Drug monitoring in long-term treatment with adalimumab for juvenile idiopathic arthritis-associated uveitis.

OBJECTIVES: Assessing influence of anti-adalimumab (ADA) antibodies (AAA) on serum trough ADA levels and uveitis activity in long-term ADA treatment of juvenile idiopathic arthritis (JIA)-associated uveitis. PATIENTS AND INTERVENTIONS: This prospective observational study included 20 patients from a single centre treated with ADA for active uveitis refractory to conventional disease-modifying antirheumatic drugs. AAA, serum ADA trough levels and uveitis activity were evaluated at regular intervals up to 6 years. RESULTS: AAA were detected in nine patients (45%). Permanent AAA in seven were associated with undetectable ADA trough levels and loss of response (LOR). Transient AAA were detected in four with measurable ADA trough levels and response of uveitis to treatment, followed in two by permanent AAA associated with LOR. Use of concomitant immunosuppression was significantly higher in patients without AAA (p<0.05). CONCLUSIONS: AAA-associated LOR frequently occurs in long-term treatment with ADA for JIA-associated uveitis. Concomitant immunosuppressive therapy significantly reduces the risk of LOR due to AAA.

Susac's syndrome: clinical course and epidemiology in a Central European population.

OBJECTIVE: Susac's syndrome is characterized by inflammation and occlusion of pre-capillary arterioles with the clinical triad of branch retinal artery occlusion (BRAO), encephalopathy and hearing loss. No epidemiological data are available for the disease. METHODS: All neurology departments in Austria were addressed to report adult patients who were on immunosuppressive treatment for a diagnosis of Susac's syndrome between 1 August 2010 and 1 August 2015. Clinical course, treatment regimens, period and point prevalence rates, and annual incidence of Susac's syndrome in Austria in people over 19 years of age are reported. RESULTS: Ten patients with Susac's syndrome were identified, and eight of them were newly diagnosed within the five-year timeframe. Minimum five-year period prevalence of the disease is 0.148/100,000 (95% confidence interval (CI) 0.071-0.272), annual incidence is 0.024/100,000 (95% CI 0.010-0.047). Minimum point prevalence rates varied from 0.030/100,000 (95% CI 0.004-0.108) to 0.088/100,000 (95% CI 0.032-0.192). Of all 10 patients, 8 showed typical callosal or internal capsule magnetic resonance imaging lesions at first presentation, 7 presented with BRAO and 5 had hearing loss or tinnitus at the beginning of the disease. Four patients developed the complete clinical triad of Susac's syndrome during the observation period. CONCLUSIONS: We provide for the first time population-based data about the clinical course, prevalence and incidence of Susac's syndrome.

Surgical management of severe complications arising from uveitis in juvenile idiopathic arthritis.

PURPOSE: Evaluate outcomes from severe ocular complications of juvenile idiopathic arthritis following surgery. METHODS: Eleven eyes of 7 patients underwent complete vitrectomy and peeling of the inner limiting membrane. Inclusion criteria were: anteroposterior segment involvement, hypotony, inflammation control of less than 3 months, compliance issues, rapidly progressive disease. Phacoemulsification was allowed if the patient was >6 years old and inflammation free >3 months. The alternative was a complete lensectomy. RESULTS: Visual acuity improved from a logMAR of 1.48 to 0.37 (p < 0.0001), and 0.20 at 6 and 12 months (p < 0.0001). No flare-up was observed within the first 6 months. Five eyes developed inflammation between 7 and 19 months. Glaucoma developed in 5 eyes at a median of 16 months. No patient developed cystoid macular edema. CONCLUSION: Extensive pars plana vitrectomy and cataract extraction can lead to significant improvement in visual acuity. Patients continue to require long-term immunosuppression and adequate follow-up.

Intravitreal methotrexate in the management of presumed tuberculous serpiginous-like choroiditis.

PURPOSE: To report on the use of intravitreal methotrexate (IVT MTX) as part of treatment of presumed tuberculous serpiginous-like choroiditis progressing despite the use of tuberculostatics. METHODS: Case series of patients suffering from serpiginous-like choroiditis with positive tuberculin skin test who received IVT injections of MTX as part of treatment. Ocular disease was active despite the use of systemic tuberculostatic (isoniazid, rifampicin, pyrazinamide, and ethambutol), and choroidal lesions showed signs of progression. A single injection of IVT MTX (400 µg/0.1 mL) was administered in the eye with macular-threatening features. Change in visual acuity, appearance of the lesion, and staining patterns on angiography were among the main outcome measurements. RESULTS: Three eyes from two patients were included. Both cases presented bilateral involvement with mild vitritis. In all three eyes, choroidal lesions healed within the first month after an IVT MTX injection with visual acuity improvement in two. No adverse reaction was related to the medication or to the procedure. Patients were followed for a mean of 13.5 months after being injected. CONCLUSION: The use of IVT MTX seems effective in the management of the inflammatory component of tuberculous serpiginous-like choroiditis, whereas systemic tuberculostatics are aimed at controlling the infectious one.

