for whites and 2.4% for blacks, and the prevalence as 10.9/100,000 population for whites and 35.5/100,000 population for blacks. Pulmonary disease is the most common abnormality, with bilateral hilar adenopathy the most characteristic feature on chest imaging (either chest radiography or computed tomography [CT]) and parenchymal lung disease having the most negative effect on pulmonary function. In multidisciplinary clinical settings, pulmonary involvement is seen in ∼85%-95% of patients. Involvement of the liver, spleen, or lymph nodes is reported in 25%-35% of patients and in 12%-25% of the skin. The presence of erythema nodosum is reported in 4%-30% of cases but is not specific for a diagnosis of sarcoidosis, as it occurs with other diseases. Neurologic involvement is present in only ∼5%. It is likely that some of that variation represents regional and racial and ethnic variation and that some of the variation represents referral bias. Ocular disease typically is reported as present in ∼12%-25% of patients with documented sarcoidosis, with variable frequencies reported depending on the extent of examination (eg, whether aqueous tear deficiency is evaluated). ^, Uveitis typically is the most common ocular manifestation of ocular sarcoidosis. In a population-based study in Olmstead County, Minnesota, USA, 7% of patients with sarcoidosis had ocular involvement, uveitis was the most common form of ocular sarcoid (61%), and anterior uveitis (71% of uveitis) was the most common anatomic class of uveitis. Conversely, sarcoidosis-associated uveitis accounts for ∼5%-10% of uveitis presenting to tertiary care eye centers in the United States. ^{, ,}

Although anterior uveitis is the most common anatomic class of uveitis seen with sarcoidosis-associated uveitis in the United States, any anatomic class of uveitis may be seen with sarcoidosis, including intermediate, a mixed anterior and intermediate type, posterior, and panuveitis, ^, and in some parts of the world, intermediate uveitis and panuveitis may be more common. ^, Vitreous inflammatory manifestations include “snowballs” and “string of pearls” inflammatory debris. Posterior segment clinical findings include choroidal nodules, optic nerve nodules, multifocal choroiditis, and perivascular sheathing (eg, “candle wax drippings”), occasionally with vascular occlusion. ^, Among patients with sarcoidosis-associated uveitis, the reported frequencies of ocular manifestations typically are 65%-70% anterior uveitis; 11%-16% iris nodules; 3%-25% vitritis; 10%-17% periphlebitis; 4%-5% paucifocal, typically elevated, choroidal nodules (sometimes inappropriately termed “sarcoid granulomas”); and ∼11% multifocal choroiditis. Among patients with sarcoidosis-associated anterior uveitis, both acute anterior uveitis and chronic anterior uveitis have been reported.

The Standardization of Uveitis Nomenclature (SUN) Working Group is an international collaboration, which has developed classification criteria for the leading 25 uveitides using a formal approach to development and classification. Among the uveitides studied was sarcoidosis-associated uveitis.

RESULTS

A total of 383 cases of sarcoidosis-associated uveitis were collected, and 278 cases (73%) achieved supermajority agreement in the diagnosis during the “selection” phase and were used in the machine learning phase. They were compared to 971 other anterior uveitides, 537 other intermediate uveitides, and 910 other panuveitides. Details of the machine learning results for these diseases are outlined in the accompanying article. The characteristics of cases with sarcoid-associated uveitis are listed in Table 1 . Biopsy confirmation of the diagnosis of sarcoidosis was obtained in 58%, and 79% had bilateral hilar adenopathy on chest imaging. Bilateral hilar adenopathy was detected in 72% of 242 cases with reported chest radiography results and 82% of 164 cases with reported chest CT scan results. Of 156 cases with both chest radiography and chest CT results reported, 116 had bilateral hilar adenopathy on both imaging modalities, 24 cases had no evidence of bilateral hilar adenopathy of both imaging modalities, and 16 cases had bilateral hilar adenopathy identified on chest CT imaging but not chest radiography. The characteristics of cases of sarcoid-associated uveitis by anatomic class are listed in Table 2 . The criteria developed after machine learning are listed in Table 3 . The key features of the criteria are a compatible uveitic syndrome and evidence of sarcoidosis. Compatible uveitic syndromes included anterior uveitis ( Figure 1 ), intermediate uveitis ( Figure 2 ), posterior uveitis with either focal choroidal nodule ( Figure 3 ) or multifocal choroiditis ( Figure 4 ), and panuveitis with either choroiditis or retinal vascular sheathing ( Figure 5 ) and/or occlusion. Evidence of sarcoidosis was either biopsy results demonstrating non-caseating granulomata or chest imaging (either chest radiography or chest CT) demonstrating bilateral hilar adenopathy. The overall accuracies by anatomic class were anterior uveitides, training set 97.5% and validation set 96.7% (95% confidence interval [CI]: 92.4-98.6); intermediate uveitides, training set 99.8% and validation set 99.3% (95% CI: 96.1-99.9); and panuveitides, training set 96.3% and validation set 94.0% (95% CI: 89.0-96.8). The overall accuracy of the diagnosis of sarcoidosis-associated uveitis in the validation set was 99.6% (95% CI: 98.8-99.9). The following misclassification rates for sarcoid-associated uveitis in the training set were: 3.2% against anterior uveitides, 2.6% intermediate uveitides, and 1.2% non-infectious panuveitides. There were too few cases of isolated posterior sarcoidosis-associated uveitis for formal testing, although they were included in the testing against the other diseases. In the validation set, the misclassification rates were 0% against anterior uveitides, 0% intermediate uveitides, and 0% non-infectious panuveitides.

