Ocular Immunology and Inflammation

ISSN: 0927-3948 (Print) 1744-5078 (Online) Journal homepage: https://www.tandfonline.com/loi/ioii20

An Algorithm for the Diagnosis of Behçet Disease

Uveitis in Adults

Ilknur Tugal-Tutkun, Sumru Onal, Miles Stanford, Mehmet Akman, Jos W.R.
Twisk, Maarten Boers, Merih Oray, Pinar Çakar Özdal, Sibel Kadayifcilar,
Radgonde Amer, Sivakumar R. Rathinam, Rajesh Vedhanayaki, Moncef
Khairallah, Yonca Akova, Fatime Nilüfer Yalcindag, Esra Kardes, Berna
Basarir, Çigdem Altan, Yilmaz Özyazgan & Ahmet Gül

To cite this article: Ilknur Tugal-Tutkun, Sumru Onal, Miles Stanford, Mehmet Akman, Jos W.R.
Twisk, Maarten Boers, Merih Oray, Pinar Çakar Özdal, Sibel Kadayifcilar, Radgonde Amer,
Sivakumar R. Rathinam, Rajesh Vedhanayaki, Moncef Khairallah, Yonca Akova, Fatime Nilüfer
Yalcindag, Esra Kardes, Berna Basarir, Çigdem Altan, Yilmaz Özyazgan & Ahmet Gül (2020):
An Algorithm for the Diagnosis of Behçet Disease Uveitis in Adults, Ocular Immunology and
Inflammation, DOI: 10.1080/09273948.2020.1736310

To link to this article: https://doi.org/10.1080/09273948.2020.1736310

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OCULAR IMMUNOLOGY AND INFLAMMATION
https://doi.org/10.1080/09273948.2020.1736310

ORIGINAL ARTICLE

An Algorithm for the Diagnosis of Behçet Disease Uveitis in Adults

Ilknur Tugal-Tutkun, MDa, Sumru Onal, MD, FEB.Ophthb, Miles Stanford, MDc, Mehmet Akman, M.D, MPHd, Jos W.
R. Twisk, Ph.De, Maarten Boers, Ph.Df, Merih Oray, MDa, Pinar Çakar Özdal, MDg, Sibel Kadayifcilar, MDh,
Radgonde Amer, MDi, Sivakumar R. Rathinam, MDj, Rajesh Vedhanayaki, MDj, Moncef Khairallah, MDk, Yonca Akova,
MDl, Fatime Nilüfer Yalcindagm, Esra Kardes, MDn, Berna Basarir, MDo, Çigdem Altan, MDo, Yilmaz Özyazgan, MDp,
and Ahmet Gül, MDq
a
Department of Ophthalmology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey; bDepartment of Ophthalmology, School of
Medicine, Koc University, Istanbul, Turkey; cMedical Eye Unit, St Thomas’ Hospital, London, UK; dDepartment of Family Medicine, School of
Medicine, Marmara University, Istanbul, Turkey; eDepartment of Epidemiology and Biostatistics, Amsterdam UMC, Vrije Universiteit Amsterdam,
Amsterdam, The Netherlands; fDepartment of Epidemiology and Biostatistics, Amsterdam Rheumatology and Immunology Center, Amsterdam
University Medical Centers, Vrije Universiteit Amsterdam, The Netherlands; gDepartment of Ophthalmology, University of Health Sciences, Ulucanlar
Eye Education and Research Hospital, Ankara, Turkey; hDepartment of Ophthalmology, Hacettepe University Faculty of Medicine, Ankara, Turkey;
i
Department of Ophthalmology, Hadassah Medical Center, Jerusalem, Israel; jDepartment of Ophthalmology, Aravind Eye Care System, Madurai,
India; kDepartment of Ophthalmology, Fattouma Bourguiba University Hospital, Faculty of Medicine, University of Monastir, Monastir, Tunisia;
l
Department of Ophthalmology, Bayindir Hospital, Ankara, Turkey; mDepartment of Ophthalmology, Ankara University Faculty of Medicine, Ankara,
Turkey; nEye Clinic, University of Health Science, Ümraniye Training and Research Hospital, Istanbul, Turkey; oEye Clinic, University of Health Science,
Beyoglu Eye Training and Research Hospital, Istanbul, Turkey; pDepartment of Ophthalmology, Istanbul Cerrahpasa University Faculty of Medicine,
Istanbul, Turkey; qDivision of Rheumatology, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

ABSTRACT ARTICLE HISTORY

Purpose: To develop an algorithm for the diagnosis of Behçet’s disease (BD) uveitis based on ocular Received 15 September 2019
findings. Revised 31 January 2020
Methods: Following an initial survey among uveitis experts, we collected multi-center retrospective data Accepted 25 February 2020
on 211 patients with BD uveitis and 207 patients with other uveitides, and identified ocular findings with KEYWORDS
a high diagnostic odds ratio (DOR). Subsequently, we collected multi-center prospective data on 127 Behçet disease; uveitis;
patients with BD uveitis and 322 controls and developed a diagnostic algorithm using Classification and diagnosis; classification
Regression Tree (CART) analysis and expert opinion. criteria; classification and
Results: We identified 10 items with DOR >5. The items that provided the highest accuracy in CART regression tree (CART)
analysis included superficial retinal infiltrate, signs of occlusive retinal vasculitis, and diffuse retinal analysis
capillary leakage as well as the absence of granulomatous anterior uveitis or choroiditis in patients
with vitritis.
Conclusion: This study provides a diagnostic tree for BD uveitis that needs to be validated in future
studies.

