PERSPECTIVE
HLA Typing in Uveitis: Use and Misuse
KATHERINE J. ZAMECKI AND DOUGLAS A. JABS
● PURPOSE: To evaluate the role of HLA typing as a
diagnostic test in patients with uveitis.
● DESIGN: Perspective derived from a literature review
and analysis of reported results.
● METHODS: Published data on the HLA associations of
several uveitis entities and their prevalence among pa-
tients and the general population were used to calculate
the positive predictive value of HLA testing as a diag-
nostic test for these disorders.
● RESULTS: For nearly all diagnostic entities evaluated
(including multiple sclerosis–associated intermediate uve-
itis, birdshot chorioretinitis, sympathetic ophthalmic, Be-
hçet disease, and Vogt-Koyanagi-Harada disease), the
positive predictive value was low (< 0.50), indicating the
limited usefulness of routinely applied HLA typing as a
diagnostic test. HLA-B27 testing may be of value in
identifying a previously undiagnosed or misdiagnosed spon-
dyloarthropathy among patients with recurrent acute ante-
rior uveitis.
● CONCLUSIONS: In general, HLA typing has limited
usefulness as a diagnostic test in patients with uveitis.
(Am J Ophthalmol 2010;149:189 –193. © 2010 by
Elsevier Inc. All rights reserved.)
W
HEN EVALUATING A PATIENT WITH UVEITIS,
the clinician will characterize the disease
along several axes, including: (1) anatomic
location of the inflammation; (2) disease course (e.g.,
acute vs recurrent acute vs chronic); (3) presence of a
causative infection (e.g., syphilis or Lyme disease); (4)
presence of an associated systemic disorder (e.g., sar-
coidosis or a spondyloarthropathy); and (5) presence of
a morphologic syndrome (e.g., birdshot chorioretinitis
[BSCR]).1 All of these characteristics help to guide
therapy and may provide information on prognosis. For
example, a chronic noninfectious posterior uveitis typ-
ically requires chronic systemic therapy, whereas a
noninfectious, recurrent, acute anterior uveitis typically
requires topical corticosteroid therapy of the acute
Accepted for publication Sep 26, 2009.
From the Departments of Ophthalmology (K.J.Z., D.A.J.) and Medi-
cine (D.A.J.), The Mount Sinai School of Medicine, New York, New
York; and the Department of Epidemiology (D.A.J.), The Johns Hopkins
University Bloomberg School of Public Health, Baltimore, Maryland.
Inquiries to Douglas A. Jabs, Mount Sinai Hospital, One Gustave L.
Levy Place, Box 1183, New York, NY 10029; e-mail: douglas.
jabs@mssm.edu
0002-9394/10/$36.00 © 2010 BY ELSEVIER INC. ALL
doi:10.1016/j.ajo.2009.09.018
attacks.2– 4 Proper identification of a morphologic syn-
drome also guides therapy. For example, some multifocal
choroidopathies, such as acute posterior multifocal pla-
coid pigment epitheliopathy, are self-limited and spon-
taneously remitting with a good prognosis, whereas
others, such as BSCR, are chronic, progressive diseases,
requiring immunosuppressive drug therapy to maintain
vision.5,6 In this process, proper, selective use of labo-
ratory testing is critical. Testing for syphilis is carried
out routinely because: (1) syphilis can produce any type
of uveitis, such that morphologic features are inadequate
to diagnose it, and (2) the treatment is radically
different (2 weeks of intravenous antibiotics vs cortico-
steroids and immunosuppression).7 Identification of a
systemic disease may be important for the patient’s
systemic health (e.g., interstitial lung disease in some
patients with sarcoid uveitis, which will require systemic
corticosteroid therapy) or may dictate therapy (e.g., a
systemic necrotizing vasculitis, such as Wegener granu-
lomatosis, in a patient with scleritis).8
HLA typing has been important in understanding the
pathogenesis of several rheumatic disorders, particularly
the spondyloarthropathies. In selected situations, HLA
typing may be useful clinically, such as testing for
HLA-B27 in the identification of a patient with what
was previously termed incomplete Reiter syndrome and
is now known as reactive arthritis.9 HLA-B27 typing
also may have usefulness in the evaluation of a patient
with uveitis. Patients with HLA-B27–associated uveitis
typically have a recurrent, acute, unilateral or unilateral
alternating, anterior uveitis.4,10,11 Indeed, a patient with
recurrent, acute, unilateral, alternating anterior uveitis
is nearly 80% likely to be HLA-B27 positive.12 In a
patient with acute anterior uveitis, HLA-B27 testing
has modest prognostic value, because patients who are
HLA-B27 positive are more likely to have recurrent
disease, although the disease may be morphologically
indistinguishable.11 However, the real value of HLA-
B27 testing comes when a positive value prompts the
clinician to search for a previously undiagnosed systemic
disease that may have permanent, debilitating effects.
Among patients with HLA-B27–associated uveitis, two
thirds to three quarters will have an associated spondy-
loarthropathy,4,10,11 of whom approximately one half
will not have been diagnosed or will have been misdi-
RIGHTS RESERVED. 189
 TABLE 1. Measures of a Test’s Performance