Table 1

Characteristics of Patients With Sarcoid Uveitis

Characteristic	Result
Number of cases	278
Demographics
Median IQR (25th 75th), y	49 (39, 61)
Men, %	29
Women, %	71
Race/ethnicity, %
White, non-Hispanic	37
Black, non-Hispanic	26
Hispanic	1
Asian, Pacific Islander	24
Other	9
Missing	3
Uveitis history
Uveitis course, %
Acute, monophasic	5
Acute, recurrent	7
Chronic	80
Indeterminate	8
Laterality, %
Unilateral	18
Unilateral, alternating	1
Bilateral	82
Ophthalmic examination
Keratic precipitates, %
None	52
Fine	18
Round	6
Stellate	0
Mutton-fat	23
Anterior chamber cells, %
Grade 0	15
½+	24
1+	28
2+	25
3+	7
4+	1
Hypopyon, %	1
Anterior chamber flare, %
Grade 0	60
1+	30
2+	9
3+	1
4+	0
Iris, %
Normal	64
Posterior synechiae	27
Iris nodules	12
Sectoral iris atrophy	0
Patchy iris atrophy	1
Diffuse iris atrophy	0
Heterochromia	0
IOP-involved eyes
Median IQR (25th, 75th), mm Hg	16 (13, 19)
Proportion of patients with IOP>24 mm Hg in either eye, %	10
Vitreous cells, %
Grade 0	31
½+	21
1+	31
2+	14
3+	3
4+	0
Vitreous haze, %
Grade 0	61
½+	11
1+	20
2+	5
3+	2
4+	0
Vitreous snowballs, %	17
Pars plana snowbanks, %	1
Choroidal nodule, %	2
Multifocal choroiditis, %	30
Retinal vascular sheathing, %	18
Anatomic class, %
Anterior uveitis	40
Intermediate uveitis	19
Posterior uveitis	4
Panuveitis	37
Evidence of sarcoidosis, %
Non-caseating granuloma on tissue biopsy a	58
Bilateral hilar adenopathy of chest imaging b	79
Non-specific tests for sarcoidosis, %
ACE	52
Lysozyme	12

 

ACE = angiotensin-converting enzyme; IOP = intraocular pressure; IQR = interquartile range.

a 161 of 161 patients’ biopsy results were positive, demonstrating non-caseating granulomata.

b 174 of 242 patients (72%) had a chest radiograph with bilateral hilar adenopathy, and 134 of 164 patients (82%) undergoing computerized tomography had bilateral hilar adenopathy.

Table 2

Characteristics of Sarcoid Uveitis by Anatomic Class of the Uveitis

Characteristic/Anatomic Class	Anterior Uveitis	Intermediate Uveitis	Posterior Uveitis	Panuveitis
Number of cases	112	52	12	102
Demographics
Median IQR (25th 75th) age, y	46 (37, 55)	52 (43, 67)	53 (50, 64)	51 (35, 63)
Men, %	24	29	33	33
Women, %	76	71	67	67
Race/ethnicity, %
White, non-Hispanic	30	63	42	31
Black, non-Hispanic	49	6	0	15
Hispanic	0	2	0	2
Asian, Pacific Islander	7	13	33	45
Other	7	12	25	4
Missing	7	4	0	3
Uveitis history
Uveitis course, %
Acute, monophasic	10	0	0	3
Acute, recurrent	14	2	0	3
Chronic	63	96	92	78
Indeterminate	13	2	8	16
Laterality, %
Unilateral	24	19	42	7
Unilateral, alternating	2	0	0	0
Bilateral	74	81	58	93
Ophthalmic examination
Keratic precipitates, %
None	46	75	92	43
Fine	19	15	8	20
Round	8	0	0	8
Stellate	1	0	0	0
Mutton-fat	27	10	0	29
Anterior chamber cells, %
Grade 0	4	35	75	12
½+	25	27	17	24
1+	32	13	8	32
2+	30	19	0	24
3+	7	6	0	8
4+	2	0	0	1
Hypopyon, %	1	0	0	0
Anterior chamber flare, %
Grade 0	63	81	100	42
1+	29	15	0	39
2+	6	2	0	18
3+	2	0	0	1
4+	0	2	0	0
Iris, %
Normal	61	60	100	66
Posterior synechiae	33	29	0	23
Iris nodules	13	10	0	16
Sectoral iris atrophy	0	0	0	0
Patchy iris atrophy	1	2	0	2
IOP-involved eyes
Median IQR (25th, 75th) mm Hg	16 (13, 19)	16 (14, 18)	15 (14, 17)	16 (13, 18)
Percentage of patients with IOP >24 mm Hg in either eye	8	8	0	16
Vitreous cells, %
Grade 0	55	10	25	17
½+	27	21	17	14
1+	14	52	33	39
2+	3	15	25	24
3+	1	2	0	6
Vitreous haze, %
Grade 0	86	46	42	44
½+	6	17	17	14
1+	5	29	33	28
2+	1	4	8	11
3+	1	4	0	3
Vitreous snowballs, %	0	58	8	26
Pars plana snowbanks, %	0	4	0	0
Choroidal nodule, %	0	0	17	5
Multifocal choroiditis, %	0	0	92	73
Retinal vascular sheathing, %	0	27	49	28
Evidence of sarcoidosis, %
Non-caseating granuloma on tissue biopsy	60	54	58	59
Bilateral hilar adenopathy of chest imaging	82	85	75	74
Non-specific tests for sarcoidosis, %
ACE	45	51	58	59
Lysozyme	14	0	0	17

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