HLA-DR, DQ Class II DNA Typing in Pediatric Panuveitis and Tubulointerstitial Nephritis and Uveitis




Purpose


To describe chorioretinal lesions in pediatric uveitis that are associated strongly with the HLA-DR, DQ class II type associated with tubulointerstitial nephritis and uveitis (TINU).


Design


Retrospective, observational case series.


Methods


Setting: University-based clinic. Patient Population: Fifteen consecutive patients with onset of bilateral panuveitis at less than 16 years of age who were seen between September 2004 and October 2012 and 6 pediatric patients with confirmed TINU. Observation Procedure: HLA-DR, DQ class II DNA typing. Main Outcome Measure: Detection of the HLA-DRB1*01 and HLA-DQB1*05 risk alleles for TINU.


Results


Fourteen (93%) of the 15 patients with otherwise unexplained pediatric panuveitis typed HLA-DRB1*01-HLA-DQB1*05. Eleven (73.3%) of 15 patients had bilateral sharply demarcated, usually inferior, 200- to 300-μm spots of chorioretinal atrophy, and 4 (27.7%) of 15 patients had bilateral clusters of 500- to 750-μm poorly defined orange choroidal lesions without overlying atrophy of the retinal pigment epithelium. None had interstitial nephritis. Four of the 6 definite TINU cases had class II typing and TINU risk alleles; all 6 had bilateral panuveitis. The frequency of risk alleles was statistically higher in those with pediatric panuveitis than in the North American population and in nonpanuveitis pediatric uveitis patients assumed to have the North American HLA distribution ( P < .0001, Fischer exact test). Positive likelihood ratios were 9.92 to 5.18, depending on assumptions regarding pretest probability of disease.


Conclusions


Recognition of characteristic chorioretinal lesions in otherwise unexplained pediatric panuveitis, supported by selective HLA class II DNA typing, is useful in narrowing diagnostic possibilities and directing further evaluations. Panuveitis is underappreciated as a manifestation of TINU.


Dobrin and associates published the first report of acute kidney inflammation accompanied by a uveitis of unknown cause in 1975. Additional case reports subsequently appeared in both nephrology and ophthalmology journals. A review of tubulointerstitial nephritis and uveitis (TINU) syndrome in children and adolescents that appeared in the pediatric nephrology literature in 1999 cited 35 published pediatric cases. Asynchronous presentation of the renal and ocular disease was noted, as well as a greater tendency to recurrence of the uveitis, rather than the renal disease. The first major review in the ophthalmologic literature cited 133 cases of all ages. Common clinical features were bilaterality, anterior location, presentation after the renal disease, and recurrence or persistence of the uveitis. Median age at onset was 15 years, emphasizing the importance of pediatric cases in the spectrum of TINU. Twenty percent of patients had posterior uveitis or panuveitis, which was not described further.


In 2003, Levinson and associates reported class I and class II HLA typing in 18 patients with TINU from 3 centers. The study group was older and had higher rates of chronic and recurrent uveitis and intermediate uveitis, posterior uveitis, or panuveitis than previously reported patients. The haplotype HLA-DQA1*01/DQB1*05/DRB1*01 was present in 13 (72.2%) of 18 patients. Focused typing revealed a relative risk of 167.1 when compared with the control population when HLA-DRB1*0102 was present.


We performed HLA class II typing in a consecutive series of pediatric patients with panuveitis, with or without accompanying renal disease, after an index sibling pair of girls was identified in 2004 in which 1 had a history of abnormal urinalyses compatible with possible TINU according to accepted definitions, but had not been diagnosed with renal disease. Our experience suggests that class II HLA typing may be useful in narrowing the differential diagnosis of panuveitis in children and in identifying those who require further evaluation of renal function.


Methods


Medical Sciences Institutional Review Board A at the University of Miami Miller School of Medicine approved the retrospective review of patient records from January 1, 2000, through October 15, 2012, with waiver of consent and authorization. After 2 index cases were identified in 2004, HLA class II typing was part of routine diagnostic evaluation in children with bilateral panuveitis of unknown cause. Consecutive patients were included in the review if they were 16 years of age or younger at onset of uveitis and had panuveitis or a history of tubulointerstitial nephritis. Patients with chronic anterior uveitis, or uveitis associated with known disorders such as juvenile idiopathic arthritis, generally did not receive class II typing and were excluded from data collection. One girl with recalcitrant, atypical anterior uveitis without chorioretinal lesions was HLA typed. She was found to have the TINU alleles without evidence of renal disease and was excluded from analysis of the panuveitis patients. During the study period, 2 adult patients, one with TINU, were typed and had the TINU alleles, but were excluded from analysis based on age. Because typing was conducted for clinical purposes, there is no concurrent control group. Demographics, medical history, ocular findings, clinical course, ocular complications, and laboratory results were recorded from pre-existing medical records.