IL2RA gene polymorphism rs2104286 A>G seen in multiple sclerosis is associated with intermediate uveitis: possible parallel pathways?

PURPOSE: Uveitis is a major cause for visual impairment. Inflammation-related gene polymorphisms have previously been shown to confer susceptibility to different types of uveitis. Recently, IL-2 receptor alpha (IL2RA, also called CD25) and IL-7 receptor alpha (IL7RA) gene variants (rs2104286, rs12722489, and rs6897932) have been identified to play an essential role in the pathogenesis of immune-mediated diseases. Their role in uveitis, however, has not yet been studied. The present study was set to investigate a hypothesized association of these gene polymorphisms and the presence of either intermediate or HLA-B27-associated acute anterior uveitis. METHODS: One hundred forty-five patients with HLA-B27-associated acute anterior uveitis (AAU), 84 patients with intermediate uveitis, 132 HLA-B27-negative controls, and 61 HLA-B27-positive controls were enrolled. Determination of genotypes was done by polymerase chain reaction. RESULTS: The frequency of carriers of the minor allele for rs2104286 was significantly lower in patients with intermediate uveitis compared with HLA-B27 positive and negative controls combined (P = 0.006). Frequencies of the minor allele for rs2104286 did not differ significantly in patients with HLA-B27-associated uveitis (28.3%) when compared with HLA-B27-negative controls (24.2%; P = 0.29) and HLA-B27-positive controls (30.3%; P = 0.72). The rs12722489 and rs6897932 polymorphisms were not significantly associated with either investigated uveitis entity (P > 0.005). CONCLUSIONS: These findings suggest an association of the rs2104286 polymorphism with intermediate uveitis, but not with HLA-B27-associated acute anterior uveitis. Because this polymorphism was associated with multiple sclerosis in previous studies, the authors suggest possible parallel pathways between multiple sclerosis and intermediate uveitis but not HLA-B27-associated uveitis.

Intravitreal ganciclovir in the management of non-AIDS-related human cytomegalovirus retinitis.

OBJECTIVE: To report and evaluate intravitreal ganciclovir injections in non-AIDS patients with human cytomegalovirus (HCMV) retinitis. DESIGN: Retrospective chart review. PARTICIPANTS: Two SLE patients and one patient post chemotherapy for a non Hodgkin's lymphoma presented with myelosuppression and persistent cytomegalovirus retinitis despite systemic ganciclovir therapy. METHODS: Patients were treated with 100 microL of intravitreal ganciclovir (4 mg/dL), initially given weekly. Systemic anti-CMV medication was stopped, and following quiescence, intravitreal injections were tapered and ultimately stopped based on therapeutic response. Patients were followed periodically for signs of recurrence. RESULTS: Intravitreal ganciclovir was well tolerated and led to remission of the retinitis in 2 patients. One patient had persistent smouldering disease and reached quiescence using an intravitreal ganciclovir implant. Fluorescence-activated cell sorting analysis in one patient showed the presence of low CD4 and CD8 while treated with systemic ganciclovir, which improved with intravitreal treatment. In another, the low ratio was maintained against cytomegalovirus-specific antigens. CONCLUSIONS: Intravitreal ganciclovir injections should be considered as a treatment option in selected iatrogenically immunocompromised patients with HCMV retinitis. Responses may vary and will require an adjusted approach to treatment.

Association of complement factor H Y402H gene polymorphism with different subtypes of exudative age-related macular degeneration.

OBJECTIVE: Exudative age-related macular degeneration (AMD) is a common cause for a severe central visual loss. The complement system has been implicated in the pathogenesis of drusen. Recently, a complement factor H (CFH) polymorphism, which is characterized by a tyrosine (Y)-to-histidine (H) exchange at position 402 of the CFH gene, has been suggested as a major risk factor for AMD in a North American population. The aim of the present study was to investigate a hypothesized association between the CFH Y402H polymorphism and the presence of exudative AMD in a Central European population of Caucasoid descent as well as to determine the genotype distribution among different types of exudative AMD. DESIGN: Retrospective case-control study. PARTICIPANTS: The study cohort consisted of 179 patients with exudative AMD and 163 controls. METHODS: Determination of genotypes was carried out by allele-specific digestion of polymerase chain reaction products. MAIN OUTCOME MEASURES: Genotypes of CFH Y402H polymorphism. RESULTS: The prevalence of the CFH 402HH genotype was significantly higher in patients with exudative AMD than among controls (35.2% vs. 8.6%; P<0.001). Homozygosity for the CFH Y402H polymorphism was associated with an odds ratio of 5.78 (95% confidence interval, 3.09-10.83) for exudative AMD. Subgroup analysis revealed that the CFH 402HH genotype was significantly more prevalent in eyes with predominantly classic with no occult choroidal neovascularization (CNV) than in those with either retinal angiomatous proliferation, occult with no classic CNV, or predominantly classic with occult CNV. CONCLUSION: Our data suggest that the CFH Y402H polymorphism is a major risk factor for exudative AMD in a Central European population.