Introduction the classification of a homogeneous population of BD patients

to be included in clinical and comparative studies.7–12
Behçet disease (BD) is a multi-system inflammatory disorder
However, these criteria sets mostly contain manifestations
of unknown etiology. Ocular involvement has been one of the
with sufficiently high prevalence, such as uveitis, and findings
major manifestations of the disease since its first description,1
included are vaguely described for their distinctive features.
and it may even be the presenting symptom of the disease.2–5
These sets also do not include some highly specific manifesta-
Since it is one of the most severe causes of noninfectious
tions because of their low prevalence, and in general, they lack
uveitis and associated with a high risk of blindness,2 early
the sensitivity and specificity required for the bedside diag-
diagnosis and appropriate treatment of BD uveitis are of
nosis of BD.13
utmost importance.
Regarding BD uveitis, its distinction from other noninfec-
The clinical spectrum of BD is quite heterogeneous, includ-
tious uveitides has therapeutic and prognostic implications.
ing mainly mucocutaneous, vascular, ocular, or arthritic
While glucocorticoid monotherapy may be an acceptable first-
manifestations.6 Since there is no single pathognomonic man-
line therapeutic approach to several other noninfectious uvei-
ifestation or laboratory feature of BD, several clinical criteria
tic conditions, in BD uveitis glucocorticoids must always be
sets have been developed both for diagnosis and especially for

CONTACT Ilknur Tugal-Tutkun itutkun@yahoo.com; itutkun@istanbul.edu.tr Istanbul Universitesi, Istanbul Tip Fakultesi, Goz Hastaliklari A.D. Capa, Fatih,
Istanbul 34093
The preliminary results of this study have been presented at the 18th International Conference on Behçet’s Disease in Rotterdam, The Netherlands, September 12-14,
2018 and at the Joint Meeting of Sociedad Panamericana de Enfermedades Inflamatorias Oculares and International Uveitis Study Group in Chicago, IL, USA,
October 26, 2018.
Supplemental material for this article can be accessed on the publisher’s website.
© 2020 Taylor & Francis Group, LLC
2 I. TUGAL-TUTKUN ET AL.
combined with other immunomodulatory agents, especially in
those patients with posterior segment inflammation14; early
biologic treatment may improve the visual prognosis.15–17 It is
even more important not to misdiagnose an infectious uveitis
that may coincidentally occur in a patient with extraocular
manifestation(s) suggesting BD.
Despite the availability of several criteria sets aiming to
classify patients as the presence or absence of the disease,
there is an unmet need for tools giving the probability of
the disease for an individual patient in a context-dependent
manner since the list of conditions to be considered for the
differential diagnosis of noninfectious and infectious uveitic
conditions vary greatly due to local epidemiological factors.18
We therefore aimed to develop a diagnostic algorithm for
BD uveitis based solely on characteristic ocular findings that
may help in the early diagnosis of BD uveitis and in distin-
guishing this condition at a high probability from other
uveitides.
Methods
This study comprised 4 steps: (i) survey of expert opinion on
characteristic features of ocular involvement in BD; (ii) retro-
spective clinical data collection and analysis; (iii) prospective
clinical data collection; (iv) development of a diagnostic
algorithm.
The Ethics Committee of Istanbul Faculty of Medicine,
Istanbul University, approved the protocol as a retrospective
study, and waiver of informed consent was obtained for the
use of de-identified clinical records. The study was conducted
under the auspices of the International Society for Behçet’s
Disease, Eye Involvement Study Group, and the convenors
(Ilknur Tugal-Tutkun and Miles Stanford) established the
Study Group for Diagnosis of Behçet Disease Uveitis
(SGBDU). The study adhered to the tenets of the
Declaration of Helsinki.
Preliminary Work
A detailed questionnaire obtained an expert opinion on the
definition of ocular symptoms and signs suggestive for the
diagnosis of BD uveitis and contrariwise, features considered
incompatible with BD uveitis. Uveitis experts were free to add
or modify items in the questionnaire. The questionnaire
shown in Supplementary Table 1 was sent to an international
group of 37 uveitis experts, and 21 (62%) responded.
Retrospective Data Collection and Analysis
Based on the survey results, retrospective data on the presence of
suggestive and also incompatible features were collected through
a standard data acquisition sheet in two groups: patients with
a definite diagnosis of BD uveitis fulfilling the International
Study Group (ISG) Criteria for the Diagnosis/Classification of
BD7; and patients with non-Behçet uveitides. Four centers in
Turkey, 1 center in Israel, and 1 in the United Kingdom (UK)
among the SGBDU contributed. We did not ask the contributors
to select specific diagnoses for the control group; therefore, the
cohort was a convenience set of non-Behçet uveitis patients
depending on the referrals to the involved sites. Patients with
neoplastic or non-neoplastic masquerading conditions, which
usually are not considered in the differential diagnosis of BD
uveitis, such as postoperative intraocular inflammation,
endophthalmitis, intraocular foreign body-associated inflamma-
tion, intraocular lymphoma or metastatic tumors were excluded.
The data sheet collected demographic information as well as
ocular symptoms, ocular findings, and fluorescein angiographic
(FA) findings, when available, seen in either eye at presentation
or at any time during follow-up of each patient. Signs of active
inflammation such as hypopyon, superficial retinal infiltrate,
and occlusive periphlebitis as well as signs of damage (sequelae)
indicating advanced disease such as ghost vessels and optic
atrophy were to be recorded irrespective of the time of their
appearance during follow-up examinations, because there may
be some sequelae and still active disease in the same eye; or there
may be an asymmetrical involvement with the presence of acute
signs in one eye and sequelae in the other eye. In order to
estimate predictive validity, we analyzed sensitivity, specificity,
positive and negative predictive values (PPV, NPV), positive and
negative likelihood ratios (PLR, NLR), and diagnostic odds ratio
(DOR) for each item.
Prospective Data Collection
Based on the results of the retrospective study, we made a list
of features with a high probability of identifying BD uveitis
and prepared a standard data acquisition sheet to collect
prospective data. Nine centers among the SGBDU (5 centers
in Turkey, one each in the UK, Israel, Tunisia, and India)
were invited to contribute prospective data, aiming to collect
50 cases of uveitis from each center. In order to avoid
a selection bias, we asked the contributors to include the
first 10 cases of uveitis, whether they were new cases or
patients returning for follow-up examinations, at each
clinic day, and to review both the present findings as well as
the findings recorded in patients’ charts at previous visits. All
adult infectious and noninfectious uveitis cases, irrespective of
the anatomic classification, type of onset, duration or course
of uveitis were included. Patients younger than 16 years of age
were excluded. Patients were to receive a standard diagnostic
approach and standard of care and were not to be subjected to
any study associated risks or benefits. The contributors were
also asked to indicate if patients with a clinical diagnosis of
BD uveitis met the ISG criteria for BD7 or not at the time of
recruitment. Patients who had a diagnosis of BD uveitis based
on the contributing ophthalmologists’ clinical judgment, but
did not fulfill the ISG criteria, were excluded from the pro-
spective data set. However, follow-up data on this subgroup
were obtained from the contributing centers at the time of
writing of this manuscript (21–23 months after the date of
visit when initial data were collected).
Development of a Diagnostic Algorithm
The prospective data set was used for the development of
a diagnostic algorithm by classification and regression tree
(CART) analysis.19 The trees with the highest scores by the
CART approach were reevaluated for their clinical relevance,