Measure Formula Measures

Sensitivity
Specificity
Positive predictive value
Negative predictive value
True positives/(true positives ⫹ false Proportion of those with disease with positive test results
negatives)
True negatives/(false positives ⫹ true Proportion of those without disease who will have negative
negatives) test results
True positives/(true positives ⫹ false Likelihood of a patient with positive results of having the
positives) disease
True negatives/(true negatives ⫹ Likelihood of a patient with negative results not having the
false negatives) disease

BSCR. The problem with this approach is illustrated by Table

TABLE 2. Results of Screening 1000 Patients with
Posterior Uveitis for HLA-A29 to Diagnose Birdshot
Chorioretinitis
HLA Typing Results
Disease Status A29⫹ A29–
BSCR⫹ 63 7 70
BSCR– 72 858
Totals 135 865
Parameter Result
Sensitivity 0.90
Specificity 0.92
Positive predictive value 0.47
Negative predictive value 0.99
BSCR ⫽ birdshot chorioretinitis; ⫹ ⫽ positive; – ⫽ negative.
HLA-A29 antigen frequencies and BSCR prevalence among
patients with posterior uveitis are drawn from the liter-
ature.15–18,40 – 42
agnosed (hence approximately one third of all patients
with HLA-B27–associated anterior uveitis).4 Therefore,
HLA-B27 testing’s primary benefit in this situation is in
improving management of the patient’s systemic health.
However, as a diagnostic test, the value of HLA
typing is limited. An important concept in understand-
ing the value of laboratory testing is the positive
predictive value of a test (Table 1).13,14 Positive predic-
tive value is the likelihood that an individual with a
positive test result will have the disease in question. It
is influenced by the frequency of the disease in the group
of patients being tested and the characteristics (sensi-
tivity and specificity) of the test. The problem with
using HLA typing diagnostically is illustrated in the case
of BSCR. BSCR is associated with HLA-A29, and 85%
to 95% of patients with BSCR possess HLA-A29, with
an overall estimate of 90%.15–18 HLA-A29 is present in
approximately 7.7% of the general population, and
BSCR has among the highest relative odds of any HLA-
associated disease.19 BSCR accounts for approximately 7% of
posterior uveitis,17 and some clinicians advocate screening
patients with posterior uveitis with HLA-A29 to diagnose
2, which shows the results of this strategy applied to 1000
patients with posterior uveitis. Despite the tight association of
BSCR with HLA-A29, the positive predictive value of
HLA-A29 is less than 50%, which means that diagnosing
BSCR based on HLA-A29 results is wrong more often than
Totals
it is right. If all uveitis patients were screened (as opposed to
just posterior uveitis), the positive predictive value would be
930 even lower, because the prevalence of BSCR is even lower
1000
among all patients with uveitis than it is among those with
posterior uveitis. One could improve the positive predictive
value of HLA-A29 testing by using it only in those situations
where the patient had a multifocal choroiditis with yellow-
orange ovoid spots, 1⫹ vitreous cells, no anterior chamber
cells, and no evidence for syphilis, Lyme disease, or sarcoid.
However, regardless of the HLA-A29 result, that patient
would be diagnosed with BSCR20 (5% to 15% of patients
with BSCR are HLA-A29 negative), so the test adds little to
the diagnosis in this situation, either.
The situation typically is more problematic for other
uveitides, where the association of the HLA type with the
disease is less strong, either because a lower percentage of
patients have the HLA type or because the population
frequency of the HLA type is higher. Table 3 lists the positive
predictive value for several uveitic syndromes where HLA
associations have been reported.15,16,21– 42 Values for the
frequency of the specific antigens among patients and
among the general population were taken from the
literature on HLA typing in these diseases and aver-
aged.15–17,21–39 The median values for disease preva-
lence among patients with a given anatomic type of
uveitis in this table were taken from 4 large, retrospec-
tive studies of patients with uveitis.18,40 – 42 Calculations
of positive predictive values and odds ratios were based
on screening all patients with uveitis affecting the
anatomic segment in question for the antigen in ques-
tion.
In only one of these situations (pars planitis in a
patient with intermediate uveitis) does the positive
predictive value even approach the more than 80% level
that characterizes a useful test, and in the rest, the
performance seems to be poor. However, further explo-
ration of the value of HLA typing of patients with

