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Research Letter |

Possession of the HLA-DRB1*1501 Allele and Visual Outcome in Idiopathic Intermediate Uveitis FREE

Harry Petrushkin, FRCOphth1; Dhanes Thomas, FRCOphth2; Robert Vaughan, PhD3; Elli Kondeatis, PhD3; Miles R. Stanford, FRCOphth4; Clive Edelsten, FRCOphth5; Graham R. Wallace, PhD6
[+] Author Affiliations
1Clinical and Diagnostic Oral Sciences, Queen Mary University of London, London, England
2Department of Medical Retina, Moorfields Eye Hospital, London, England
3Clinical Transplantation Laboratory, Guy’s Hospital, London, England
4Department of Ophthalmology, St Thomas’ Hospital, London, England
5Department of Ophthalmology, Ipswich Hospital, Ipswich, England
6Centre for Translational Inflammation Research, University of Birmingham, Birmingham, England
JAMA Ophthalmol. 2015;133(4):482-483. doi:10.1001/jamaophthalmol.2014.5868.
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Published online

Idiopathic intermediate uveitis (IIU) is a potentially sight-threatening inflammatory disease characterized by breakdown of the blood-retina barrier with consequent leukocytic infiltration of the vitreous and retina. Poor visual outcome has been associated with cystoid macular edema, poor vision at presentation, and male sex.1 The human leukocyte antigen (HLA) allele DRB1*1501 has long been associated with multiple sclerosis (MS). Tang et al2 prospectively analyzed 18 patients and found that HLA-DRB1*1501 conferred increased risk of developing IIU associated with MS in some patients.

The purposes of this study were to prospectively evaluate the association between the HLA-DRB1*1501 allele and IIU in patients and to determine whether HLA-DRB1*1501 might be a separate independent risk factor for visual loss.

Participants included 85 patients with IIU and 300 healthy, demographically matched controls. Idiopathic intermediate uveitis was classified on the basis of ophthalmological examination and fluorescein angiography findings. Patients with systemic inflammatory, neoplastic, or infectious diseases were excluded, as were patients with a history of optic neuritis. Written informed consent for HLA typing was obtained from all individuals. This study received approval from the St Thomas’ Ethical Committee and adheres to the Declaration of Helsinki.

Patients were reviewed at 3 months, 5 years, and 10 years (where possible) between 2000 and 2014. Additional appointments were given as required to adequately maintain control of intraocular inflammation.

Visual acuity (VA) of 6/12 or better was defined as a good outcome. Genomic DNA was extracted and genotyped for the HLA class II allele HLA-DRB1*1501 using polymerase chain reaction amplification with sequence-specific primers.3 Polymerase chain reaction products were electrophoresed and read using ethidium bromide and UV illumination.

The Table shows VA and demographic data. Thirty-eight cases (45%) were HLA-DRB1*1501 positive compared with 90 controls (30%) (15% difference; χ2 = 6.45; P = .007; odds ratio = 1.89; 95% CI, 1.15-3.09).

Table Graphic Jump LocationTable.  Patient Demographic Characteristics and Visual Acuity During the Study Perioda

We found no association between VA and possession of the HLA-DRB1*1501 allele. Twelve HLA-DRB1*1501–positive patients (31%) had a VA less than 6/12 at the end of the study, compared with 8 HLA-DRB1*1501–negative patients (17%) (14% difference; P = .15; relative risk = 1.52; 95% CI, 0.94-2.47). There was no identifiable difference in sex between HLA-DRB1*1501–positive and HLA-DRB1*1501–negative patients (2.5% difference; P = .65; odds ratio = 0.77; 95% CI, 0.31-1.91). The mean (SD) age at presentation was 62.09 (11.6) years for the HLA-DRB1*1501–positive patients and 59.72 (16.04) years for the HLA-DRB1*1501–negative patients (P = .46).

Our findings are in agreement with the previously reported association between IIU and HLA-DRB1*1501. However, we were unable to identify any association between possession of the HLA-DRB1*1501 allele and sex or age at presentation, as has been found in MS. We also did not find an association between HLA-DRB1*1501 and final VA.4

Our exclusion criteria, prospective design, and extended follow-up distinguish this study from those previously reported. The patient population was comparable to those in other studies in terms of race, sex, and age.2,5,6

The results reflect the relatively benign nature of IIU in that 76% of our patients had good vision at 10 years. Similarly, Raja et al5 reported a VA higher than 6/12 in 82% of their patients after 4 years.