and scores for the trees modified by the investigators were
also calculated using the same method for the comparison
with the automatically generated ones.
Statistical Methods
For group comparisons of continuous variables Mann–
Whitney U test and for group comparisons of categorized
variables Chi-square or Fisher exact test were used. We cal-
culated sensitivity, specificity, PPV, NPV, PLR, NLR, DOR,
and 95% confidence intervals (CI) for each item studied in the
retrospective data. PLR value in the range of <2, 2–5, 5–10,
and >10 are recognized as showing a not meaningful, small,
moderate, and large increase of probability, respectively. NLR
in the range of >0.5, 0.2–0.5, 0.1–0.2, and <0.1 represents
a not meaningful, small, moderate, and large decrease of
probability, respectively.20 DOR was used as a measure of
the effectiveness of a diagnostic test; wherein DOR equal to
1 means no diagnostic value, DOR >1 means higher odds of
disease, and DOR <1 means lower odds of disease.
In order to develop a diagnostic algorithm for BD uveitis,
three classification and regression trees (CART) were devel-
oped. CART analysis is based on the method of recursive-
partitioning analysis.21,22 In this analysis, the total group is
split into subgroups based on the variable with the highest
risk for BD uveitis. These subgroups are again partitioned,
until no further significant partitioning was possible or when
the group size became below 10, resulting in a tree with the
best diagnostic accuracy. The terminal nodes in the diagnostic
tree were used to classify patients’ risk for BD uveitis.
The first diagnostic tree was automatically generated by
using all variables in the prospective data set. Second, since
vitritis was seen in almost all patients with posterior segment
involvement, the CART analysis was repeated by selecting
vitritis as the first variable of the diagnostic tree. Third,
because it is possible that the automatically generated diag-
nostic tree contains clinically less relevant variables, an expert-
guided diagnostic tree was also developed.
The diagnostic quality of the prognostic trees was assessed
by the area under the curve (AUC) of the receiver operating
characteristic (ROC) curve, which is also known as the
C-statistic. An AUC in the range of <0.5, ≥0.7–0.8, ≥0.8–0.9,
and ≥0.9 defined no discrimination, acceptable discrimina-
tion, excellent discrimination, and outstanding discrimina-
tion, respectively.23
Statistical analyses were performed by SPSS 24.0 (SPSS,
Inc., Chicago, IL, USA). A P value of less than 0.05 was
considered statistically significant.
Results
The results of the initial survey showed that uveitis experts
almost unanimously agreed that granulomatous anterior uvei-
tis, active or inactive choroiditis, and acute open-angle intrao-
cular pressure rise at relapses that are not associated with
glucocorticoid use were incompatible with a diagnosis of BD
uveitis. Chronic anterior uveitis with a high-grade flare and
the presence of snowballs or snowbanks was also deemed
incompatible with BD uveitis by 33% of the responders.
OCULAR IMMUNOLOGY AND INFLAMMATION 3
Table 1. Features ranked as “highly or fairly characteristic” of Behçet disease
uveitis by more than 50% of uveitis experts (N = 21) who participated in a survey
on ocular diagnostic features of Behçet disease uveitis.
Percentage of positive
responders
Clinical features
● Smooth layered shifting hypopyon 86
● Spontaneous relapsing and remitting nature of 86
any inflammatory sign
● Transient superficial retinal infiltrate(s) 76
● Full-thickness retinal infiltrate(s) 71
● Diffuse gliotic sheathing of retinal veins 71
● Peripheral occlusive periphlebitis 71
● Retinal hemorrhages 71
● BRVO 67
● Inferior vitreous precipitates 65
● Ghost retinal vessel(s) 62
● Diffuse retinal periphlebitis (fluffy-white cuffing) 57
● Conjunctival ulcers 55
● Bilateral involvement 52
● Disproportionately mild ciliary injection 52
● Diffuse retinal atrophy and gliosis 52
Fluorescein angiographic signs
● Diffuse retinal capillary leakage 62
● Retinal capillary nonperfusion 57
● Optic disc hyperfluorescence/leakage 52
Table 1 shows features that were ranked as highly or fairly
characteristic of BD uveitis by more than 50% of the respon-
ders. While none of the ocular symptoms, such as recurrent
visual blurring and floaters, or sudden onset of symptomatic
uveitis flare, were considered as highly or fairly characteristic
of BD uveitis by more than 50% of the experts, spontaneous