190 AMERICAN JOURNAL OF OPHTHALMOLOGY FEBRUARY 2010

 TABLE 3. Positive Predictive Values of HLA Typing in Selected Uveitides

Antigen Frequency (%)

Presentation Disease Prevalence (%)a HLA Antigen Disease Population Relative Odds Positive Predictive Value

Intermediate uveitis (all)

Pars planitis 73.8 DR2 51.9 27.3 2.9 0.84
DR15 41.4 22.4 2.4 0.84
Posterior uveitis
Birdshot chorioretinitis 7.0 A29 90.4 7.7 107.2 0.47
Panuveitis
Sympathetic ophthalmia 5.0 DR4 71.6 69.5 1.1 0.05
b
DR53 100 62 0.08
Vogt-Koyanagi-Harada disease 4.5 DR1 36 8.8 5.7 0.16
DR4 70.9 18.3 11.0 0.15
DR53 98.2 67.5 21.1 0.06
DQ4 82.4 32.1 9.8 0.1
Behçet disease 16.9 B51 68.6 19.1 9.2 0.3

a
Prevalence of the given uveitic diagnostic entity among patients with inflammation at the specific anatomic location.
b
Unable to calculate because antigen frequency in disease is 100%.

intermediate uveitis suggests that even here the test has
limited usefulness. The high positive predictive value in
this situation is the result of the very high a priori
likelihood of the disease (73.8%). A patient with
vitreous cells, snowball and snowbank formation, and
no evidence for Lyme disease, syphilis, or sarcoid would
be diagnosed with pars planitis,1 regardless of the HLA
typing results. Finally, HLA typing does not distinguish
between pars planitis and multiple sclerosis–associated
intermediate uveitis. Therefore, the HLA typing has
marginal diagnostic value. As such, when applied rou-
tinely as part of routine laboratory testing, none of these
HLA typings seem to be a very useful diagnostic test.
The analysis outlined in this perspective is an appli-
cation of the Bayes theorem and is applicable to any
analysis of diagnostic testing.43,44 In general, the useful-
ness of the test is related to its sensitivity and specificity,
which are characteristics of the test, and the a priori
prevalence of the disease in the set of patients being
studied. Previous published analyses of testing for anti-
nuclear antibodies and tuberculosis among patients with
uveitis have reached similar conclusions: namely, that
routine screening of all patients with uveitis is unwar-
ranted and that such testing should be reserved for
selected situations in which the pretest probability of
disease is reasonably high, but not high enough to make
the diagnosis conclusively.44 HLA testing is a situation
in which the published high relative odds for some
diseases make routine testing seem potentially reason-
able, but in which a Bayesian analysis demonstrates that
it is not.
Although HLA typing has value as a research tool, given
that it should not be used routinely, how should one use HLA
typing in clinical situations? HLA-B27 testing in patients
with acute anterior uveitis may help to identify a previously
undiagnosed systemic disease and may affect the patient’s
systemic health; therefore, there is potential usefulness. Oc-
casionally, there may be specific situations in which HLA
typing has value. For example, if a patient has end-stage
chorioretinal scarring and the diagnosis can be narrowed
down to BSCR versus multifocal choroiditis with panuveitis,
but the diagnosis cannot be made on morphologic grounds,
with a 50:50 chance of either diagnosis, then the positive
predictive value of HLA-A29 rises to 0.92 and the negative
predictive value is 0.90. In some populations with a much
higher prevalence of certain diagnostic entities, the positive
predictive value of HLA testing may be better, but not if the
prevalence of the antigen also is increased in the population.
However, in most diagnostic situations in the United States,
HLA typing currently has limited usefulness as a diagnostic
test, and probably should not be ordered routinely. Neverthe-
less, HLA testing has value in addressing research questions
and should continue to be important in understanding better
the pathogenesis of ocular inflammation.