Low-resolution HLA-DR, DQ class II DNA typing was performed in a commercial reference lab (Quest Diagnostics, Madison, New Jersey, USA) by polymerase chain reaction using sequence-specific oligonucleotides to detect HLA-DRB1*01 and HLA-DQB1*05, 2 key elements of the TINU haplotype. Low-resolution 2-digit typing is considered equivalent to older serologic methods and is used for disease associations and for screening transplant recipients and donors for compatibility before conducting more detailed evaluations. Four-digit testing was available for some patients. HLA-DQA testing and high-resolution testing with sequence-based typing were not ordered to reduce the cost of testing to the patient. Patients with the HLA-DRB1 and HLA-DQB1 markers associated with TINU were referred for medical evaluation for renal disease.


The Fisher exact test ( www.graphpad.com ; accessed November 8, 2013) compared the frequency of the HLA-DRB1*01–DQB1*05 haplotypes in cases versus North American European, Hispanic, and African American populations ( www.allelefrequencies.net ; accessed November 8, 2013); data were available from 5909 population controls, 10.4% of whom had the haplotype and all of whom were assumed not to have panuveitis because it is a rare disease. Descriptive statistics of sensitivity, specificity, likelihood ratios, and predictive values were calculated for HLA-DR class II DNA typing if used as a screening test for suspected TINU in pediatric panuveitis ( www.medCalc.org ; accessed November 8, 2013). A positive likelihood ratio was defined as sensitivity divided by 100 minus specificity. An historical control group of 112 published noninfectious pediatric patients from our institution from 1996 through 2002 also was used for statistical calculations by assuming that the haplotype would be found in 2 TINU patients (true-positive results), 10 idiopathic panuveitis (false-positive results), and 10.4% percent of the remaining 100 patients (false-positive results).




Results


Twenty-one pediatric uveitis patients met inclusion criteria: 6 with definite TINU and 15 with unexplained panuveitis. Demographics and clinical course are tabulated in Table 1 . Age at the time of diagnosis uveitis was a median of 11 years (range, 4 to 14 years) in the definite TINU group and a median of 10 years (range, 4 to 15 years) in the panuveitis group. Twenty were white or Hispanic; Patient 18 was black. Two (33%) of 6 children with definite TINU were female versus 9 (60%) of 15 children with panuveitis. Patients with definite TINU were diagnosed with renal disease before uveitis by a median of 3 months (range, 0 to 12 months). In the panuveitis group, detection of the TINU risk alleles occurred a median of 6 months (range, 1.4 to 33 months) after onset of uveitis. Most of the panuveitis patients initially were diagnosed with bilateral iridocyclitis and were referred because of recurrent or uncontrolled uveitis. Evaluation by pediatric specialists of the panuveitis patients after identification of the TINU risk alleles did not reveal evidence of tubulointerstitial nephritis.



Table 1

Demographics and Clinical Course in Pediatric Patients with Definite Tubulointerstitial Uveitis Syndrome and in Consecutive Pediatric Patients with Idiopathic Panuveitis




































































































































































































































Patient No. Age (y) Sex Delay (mos) Follow-up (y) Initial BCVA Last BCVA Treatment a Ocular Complications
Definite TINU
1 11 M b 2 2.6 c 20/25, 20/25 20/20, 20/25 CS, MTX None
2 4 F 5 2.4 c 20/40, 20/40 20/30, 20/30 CS, MTX, MM None
3 10 M 0 14.5 20/20, 20/15 20/20, 20/30 CS, MTX None
4 14 F 12 7.4 c CF 1 ft, 20/20 CF 1 ft, 20/20 CS, MM, TNF RD, glaucoma d
5 9 M 6 4.5 c 20/25, 20/25 20/30, 20/25 CS, MM, CSA Glaucoma d , cataract surgery
6 11 M 0 0.6 c 20/20, 20/40 20/20, 20/15 CS, MM None
Panuveitis associated with the TINU haplotype
7 10 M b 3 2.7 c 20/30, 20/20 20/20, 20/20 CS, MTX None
8 12 M 4 2.4 20/25, 20/20 20/20, 20/20 CS, MTX, TNF None
9 10 F e 7 7.6 20/20, 20/20 20/20, 20/20 MTX, MM PS
10 9 F e 7 7.9 20/20, 20/20 20/20, 20/20 MM, MTX None
11 12 F 4 1.6 20/20, 20/20 20/15, 20/15 PSTA (left eye) PS
12 10 F 3 6.5 20/30, 20/25 20/20, 20/20 CS, MTX, sirolimus Peripapillary CNVM
13 11 M 3 12.2 20/40, 20/20 20/20, 20/20 CS, MTX, MM, TNF None
14 15 F 33 2.3 c 20/15, 20/15 20/20, 20/20 MTX PS
15 8 F 6 3.8 c 20/20, 20/20 20/20, 20/30 CS, CSA, MTX, TNF Glaucoma d /cataract surgery
16 8 F 13 2.8 c 20/40, 20/40 20/60, 20/60 CS, MTX, CSA, MM, TNF PS
17 13 M 31 f 4.2 20/15, 20/15 20/15, 20/15 MTX, CSA Peripapillary CNVM
18 4 F 33 f 8.1 c 20/100, 20/30 20/80, 20/20 MTX, TNF Glaucoma d /cataract surgery
19 12 M 5 0.2 20/20, 20/20 20/20, 20/20 PSTA (left eye) None
20 13 F 5 5.0 c 20/15, 20/15 20/15, 20/15 MTX, MM, TNF PS
21 7 F 1 2.1 20/30, 20/30 20/15, 20/15 CS, MTX None