relapsing and remitting nature of any inflammatory sign was
thought to be the characteristic feature of BD by the majority.
Results of the Retrospective Data Analysis
In the retrospective data set, there were 211 patients in the BD
uveitis group and 207 patients in the control group. The
diagnoses in the control group are listed in Supplementary
Table 2. The mean age of patients with BD uveitis was
33 ± 12 years (median, 30 years; range, 13–76 years) and the
mean age of the control group was 39 ± 14 years (median,
37 years; range, 10–76 years), (p < .001). There were five
pediatric cases (2.4%) in the BD uveitis group and 8 pediatric
cases (3.8%) in the control group. Table 2 shows the sensitiv-
ity, specificity, PPV, NPV, PLR, NLR, and DOR of each item
analyzed in the retrospective data set. The presence of super-
ficial retinal infiltrate had the highest DOR (DOR, 33; 95% CI,
16–67), followed by the absence of choroiditis (DOR, 21; 95%
CI, 7–59) and the absence of granulomatous anterior uveitis
(DOR, 21; 95% CI, 8–53).
In Supplementary Table 3, the list of items used for pro-
spective data collection is shown, which included all items
with a high DOR except for the findings of “diffuse retinal
atrophy” and “spontaneous remission” that were not expected
to be uniformly assessable. Items with DOR less than 5 were
omitted, except gender, hypopyon, branch retinal vein occlu-
sion (BRVO), gliotic retinal vascular sheathing, peripheral
occlusive periphlebitis, and optic atrophy, as well as FA find-
ings of diffuse retinal capillary leakage and retinal capillary
non-perfusion, because these features have long been consid-
ered as the characteristic features of BD uveitis.24 Two
4 I. TUGAL-TUTKUN ET AL.
additional features were added into the prospective data col-
lection sheet, including a recurrent disease course and retinal
nerve fiber layer (RNFL) defect at this stage. The latter feature
had been more recently described as a helpful diagnostic clue
for BD uveitis.25
Results of the Prospective Data Analyses
In the prospective data set, there were 127 patients in the BD
uveitis group and 322 patients in the non-BD uveitis control
group. The diagnoses of the patients in the control group are
shown in Supplementary Table 4. Thirteen patients in the BD
uveitis group did not meet the ISG criteria for BD and thus
were excluded from statistical analyses. The mean age of the
remaining 114 patients with BD uveitis was 36 ± 10 years
(median, 34 years; range, 16–58 years) and the mean age of
patients in the control group was 44 ± 14 years (median,
44 years; range, 17–84 years), (p < .001). The mean duration
of uveitis was 75 ± 86 months (median, 41 months; range,
3 days-420 months) in the BD uveitis group and
57 ± 67 months (median, 32 months; range, 2 days-
360 months) in the control group (p = .173). Male gender
comprised 93 of 114 patients (82%) in the BD uveitis group
and 136 of 322 patients (42%) in the control group (p < .001).
The automatically generated diagnostic tree with a ROC
curve that provided the AUC score of 0.91 (95% CI, 0.87–-
0.94) is shown in Supplementary Figure 1. The second diag-
nostic tree with vitritis as the first selected variable gave an
AUC score of 0.92 (95% CI, 0.89–0.95) (Supplementary
Figure 2). The expert-guided diagnostic tree provided an
AUC of 0.92 (95% CI, 0.89–0.96) (Figures 1,2). The probabil-
ities of BD uveitis diagnosis at the branches of this tree are
shown in Figure 3.
Among the subgroup of 13 patients who were diagnosed
with BD uveitis by the investigators, but did not fulfill the ISG
criteria at the time of prospective data collection, 5 of them
developed additional extraocular manifestation(s) during the
subsequent 2 years of follow-up and fulfilled the ISG criteria
for BD.
Discussion
The diagnosis of BD uveitis has usually been made with the
help of extraocular manifestations along with the guidance of
classification criteria and expert opinion.7,8,26 The present
study is the first to identify a set of variables of intraocular
inflammation that would help the diagnosis of BD uveitis in
patients with or without suggestive extraocular manifestations
of BD. Due to the absence of a gold-standard specific clinical
finding or diagnostic test, fulfillment of ISG criteria for BD7
was required to define the BD uveitis group in this study, and
the control group consisted of uveitis patients with diverse
diagnoses, including those causing challenges in the differen-
