Tumor necrosis factor polymorphisms associated with tumor necrosis factor production influence the risk of idiopathic intermediate uveitis.

PURPOSE: Idiopathic intermediate uveitis (IIU) is a potentially sight-threatening inflammatory disorder with well-defined anatomic diagnostic criteria. It is often associated with multiple sclerosis, and both conditions are linked to HLA-DRB1*15. Previously, we have shown that non-infectious uveitis (NIU) is associated with interleukin 10 (IL10) polymorphisms, IL10-2849A (rs6703630), IL10+434T (rs2222202), and IL10+504G (rs3024490), while a LTA+252AA/TNFA-238GG haplotype (rs909253/rs361525) is protective. In this study, we determined whether patients with IIU have a similar genetic profile as patients with NIU or multiple sclerosis. METHODS: Twelve polymorphisms were genotyped, spanning the tumor necrosis factor (TNF) and IL10 genomic regions, in 44 patients with IIU and 92 population controls from the UK and the Republic of Ireland. RESULTS: IIU was strongly associated with the TNFA-308A and TNFA-238A polymorphisms. We found the combination of TNFA-308 and -238 loci was more strongly associated with IIU than any other loci across the major histocompatibility complex, including HLA-DRB1. CONCLUSIONS: TNF polymorphisms, associated with increased TNF production, are highly associated with IIU. These results offer the potential to ascribe therapeutic response and risk (i.e., the influence of HLA-DRB1*15 status and TNFR1 polymorphism) to anti-TNF therapy in IIU.

Punctate inner choroidopathy and multifocal choroiditis with panuveitis share haplotypic associations with IL10 and TNF loci.

PURPOSE: The white-dot syndromes are a heterogenous group of chorioretinal disorders that have many common clinical features. Whether these disorders represent distinct clinical entities or different manifestations of the same disease warrants further interrogation. Two white-dot syndromes were investigated, with closely overlapping phenotypes--multifocal choroiditis with panuveitis (MFCPU) and punctate inner choroidopathy (PIC)--for differences in clinical course and genotype frequency at IL10 and TNF loci, known to be associated with noninfectious uveitis. METHODS: Twelve polymorphisms were genotyped, spanning the TNFA and IL10 genomic regions, in 61 patients with MFCPU or PIC and 92 population controls from the United Kingdom and Republic of Ireland. RESULTS: There were clear differences in clinical course between patients with MFCPU and PIC which had prognostic significance. However, both patient groups demonstrated similar associations with the IL10 haplotype, IL10htSNP2(-2849)AX/htSNP5(+434)TC and negative associations with the TNF haplotype, LTA+252A/TNFhtSNP1(-308)G/TNFhtSNP2(-238)G/TNFhtSNP3(+488)A/TNFd3. CONCLUSIONS: Despite clear differences in clinical course and outcome, MFCPU and PIC may still represent two manifestations of the same disease, given their similar genetic associations with IL10 and TNF loci, which are known to be associated with noninfectious uveitis and autoimmunity, in general. Definitive proof will necessitate genomewide sequence analysis. However, the data also support the notion that epigenetic factors have a strong effect on clinical phenotype.

Syphilis consequences and implications in delayed diagnosis: five cases of secondary syphilis presenting with ocular symptoms.

Ocular manifestations of syphilis are uncommon. Five cases of ocular syphilis are presented, in four of which there was a delay in diagnosis. Four of the patients were men who have sex with men (MSM), and four patients were HIV negative.

Cytokine polymorphism in noninfectious uveitis.