BCVA = best-corrected visual acuity in Snellen notation; CF 1 ft = counting fingers visual acuity at 1 foot; CNVM = choroidal neovascular membrane; CS = oral corticosteroids; CSA = cyclosporine; F = female; M = male; MM = mycophenolate mofetil; MTX = methotrexate; PS = posterior synechiae; PSTA = posterior sub-Tenon corticosteroid injection; RD = retinal detachment; TINU = tubulointerstitial nephritis and uveitis syndrome; TNF = adalimumab or infliximab.

a Treatment column lists injected or systemic therapies given sequentially or in combination. All patients received topical corticosteroids.


b Male sibling pair.


c Patient still taking immunosuppressive therapy at last follow-up visit.


d Glaucoma surgery after failure of maximal medical therapy.


e Female sibling (index) pair.


f Delay in diagnosis in Patient 17 was related to delay in development of choroidal orange lesions. In Patient 18, punched-out chorioretinal lesions were diagnosed after extraction of mature cataracts after prolonged noncompliance with follow-up.



There were 2 sibling pairs. The index sisters, Patients 9 and 10, were diagnosed simultaneously with bilateral panuveitis ( Figure 1 ); the younger sister had a remote history of abnormal urinalyses as her only medical illness and was believed to have possible TINU. Neither girl had current renal or systemic disease based on examinations by a nephrologist and a rheumatologist. The second sibling pair was 2 brothers, Patients 1 and 7. The younger brother had anterior and vitreous inflammation with mid-equatorial deep orange lesions at presentation. The elder recently had been treated for tubulointerstitial nephritis and was brought in for an eye examination and was diagnosed with panuveitis. Examinations of the younger sibling by a pediatric nephrologist, immunologist, and rheumatologist showed negative results for significant renal or other systemic disease, despite elevated creatinine and proteinuria. Clinically significant renal disease did not develop during follow-up.




Figure 1


Color fundus photograph of the left eye of the index Patient 9 showing the typical appearance of small atrophic chorioretinal lesions in pediatric panuveitis with risk alleles for tubulointerstitial nephritis and uveitis. There are small, peripheral, atrophic chorioretinal scars inferiorly. The appearance of the other eye was similar. Her younger sister had similar lesions in each eye that were more numerous but did not photograph well.


All 21 patients had anterior chamber and vitreous inflammation. Three (50%) of the 6 TINU patients and 11 (73.3%) of 15 panuveitis patients had small, sharply marginated chorioretinal inflammatory lesions, usually 200 to 300 μm, often located predominantly inferiorly, anterior to the equator, similar to those seen in Figure 1 and Figure 2 , Left. Clusters of larger, usually 500- to 750-μm, deep orange choroidal lesions, similar to those in Figure 3 , were seen in the 3 remaining TINU patients and the 4 remaining panuveitis patients. The deep orange lesions were observed to fade and enlarge during follow-up ( Figure 4 , Bottom left and Bottom right), but usually were without overlying RPE atrophy. Extensive vascular leakage was found in 4 of the panuveitis patients on fluorescein angiography ( Figure 2 , Right). There was optic nerve edema in 2 TINU patients and 4 panuveitis patients.




Figure 2


Punched-out chorioretinal lesions in pediatric panuveitis with tubulointerstitial nephritis and uveitis risk alleles with evidence of active retinal inflammation. (Left) Montage color photograph of the right fundus of Patient 16. There are multiple punched-out chorioretinal scars. The left eye had similar lesions. (Right) Montage mid-phase fluorescein angiogram of the right eye of Patient 16 showing optic nerve, macular, and peripheral small-vessel leakage.