tial diagnosis of BD, in both the retrospective and prospective
data sets. In this study, ocular variables of BD uveitis were
first identified by a survey among uveitis experts and tested in
a retrospective study which then revealed variables with
a high DOR and clinical relevance. CART analysis of the
prospectively collected data on the variables with a high
DOR disclosed possible algorithms with a high probability
of accurate diagnosis. An expert-guided modification of the
algorithm for a better clinical relevance resulted in a high
prediction accuracy score with a ROC curve that had an
AUC of 0.92, which was equal to the highest score achieved
by the automatically generated CART. The variables that
provided the highest accuracy for the diagnosis of BD uveitis
included the presence of superficial retinal infiltrate or its
sequel, RNFL defect, signs of occlusive retinal vasculitis, and
diffuse retinal capillary leakage on fluorescein angiography as
well as the absence of granulomatous anterior uveitis or
choroiditis in patients with vitritis.
A masked study has previously shown that Turkish uveitis
experts could differentiate BD uveitis from other uveitides in
up to 80% of clinical photographs, suggesting that certain
features of ocular involvement are recognizable by experi-
enced ophthalmologists.27 Clinical photographs of smooth-
layered hypopyon, superficial retinal infiltrate with retinal
hemorrhages, and BRVO with vitreous haze were correctly
recognized as BD uveitis by the majority of reviewers, who
were masked to the demographic and any other clinical data
of the patients or evolution of the lesions captured in the
photographs. The authors found that a combination of ocular
findings, including vitreous haze, retinal infiltrates and occlu-
sive retinal vasculitis, was more easily recognized than indivi-
dual lesions associated with BD uveitis.27 In the expert-guided
algorithm generated in the present study, the highest prob-
ability of BD uveitis (92%) was found in the end node of the
branch that carried the same combination of ocular features,
namely, the presence of vitritis, the absence of granulomatous
anterior uveitis or choroiditis, the presence of superficial
retinal infiltrate or RNFL defect, and the presence of occlusive
retinal vasculitis or its sequelae.
Spontaneous remission is a characteristic feature of BD
uveitis, showing a high specificity and high DOR; however,
in clinical practice, patients almost always receive treatment
without waiting for the spontaneous resolution of acute
inflammatory signs, such as hypopyon, vitreous haze, retinal
infiltrates, or inflammatory sheathing of retinal vessels,
explaining the low sensitivity of this feature in the retrospec-
tive data set. Although hypopyon was ranked as
a characteristic feature by the majority of experts in the
survey, its DOR was not high. While the CART analysis in
Supplementary Figure 1 selected this finding as a final variable
in one of its branches, the end-node showing the presence of
hypopyon did not seem to have a discriminating power. Since
diffuse vitritis is a constant feature of posterior segment
inflammation and it is typically absent in eyes with profound
retinal atrophy at the end stage, we thought that vitritis would
be the most clinically relevant finding in order to identify BD
uveitis with ongoing activity; and indeed its selection as the
first variable in the CART analysis in Supplementary Figure 2
revealed a higher AUC score. While the absence of granulo-
matous anterior uveitis can easily be determined by clinical
examination, the absence of occult choroiditis may need to be
confirmed by imaging studies, including indocyanine green
angiography (ICGA) and enhanced depth imaging (EDI) opti-
cal coherence tomography (OCT). Even though signs of chor-
oidal vasculitis may be found on ICGA, dark dots indicating
Table 2. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR), negative likelihood ration (NLR), diagnostic odds ratio (DOR), and 95% confidence intervals (CI) of
items studied in the retrospective data collected from patients with a definite diagnosis of Behçet disease uveitis and patients with uveitis of other diagnoses.
Description Sensitivity (95% CI) Specificity (95% CI) PPV (95% CI) NPV (95% CI) PLR (95% CI) NLR (95% CI) DOR (95% CI)
Demographics
Male gender (n = 418) 75.83 (69.62–81.11) 61.35 (54.57–67.72) 66.67 (62.37–70.70) 71.35 (65.70–76.40) 1.96 (1.62–2.36) 0.39(0.30–7.59) 4.98(3.26–7.59)
Ocular Symptoms