PURPOSE: Noninfectious uveitis is a sight-threatening immune-mediated intraocular inflammatory disorder. The inheritance of uveitis in multiplex families and its association with known monogenic and polygenic immunologic disorders suggests that common genetic variants underlie susceptibility to uveitis as well as to other immunologic disorders. TNFA and IL10 are strong candidate genes, given the influence of these cytokines on inflammation, immune tolerance, and apoptosis. METHODS: The role of 12 polymorphisms spanning the TNFA and IL10 genomic regions was investigated in 192 uveitis patients and 92 population control subjects from four regional centers in the United Kingdom and Republic of Ireland. RESULTS: The results demonstrate that uveitis is associated with three haplotype-tagging SNPs (htSNPs) in the IL10 gene: htSNP2 (rs6703630), htSNP5 (rs2222202), and htSNP6 (rs3024490). IL10htSNP2AG/htSNP5TC was the most significantly associated haplotype (P = 0.00085), whereas the LTA+252AA/TNFhtSNP2GG haplotype was protective (P = 0.00031). Furthermore, subgroup analysis showed that the frequency of the TNFd4 allele was higher in patients with nonremitting ocular disease and/or those requiring higher levels of maintenance immunosuppression. Although these associations lost significance after Bonferroni correction, they infer a relationship that may be validated by a larger study. CONCLUSIONS: Since these variants are implicated in the susceptibility and severity of several immunologic disorders, the results support the hypothesis that common genetic determinants influence shared mechanisms of autoimmunity.

Mycophenolate mofetil for the treatment of uveitis.

PURPOSE: To evaluate the efficacy and tolerance of mycophenolate mofetil (MMF) for the treatment of noninfectious uveitis using the methods of analysis advocated by the Standardization of Uveitis Nomenclature (SUN) Working Group, and to compare this with other SUN-compliant reports of immunosuppression in ocular inflammation. DESIGN: Retrospective case series. MEDHODS: A predefined data set was retrospectively obtained from the case notes of 100 consecutive uveitis patients treated with MMF at a single academic referral center between April 1, 2000 and August 1, 2006. These data were then analyzed in accordance with SUN recommendations. The main outcome measures were: 1) rate of tapering oral prednisone to 10 mg daily, 2) requirement for alternative second-line immunosuppressive therapy, and 3) rate of MMF dose discontinuation because of side effects. RESULTS: In this large cohort with noninfectious persistent, chronic, or recurrent uveitis, there was an 84.6% probability of achieving a prednisone dose of < or =10 mg daily after one year of MMF treatment. Alternative second-line immunosuppressive therapy was introduced at a rate of 0.18 per patient-year (PY) and MMF was discontinued because of intolerance at a rate of 0.09/PY, predominantly because of gastrointestinal upset. This corroborates the findings of the only previous SUN-compliant study of MMF in ocular inflammation and is comparable to the rates of treatment success and intolerance we have recently reported for tacrolimus. CONCLUSION: This data generates concordant evidence with other SUN-compliant studies supporting the use of MMF in uveitis.

Long-term efficacy and tolerance of tacrolimus for the treatment of uveitis.

PURPOSE: To evaluate the long-term efficacy and tolerance of tacrolimus for the treatment of uveitis. DESIGN: Retrospective case series. PARTICIPANTS: Sixty-two consecutive patients with noninfectious uveitis treated with tacrolimus at a single academic referral center between April 2000 and April 2004. METHODS: A standard data set was obtained from patients' medical records and analyzed according to the recommendations of the Standardization of Uveitis Nomenclature Working Group. MAIN OUTCOME MEASURES: (1) Rate of tapering oral prednisone to 10 mg daily, (2) requirement for alternative second-line immunosuppressive therapy, and (3) rate of tacrolimus dose reduction or discontinuation due to side effects. RESULTS: In this cohort with well-established ocular inflammation, patients successfully tapered their oral prednisone to 10 mg daily at an average rate of 1.62 per patient-year (PY), with an 85% probability of achieving < or =10 mg after 1 year 2 months of treatment. Tacrolimus was discontinued due to intolerance at a rate of 0.13/PY. This was predominantly due to noncardiovascular adverse events, and rates of introducing or increasing concomitant treatment for hypertension, hypercholesterolemia, and diabetes mellitus were all below 0.05/PY. Creatinine rises of > or =30% were also notably uncommon (0.05/PY). CONCLUSION: Tacrolimus's efficacy for the treatment of uveitis is maintained long-term, and its cardiovascular risk profile is excellent.