The prediction of visual outcome from haplotype analysis has not been supported by this study. However, our findings cannot rule out the possibility that IIU is made up of a number of separate disease processes, of which some affect all age groups and others (HLA-DRB1*1501 related) represent a forme fruste of MS. It is possible that patients in this study developed an associated systemic disease after their second review at 5 years but were not seen again at 10 years.

Finally, our data suggest that VA at 3 months reliably predicts vision at 5 and 10 years. This is important for future clinical studies as a shorter follow-up time can be used to determine clinical efficacy.

Corresponding Author: Graham R. Wallace, PhD, Centre for Translational Inflammation Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, England (g.r.wallace@bham.ac.uk).

Published Online: January 29, 2015. doi:10.1001/jamaophthalmol.2014.5868.

Author Contributions: Dr Wallace had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Stanford, Wallace.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Petrushkin, Thomas, Stanford, Wallace.

Critical revision of the manuscript for important intellectual content: Petrushkin, Vaughan, Kondeatis, Stanford, Edelsten, Wallace.

Statistical analysis: Petrushkin, Thomas.

Administrative, technical, or material support: Petrushkin, Kondeatis.

Study supervision: Vaughan, Stanford, Edelsten, Wallace.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Palimeris  G, Marcomichelakis  N, Konstantinidou  V, Trakaniari  AN.  Intermediate uveitis: what is the natural course of the disease and its relationship with other systemic diseases? Eur J Ophthalmol. 1994;4(4):223-227.
PubMed
Tang  WM, Pulido  JS, Eckels  DD, Han  DP, Mieler  WF, Pierce  K.  The association of HLA-DR15 and intermediate uveitis. Am J Ophthalmol. 1997;123(1):70-75.
PubMed   |  Link to Article
Olerup  O, Zetterquist  H.  HLA-DR typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours: an alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation. Tissue Antigens. 1992;39(5):225-235.
PubMed   |  Link to Article
Masterman  T, Ligers  A, Olsson  T, Andersson  M, Olerup  O, Hillert  J.  HLA-DR15 is associated with lower age at onset in multiple sclerosis. Ann Neurol. 2000;48(2):211-219.
PubMed   |  Link to Article
Raja  SC, Jabs  DA, Dunn  JP,  et al.  Pars planitis: clinical features and class II HLA associations. Ophthalmology. 1999;106(3):594-599.
PubMed   |  Link to Article
Messenger  W, Hildebrandt  L, Mackensen  F, Suhler  E, Becker  M, Rosenbaum  JT.  Characterisation of uveitis in association with multiple sclerosis [published online August 28, 2014]. Br J Ophthalmol. doi:10.1136/bjophthalmol-2014-305518.
PubMed

Figures

Tables

Table Graphic Jump LocationTable.  Patient Demographic Characteristics and Visual Acuity During the Study Perioda

References

Palimeris  G, Marcomichelakis  N, Konstantinidou  V, Trakaniari  AN.  Intermediate uveitis: what is the natural course of the disease and its relationship with other systemic diseases? Eur J Ophthalmol. 1994;4(4):223-227.
PubMed
Tang  WM, Pulido  JS, Eckels  DD, Han  DP, Mieler  WF, Pierce  K.  The association of HLA-DR15 and intermediate uveitis. Am J Ophthalmol. 1997;123(1):70-75.
PubMed   |  Link to Article
Olerup  O, Zetterquist  H.  HLA-DR typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours: an alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation. Tissue Antigens. 1992;39(5):225-235.
PubMed   |  Link to Article
Masterman  T, Ligers  A, Olsson  T, Andersson  M, Olerup  O, Hillert  J.  HLA-DR15 is associated with lower age at onset in multiple sclerosis. Ann Neurol. 2000;48(2):211-219.
PubMed   |  Link to Article
Raja  SC, Jabs  DA, Dunn  JP,  et al.  Pars planitis: clinical features and class II HLA associations. Ophthalmology. 1999;106(3):594-599.
PubMed   |  Link to Article
Messenger  W, Hildebrandt  L, Mackensen  F, Suhler  E, Becker  M, Rosenbaum  JT.  Characterisation of uveitis in association with multiple sclerosis [published online August 28, 2014]. Br J Ophthalmol. doi:10.1136/bjophthalmol-2014-305518.
PubMed

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