History of visual blurring(n = 418) 82.46 (76.77–87.00) 14.01 (9.93–19.40) 49.93 (47.36–51.51) 43.94 (33.40–55.06) 0.95(0.88–1.04) 1.25(0.80–1.95) 0.76 (0.45–1.30)
Red eyes(n = 418) 35.35(29.4–42.21) 63.29(56.53–69.55) 49.67(43.33–56.01) 49.06(45.47–52.67) 0.96(0.75–1.24) 1.01(0.88–1.177) 0.95(0.63–1.41)
Decreased vision (n = 418) 73.46 (67.12–78.96) 21.26 (16.23–27.33) 48.74 (46.06–51.43) 44 (35.75–52.60) 0.93 (0.83–1.03) 1.24 (0.88–1.76) 0.74 (0.47–1.17)
Floaters (n = 418) 33.65 ((27.62–40.27) 61.35 (54.57–67.72) 47.02 (40.73–53.40) 47.57 (43.98–51.18) 0.87 (0.67–1.12) 1.08 (0.93–1.25) 0.80 (0.54–1.20)
Sudden symptomatic attack (n = 418) 73.46 (67.12–78.96) 50.24 (43.49–56.99) 60.08 (56.21–68.83) 65.00 (58.83–70.71) 1.47 (1.25–1.73) 0.52 (0.40–0.68) 2.79 (1.85–4.20)
Ocular findings
Bilateral involvement (n = 418) 89.10 (84.17–92.63) 39.13 (32.74–45.92) 59.87 (56.98–62.69) 77.88 (69.79–84.30) 1.46 (1.30–1.64) 0.27 (0.18–0.42) 5.25 (3.13–8.79)
Conjunctival ulcer (n = 418) 1.42 (0.48–4.10) 99.03(96.55–99.73) 60.00 (20.21–89.88) 49.64(49.11–50.16) 1.47 (0.24–8.71) 0.99 (0.97–1.01) 1.47 (0.24–8.94)
Mild ciliary injection (n = 417) 49.52 (42.83–56.23) 68.12 (61.49–74.08) 61.18 (55.31–66.73) 57.09 (53.05–61.03) 1.55 (1.22–1.97) 0.74 (0.62–0.87) 2.09 (1.40–3.12)
Anterior chamber cells (n = 418) 85.31 (79.90–89.45) 20.29 (15.38–26.29) 52.17 (49.96–54.38) 57.53 (47.03–67.40) 1.07 (0.97–1.16) 0.72 (0.47–1.10) 1.47 (0.88–2.46)
Hypopyon (n = 417) 20.00 (15.15–25.93) 92.75 (88.39–95.56) 73.68 (61.59–83.02) 53.33 (51.40–55.26) 2.76 (1.58–4.81) 0.86 (0.79–0.93) 3.20 (1.71–5.97)
Chronic anterior uveitis (n = 417) 20.48 (15.57–26.44 75.43 (67.03–78.98) 43.88 (35.53–52.59) 47.65 (44.99–50.32) 0.77 (0.54–1.09) 1.08 (0.97–1.20) 0.71 (0.45–1.12)
Acute IOP rise (n = 417) 10.95 (7.41–15.9) 92.27 (87.81–95.19) 58.97 (43.89–72.54) 50.53 (48.99–52.07) 1.41 (0.77–2.60) 0.96 (0.90–1.02) 1.46 (0.75–2.86)
Absence of granulomatous AU (n = 417) 97.62 (94.55–98.98) 33.82 (27.72–40.50) 59.94 (57.53–62.31) 93.33 (85.22–97.14) 1.47 (1.33–1.63) 0.07 (0.02–0.17) 20.94 (8.24–53.23)
Vitritis (n = 417) 93.33 (89.12–95.99) 32.37 (26.36–39.01) 58.33 (55.86–60.76) 82.72 (73.55–89.17) 1.38 (1.24–1.52) 0.20 (0.12–0.35) 6.70 (3.62–12.39)
Snowball (n = 417) 12.38 (8.59–17.52) 73.43 (67.03–78.98) 32.10 (23.61–41.97) 45.24 (42.86–67.64) 0.46 (0.30–0.71) 1.19 (1.08–1.31) 0.39 (0.23–0.65)
Inferior vitreous precipitates (n = 418) 40.28 (33.90–47.02) 88.89 (83.88–92.48) 78.70 (70.85–84.89) 59.35 (56.41–62.23) 3.62 (2.38–5.51) 0.67 (0.59–0.75) 5.39 (3.23–9.01)
Fluffy vascular sheathing (n = 417) 30.48 (24.05–37.01) 75.85 (69.58–81.17) 56.14 (48.27–63.72) 51.82 (48.87–54.75) 1.26 (0.92–1.73) 0.91 (0.81–1.03) 1.37 (0.89–2.12)
Gliotic vascular sheathing (n = 378) 43.46 (36.62–50.55) 85.03 (79.21–89.43) 74.77 (67.01–81.22) 59.55 (56.18–62.83) 2.90 (1.98–4.23) 0.66 (0.57–0.76) 4.36 (2.66–7.14)
Nodular vascular sheathing (n = 417) 1.90 (0.74–4.79) 93.24 (88.97–95.93) 22.22 (8.73–46.05) 48.37 (47.34–49.40) 0.28 (0.09–0.84) 1.05 (1.01–1.09) 0.26 (0.08–0.82)
BRVO (n = 417) 19.05 (14.31–24.90) 94.20 (90.14–96.65) 76.92 (64.29–86.05) 53.42 (51.58–55.26) 3.28 (1.77–6.08) 0.85 (0.79–0.92) 3.82 (1.94–7.52)
CRVO (n = 417) 4.29 (2.27–7.94) 100.00 (98.48–1.00) 100.00 50.74 (50.02–51.45) 0.95 (0.93– .98)
Retinal arteriolar occlusion (n = 416) 12.38 (8.59–17.52) 93.20 (88.92–95.91) 65.00 (49.96–77.55) 51.06 (49.49–52.63) 1.82 (0.97–3.38) 0.94 (0.88–1.00) 1.93 (0.98–3.82)
Peripheral occlusive periphlebitis (n = 417) 26.19 (20.71–32.53) 87.92 (82.78–91.68) 68.75 (58.82–77.22) 54.01 (51.64–56.36) 2.16 (1.40–3.34) 0.83 (0.76–0.92) 2.58 (1.53–4.34)
Ghost vessels (n = 418) 36.49 (30.29–43.18) 91.79 (87.24–94.81) 81.91(73.53–88.08) 58.64(55.95–61.28) 4.44 (2.72–7.24) 0.69(0.62–0.77) 6.42 (3.63–11.35)
Retinal hemorrhages (n = 417) 56.19 (49.43–62.73) 82.13 (76.34–86.74) 76.13 (69.94–81.39) 64.89(61.02–68.56) 3.14 (2.29–4.31) 0.53 (0.45–0.63) 5.89 (3.76–9.22)
Superficial retinal infiltrate(s) (n = 418) 59.72 (52.98–66.10) 95.65 (91.94–97.70) 93.33 (87.98–96.40) 69.96 (66.35–73.35) 13.73 (7.18–26.27) 0.42 (0.35–0.49) 32.61 (15.83–67.16)
Full thickness retinal infiltrate(s) (n = 417) 10.95 (7.41–15.90) 86.96 (81.69–90.88) 46.00 (33.57–58.94) 49.05 (47.28–50.82) 0.84 (0.49–1.41) 1.02 (0.95–1.09) 0.82 (0.45–1.48)
Diffuse retinal whitening (n = 417) 8.57 (5.49–13.14) 97.58 (94.47–98.96) 78.26 (57.66–90.49) 51.27 (50.10–52.43) 3.54 (1.34–9.38) 0.93 (0.89–0.98) 3.78 (1.37–10.40)