Figure 3


Montage photograph of the right fundus of Patient 12 showing the typical appearance of the large orange choroidal lesions in pediatric panuveitis with tubulointerstitial nephritis and uveitis risk alleles. The large, orange, indistinctly bordered choroidal lesions are most visible temporally. The other eye also had clusters of orange lesions of the same size and location that were less numerous. No sharply demarcated areas of chorioretinal atrophy were present. The orange lesions remained stable after discontinuation of systemic immunosuppression.



Figure 4


New onset of focal choroidal lesions during treatment with methotrexate of pediatric panuveitis with tubulointerstitial nephritis and uveitis risk alleles. (Top left) Right macula at presentation of Patient 7, brother of Patient 1, who had confirmed tubulointerstitial nephritis and uveitis. There are no visible choroidal lesions. (Top right) Left macula of the same patient. There are small, faint orange lesions below the inferior arcade and in the temporal macula. (Bottom left) Same patient, right macula 13 months after presentation while being treated with methotrexate. There are new lesions in the inferior macula and also along the superotemporal arcade. (Bottom right) Same patient, left macula 13 months after presentation. There are new lesions in the central macula and an atrophic spot below the inferotemporal arcade. Some of the original orange lesions are no longer apparent.


Laboratory testing varied between patients and often was conducted before referral. Selected tests are tabulated in Table 2 . Typical biomarkers for iridocyclitis related to systemic disease were present in some children, but did not seem to have pathogenic significance based on the pattern of uveitis. Of 3 tested patients with definite TINU, 1 (33%) demonstrated positive results for HLA-B27, versus 3 (60%) of 5 tested panuveitis patients. None of 4 tested TINU patients (0%) had positive results for anti-nuclear antibodies (ANA) versus 3 (21%) of 14 tested panuveitis patients. Pediatric consultation results were negative for rheumatologic or renal disease in the panuveitis patients.



Table 2

HLA Class II DNA Typing and Laboratory Testing for Other Causes of Uveitis in Consecutive Patients with Pediatric Panuveitis






















































































































Patient No. Class II HLA DNA Type a Negative Test Results Positive Test Results
Definite TINU
1 HLA-DRB1*0102,*0402-HLA-DQB1*03,*0501 ANA ASO, CRP
2 HLA-DRB1*01,14-HLA-DQB1*05 ANA, ACE, ANCA, ESR HLA-B27
3 HLA-DRB1*01-HLA-DQB1*05 Unknown Unknown
4 Not done Unknown Unknown
5 Not done ANA, ANCA, CCP, HLA-B27, RF None
6 HLA-DRB1*01,*03-HLA-DQB1*02,*05 ACE, Bartonella, FTA-ABS, HSV, HLA-B27, Lyme, Lysozyme, Varicella None
Panuveitis with TINU haplotype
7 HLA-DRB1*01-HLA-DQB1*05 ANA, ACE, Bartonella, HLA-B27, HSV, Lyme, RPR, VZV ASO, serum creatinine, proteinuria, leukocytosis
8 HLA-DRB1*01-HLA-DQB1*05 ANA, ACE, ANCA, CRP, Bartonella, CMV, hepatitis B, rubella, toxoplasmosis ASO, urine calcium oxalate crystals
9 HLA-DRB1*01,*07-HLA-DQB1*02,*05 ACE, CRP, ESR, HLA-B27, RF, toxoplasmosis ANA
10 HLA-DRB1*01-HLA-DQB1*05 ANA Remote, recurrent pyuria
11 HLA-DRB1*0101,*0102-DQB1*0501 ANA, ACE, ESR, lyme, RF HLA-B27
12 HLA-DRB1*01-HLA-DQB1*05 ANA, ACE, CRP, lyme, lysozyme, UA HLA-B27
13 HLA-DRB1*01-HLA-DQB1*05 Creatinine ANA, HTN
14 HLA-DRB1*0103-HLA-DQB1*0501 Creatinine β-thalassemia
15 HLA-DRB1*01-HLA-DQB1*05 ANA None
16 HLA-DRB1*0102,*1302-HLA-DQB1*0501 ANA, ACE, β2 microglobulin, creatinine, RF None
17 HLA-DRB1*01-HLA-DQB1*05 ANA HLA-B27
18 HLA-DRB*01,*11-HLA-DQB1*05,*09 ANA None
19 HLA-DRB1*01-HLA-DQB1*05 ANA, creatinine, CRP, ESR, RF None
20 HLA-DRB1*01,*12-HLA-DQB1*03,*05 Creatinine, HLA-B27, urinalysis ANA
21 HLA-DRB1*01-HLA-DQB1*01,*04 ANA, ACE, β2 microglobulin, CRP, FTA-ABS, HLA-B27, RF, toxoplasmosis Proteinuria

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Jan 8, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on HLA-DR, DQ Class II DNA Typing in Pediatric Panuveitis and Tubulointerstitial Nephritis and Uveitis

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