SUPPORTED IN PART BY AN UNRESTRICTED GRANT FROM RESEARCH TO PREVENT BLINDNESS, INC, NEW YORK, NEW YORK.
Douglas A. Jabs is Chairman of the Multicenter Uveitis Steroid Treatment (MUST) Trial supported by the National Eye Institute, Bethesda, Maryland.
Bausch & Lomb, Rochester, New York, is providing a limited amount of drug for this study. Dr Jabs has acted as a consultant for Roche Pharmaceuticals,
Ciba Vision, Bayer Corporation, EMMES Corporation, Novartis Pharmaceutical Corp, Centocor, Inc, and SmithKline Beecham. Currently, Dr Jabs is
a consultant for Allergan, Abbott Laboratories, Genzyme Corporation, Novartis Pharmaceutical Corp, Roche Pharmaceuticals, and GlaxoSmithKline.
Dr Jabs currently acts as a Data and Safety Monitoring Board (DSMB) member for Applied Genetic Technologies Corporation (AGTC). Involved in

VOL. 149, NO. 2 HLA TYPING IN UVEITIS 191

design of the study (D.A.J.); Conduct of the study (D.A.J., K.J.Z.); Collection of the data (K.J.Z.); Management of the data (D.A.J., K.J.Z.); Analysis
of the data (K.J.Z., D.A.J.); Interpretation of the data (K.J.Z., D.A.J.); Preparation of the manuscript (K.J.Z.); Review of the manuscript (K.J.Z., D.A.J.);
and Approval of the manuscript (K.J.Z., D.A.J.). The institutional review board waived the need for approval of this type of study.
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IN UVEITIS 193
 Biosketch
Katherine J. Zamecki received her MD degree from UMDNJ – New Jersey Medical School in 2005, where she was a
member of the Alpha Omega Alpha honor society. She completed a residency in Ophthalmology at Mount Sinai Hospital
in New York City and is currently in an oculoplastics fellowship at the Eye and Ear Institute of the University of Pittsburgh
Medical Center.

193.e1 AMERICAN JOURNAL OF OPHTHALMOLOGY FEBRUARY 2010

 Biosketch
Douglas A. Jabs, MD, MBA, is Chief Executive Office of the Mount Sinai Faculty Practice Associates, Dean for Clinical
Affairs of the Mount Sinai School of Medicine, and Professor and Chairman of the Mount Sinai School of Medicine
Department of Ophthalmology. He is the study chairman of The Studies of the Ocular Complications of AIDS and the
Multicenter Uveitis Steroid Treatment Trial Research Groups. His interests include uveitis, its treatment, epidemiology,
and clinical trials.

VOL. 149, NO. 2 HLA TYPING IN UVEITIS 193.e2