Diffuse retinal atrophy (n = 418) 19.43 (14.66–25.30) 98.07 (95.14–99.25) 91.11 (78.90–96.56) 54.42 (52.71–56.13) 10.05 (3.66–27.57) 0.82 (0.76–0.88) 12.24 (4.29–34.86)
Absence of choroiditis (n = 417) 98.10 (95.21–99.26) 28.99 (23.23–35.50) 58.36 (56.18–60.50) 93.75 (84.74–97.59) 1.38 (1.26–1.51) 0.06 (0.02–0.17) 21.02
(7.47–59.11)
Papillitis (n = 417) 16.19 (11.82–21.77) 87.44 (82.23–91.28) 56.67 (44.90–67.73) 50.70 (48.73–52.67) 1.28 (0.80–2.06) 0.95 (0.88–1.03) 1.34 (0.77–2.33)
Optic disc hyperemia (n = 417) 56.19 (49.43–62.73) 66.18 (59.50–72.28) 62.77 (57.38–67.85) 59.83 (55.40–64.10) 1.66 (1.32–2.08) 0.66 (0.55–0.79) 2.51 (1.68–3.73)
Optic disc infiltrates (n = 417) 6.19 (3.65–10.30) 95.17 (91.34–97.36) 56.52 (36.83–74.35) 50.00 (48.84–51.16) 1.28 (0.57–2.85) 0.98 (0.94–1.03) 1.30 (0.55–3.03)
Optic atrophy (n = 418) 31.28 (25.41–37.82) 91.30 (86.67–94.43) 78.57 (69.31–85.62) 56.59 (54.11–59.03) 3.59 (2.21–5.84) 0.75 (0.68–0.83) 4.77 (2.71–8.40)
Cystoid macular edema (n = 417) 56.67 (49.90–63.19) 64.25 (57.52–70.47) 61.66 (56.40–66.66) 59.38 (54.85–63.75) 1.58 (1.27–1.97) 0.67 (0.56–0.81) 2.35 (1.58–3.48)
NVD-NVE (n = 417) 14.76 (10.60–20.19) 93.72 (89.55–96.29) 70.45 (56.23–81.57) 52.01 (50.35–53.67) 2.35 (1.26–4.36) 90 (0.85–0.97) 2.58 (1.31–5.09)
Spontaneous remission of uveitis (n = 405) 9.60 (6.23–14.50) 99.03 (96.55–99.73) 90.48 (69.15–97.58) 53.39 (52.21–54.56) 9.93 (2.34–42.08) 0.91 (0.87–0.95) 10.88 (2.50–47.35)
Fluorescein angiography findings
Diffuse capillary leakage (n = 302) 67.03 (59.97–73.39) 63.25 (54.22–71.43) 74.25 (69.01–78.87) 54.81 (48.64–60.84) 1.82 (1.40–2.36) 0.52 (0.40–0.66) 3.49 (2.15–5.68)
Capillary non-perfusion (n = 289) 35.26 (28.53–42.63) 82.76 (74.86–88.55) 75.31 (66.11–82.66) 46.15 (42.75–49.59) 2.04 (1.30–3.19) 0.78 (0.68–0.89) 2.61 (1.47–4.64)
Disc hyperfluorescence (n = 314) 74.35 (67.71–80.02) 39.84 (31.62–48.67) 65.74 (61.91–69.38) 50.00 (41.95–58.05) 1.23 (1.04–1.45) 0.64 (0.46–0.89) 1.91 (1.18–3.11)
IOP, Intraocular pressure; BRVO, Branch retinal vein occlusion; CRVO, Central retinal vein occlusion; NVD, Neovascularization of the disc; NVE, Neovascularization elsewhere.
OCULAR IMMUNOLOGY AND INFLAMMATION
5
6 I. TUGAL-TUTKUN ET AL.
Figure 1. The classification and regression tree analysis where all variables were selected based on their clinical relevance from a set of demographic features,
intraocular inflammatory findings, and their sequelae recorded in a cohort of 114 patients with BD uveitis and 322 patients with non-Behçet uveitides. (BD: Behçet
disease; RNFL: Retinal nerve fiber layer; BRVO: Branch retinal vein occlusion; FA: Fluorescein angiography).
Figure 2. The receiver operating characteristic (ROC) curve of the classification
and regression tree analysis shown in Figure1.
choroidal granulomas are never seen on ICGA in BD
uveitis.28 ICGA findings reported for BD uveitis include
delayed and irregular filling of choriocapillaris, staining of
choroidal vascular walls, stromal vessel hyperfluorescence,
hyperfluorescent spots and hypofluorescent plaques.29–33 All
of these findings are nonspecific and do not correlate with FA
findings of activity.28,34 The results of EDI OCT studies are
conflicting. While there are reports of an increased choroidal
thickness during the active phase of the disease and a decrease
with resolution of intraocular inflammation,35–37 Onal et al.34
did not find any significant thickening of the choroid in
patients with an acute attack of BD uveitis at an early stage
of the disease, but showed an increased choroidal stroma-to-
choroidal vessel lumen ratio, suggesting a predominant invol-
vement of inner choroidal vessels.
Superficial retinal infiltrates, also variably defined as foci of
retinitis or retinal exudates,2,3 are the most commonly seen
fundus lesions during activations of BD uveitis.24 The char-
acteristic OCT features of superficial retinal infiltrates include
hyper-reflective thickening of the retina with blurring of espe-
cially inner retinal layers and optical shadowing without
thickening of the underlying choroid.28 There may be outer
retinal disruption, but the retinal pigment epithelial contour is
not affected.28 These OCT features may need to be confirmed
in order to rule out retinochoroiditis of different etiologies.24
The finding of superficial retinal infiltrates was automatically
selected as the first variable in Supplementary Figure 1 and as
the second variable following vitritis in Supplementary Figure
2 in the CART analysis. In the expert-guided analysis, we

Figure 3. The diagnostic algorithm showing probabilities of Behçet disease uveitis based on the classification and regression tree analysis shown in Figure 1. (BD:
Behçet disease; FA: Fluorescein angiography).
selected superficial retinal infiltrates as the most clinically
relevant finding following the presence of vitritis and the
absence of granulomatous anterior uveitis or choroiditis. At
this split point, we also included an alternative finding, RNFL
defect, which is a sequel of a past episode of activation with
retinal infiltrate at the posterior pole.25 Since a RNFL defect
can be detected by fundus examination, we think that this
finding could be captured in the progressive data set.
Although OCT findings have been described as sequelae of
prior posterior ocular attacks in BD patients, including loss of
retinal nerve fiber layer causing an indentation of the inner
retinal surface24 and elevations of outer plexiform layer,38
a standard OCT imaging and longitudinal evaluation would
be required to test the diagnostic value of these OCT findings
for BD uveitis among uveitis patients. Although the
OCULAR IMMUNOLOGY AND INFLAMMATION 7
appearance of inferior vitreous precipitates is considered as
a helpful clue for the diagnosis of BD uveitis24 and its DOR
was found to be higher than 5 in this study, it was not selected
in either of the automatically generated diagnostic trees and
did not show a discriminating power when tested in the
expert-guided algorithm. A characteristic feature of BD uveitis
is retinal perivasculitis, which tends to be occlusive in nature
and especially involves the retinal veins.24 The ophthalmo-
scopic findings of this feature may include BRVO or periph-
eral occlusive periphlebitis based on the appearance of the
inflammatory sheathing of involved vessels and hemorrhages
along the involved retinal vasculature. After the resolution of
such an episode, sequelae may be seen, including the gliotic
sheathing of retinal vessels or ghost vessels. Therefore, in the
expert-guided algorithm, we combined these features at the
8 I. TUGAL-TUTKUN ET AL.
same split point as alternative findings of occlusive retinal
perivasculitis. On the other hand, retinal capillaritis can only
be reliably detected by FA. The end-nodes in Figure 3 show
that the probability of the diagnosis of BD uveitis increases by
the presence of diffuse capillary leakage especially in the
absence of clinical findings of occlusive retinal perivasculitis
or the absence of retinal infiltrates or their sequelae. Optical
coherence tomography angiography (OCTA) is a noninvasive
imaging modality that could partially replace FA for imaging
of the retinal vasculature, especially the microvascular changes
in the foveal region.39–42 Although OCTA has been found to
be more sensitive than FA in evaluating macular nonperfu-
sion/hypoperfusion and capillary network disorganization,
and in predicting visual outcome,39–42 FA is better at showing
retinal vascular and capillary leakage at the posterior pole as
well as in the peripheral retina,39–41 which are clear signs of
active BD uveitis. Furthermore, OCTA has not yet become
widely available or routinely used at all centers; therefore,
OCTA findings could not be included in this study.
Although classification criteria were not developed for the
bedside diagnosis of any disease, they have been used fre-
quently for this purpose despite all their shortcomings asso-
ciated with relatively low sensitivity, ignorance of less frequent
but more specific manifestations, and lack of data from dif-
ferent clinical settings with variable epidemiological features
affecting the conditions in the differential diagnosis.13,18,43
Diagnosis of a disease has always been considered as an
assessment of probabilities depending on factors associated
with patients’ and/or clinical setting’s characteristics, espe-
cially in diseases with high heterogeneity at the onset or
during the course of the disease. Therefore, the proposed
algorithm is expected to provide a solution to the bedside
challenges of the clinicians by both delineating the importance
of certain clinical findings in the accurate diagnosis and also
by providing a tool, which can give probabilities for the
different combinations of disease manifestations. In the pre-
sent dataset, 114/436 (26%) of the patients had the diagnosis
of BD uveitis fulfilling the ISG criteria; and this algorithm,
which was based only on ocular findings, achieved a highly
likely diagnosis in 58/114 cases (51%) and a probable diag-
nosis in 36/114 cases (32%) (Figures 1–3). The performance of
the algorithm may improve with additional information col-
lected during the course of the disease, and these diagnostic
probabilities would be helpful to the clinicians in their deci-
sion for more specific treatments at certain time points. There
may be a considerable time interval, sometimes many years,
between the onset of first manifestation and the development
of other manifestations of BD.4 Most importantly, the pro-
posed algorithm would give the ophthalmologist the possibi-
lity to consider BD uveitis, when uveitis is the initial
manifestation of the disease, as has been reported in 6%-
20% of patients,2–5 or when all the extraocular manifestations
of the disease have not appeared yet. Provided that any
infectious etiology has already been ruled out, this might
allow a prompt and aggressive treatment, usually with immu-
nomodulatory agents, from the onset of ocular involvement,
thus providing a better long-term visual prognosis.
Our study has some limitations. This study did not aim to
develop classification criteria for BD uveitis using discovery
and validation sets, and the quality of the diagnostic tree was
tested in the same dataset that was used to develop the tree.
Unfortunately, we did not have an external dataset available
for an external validation and our sample was not big
enough to split for cross validation. Thus, the current ana-
lyses, including the prospective part of the study that was
conducted in 9 centers from 5 countries from different
geographic regions, just provides the correlation of selected
items with the decision tree model through dataset fitting.
Therefore, our next step will be validating the performance
of the diagnostic tree in an independent prospective dataset
collected from different parts of the world that consists of
real-life portfolio of patients, including BD patients (with
only ocular or with additional systemic findings fulfilling
the ISG criteria) and patients with other noninfectious and
infectious uveitides. During the validation studies, a more
detailed analysis of the diagnostic tree items such as FA
findings or recurrent nature of the disease with spontaneous
remission may improve the diagnostic probabilities. Lastly,
the data collection did not include extraocular manifestations
or laboratory findings such as HLA-B*51, which may affect
the probability scores critically, even in patients with limited
number of clinical findings that do not meet the classifica-
tion criteria.
In conclusion, we propose an algorithm for the diagnosis
of BD uveitis by using only characteristic ocular findings, and
this diagnostic tree approach needs to be tested whether it can
provide the probabilities of an accurate diagnosis at the time
of evaluation, which can be helpful in prompt management of
the patients as well as the decision for specific treatment in
routine clinical practice. The results of this study need to be
validated in larger clinical cohorts to document its perfor-
mance in different settings.
Acknowledgments
The authors thank the uveitis experts who answered the questionnaire on
diagnostic features of BD uveitis: Yonca Akova (Turkey), Sibel Kadayifcilar
(Turkey), Gungor Sobaci (Turkey), Merih Soylu (Turkey), Sumru Onal
(Turkey), Pinar Ozdal (Turkey), Yilmaz Ozyazgan (Turkey), Nilufer
Yalcindag (Turkey), Nida Sen (USA), Narsing Rao (USA), Emmett
Cunningham (USA), Andrew Dick (UK), Miles Stanford (UK), Arnd
Heiligenhaus (Germany), Uwe Pleyer (Germany), Luca Cimino (Italy),
Pia Allegri (Italy), Soon Phaik Chee (Singapore), Radgonde Amer (Israel),
Khalid Tabbara (Saudi Arabia), and Moncef Khairallah (Tunisia).
Disclosures
The following authors disclose financial support outside the submitted
work:
Ilknur Tugal-Tutkun: Consultant, AbbVie; Lecturer, Allergan
Miles Stanford: Lecturer, Allergan and AbbVie
Ahmet Gül: Consultant, AbbVie, Amgen, and MSD
Declaration of interest
The authors report no conflicts of interest. The authors alone are
responsible for the content and writing of the paper.

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