Haplotype-tagging interleukin-10 promoter polymorphism is associated with reduced risk of retinal artery occlusion.

PURPOSE: Pro- and anti-inflammatory cytokines, including interleukin 10 (IL-10), play an essential role in atherogenesis. Increased IL-10 production has been found among carriers of the IL10 [TCATA] haplotype, which is formed by five polymorphisms at position -3575, -2763, -1082, -819, and -592 in the promoter region of the IL10 gene. Due to linkage disequilibrium, the presence of the [TCATA] haplotype can be unequivocally determined by analysis of the IL10-592C>A polymorphism. The purpose of the present study was to investigate a hypothesized association between the haplotype-tagging IL10 -592C>A polymorphism and the presence of retinal artery occlusion (RAO). METHODS: The present case-control study was comprised of 194 patients with RAO and 257 normal control subjects. Genotypes of the IL10 -592C>A polymorphism were determined by fluorogenic exonuclease (TaqMan) assay. RESULTS: Carriers of the IL10 -592A-allele, indicating the presence of the IL10 [TCATA] haplotype, were found significantly more often in controls than among patients with RAO (48.6% versus 36.1%; p=0.008). In a logistic regression analysis after adjusting for age, sex, arterial hypertension, diabetes mellitus, hypercholesterolemia, and smoking habits, carriage of the IL10 -592A-allele was associated with an odds ratio of 0.65 (95% CI: 0.44-0.97) for RAO. CONCLUSIONS: Our data suggest that the IL10 [TCATA] haplotype, identified by the presence of the IL10 -592A-allele, may exert a protective effect against RAO.

Polymorphisms within the tumor necrosis factor-alpha promoter region in patients with HLA-B27-associated uveitis: association with susceptibility and clinical manifestations.

PURPOSE: The existence of genetic variations in a number of cytokines has been considered to influence susceptibility or relate to disease severity in various autoimmune diseases. Among these, single-nucleotide polymorphisms (SNPs) of the tumor necrosis factor alpha (TNF-alpha) promoter at nucleotides -308 and -238 are considered to be protective against inflammation in HLA-B27-positive individuals, whereas the SNP at position -857 has been associated with disease development in anterior uveitis. We investigate a hypothesized association between the TNF-alpha -857 C-to-T, -308 G-to-A, and the TNF-alpha -238 G-to-A SNPs and the presence of HLA-B27-associated uveitis. DESIGN: Retrospective case-control study. PARTICIPANTS: One hundred fourteen Caucasian patients with HLA-B27-associated uveitis were studied. Mean age of patients was 44.9+/-14 years (range, 16-81), and mean duration of HLA-B27-associated uveitis was 115.6+/-104 months (range, 6 months-51 years). Eighty-six patients (75.4%) suffered from an additional systemic manifestation of the disease. Sixty-three unrelated healthy HLA-B27-positive blood donors and 88 unrelated healthy HLA-B27-negative individuals served as controls. METHODS: Genotypes were determined by polymerase chain reaction. MAIN OUTCOME PARAMETERS: Association of genotypes at positions -857, -308, and -238 of the TNF-alpha gene with disease development. RESULTS: Frequencies of the TNF-alpha -308GA and TNF-alpha -238GA genotypes were significantly lower in patients with HLA-B27-associated uveitis (6.1% and 0%, respectively) when compared with the HLA-B27-negative control group, 23% at -308 (P = 0.003), and 7.9% at -238 (P = 0.0003). When compared with healthy HLA-B27-positive controls, a significantly lower frequency of the TNF-alpha -238GA genotype was found among patients (6.3%, P = 0.015). The frequency of the TNF-alpha -308GA genotype was also found to be lower in patients than among HLA-B27-positive control subjects, without, however, reaching statistical significance (6.1%, P = 0.07). No difference in frequencies was seen among the different groups for the SNPs at position -857. CONCLUSION: Our data suggest that HLA-B27-positive individuals show a higher susceptibility towards development of an intraocular inflammation in the presence of an A allele at nucleotide -238 and, to a lesser degree, at nucleotide -308 of the TNF-alpha gene promoter.

Role of the CCL2/MCP-1 -2518A>G gene polymorphism in HLA-B27 associated uveitis.

PURPOSE: Acute anterior uveitis (AAU) is the most common form of uveitis. Up to 50% of patients with AAU are HLA-B27 positive. Since HLA B27 itself plays only a minor role in the overall genetic background, other genetic variants are likely to contribute to the susceptibility to AAU. The chemokine (C-C motif) ligand 2 (CCL2) gene, coding for monocyte chemoattractant protein-1 (MCP-1), a chemotactic cytokine, is involved in the induction of uveitis. A CCL2 gene polymorphism, which is characterized by an A>G substitution at nucleotide -2518 in the promoter region of CCL2 has been previously shown to affect MCP-1 synthesis. The purpose of the present study was to investigate a hypothesized association between this genetic variant and the presence of HLA-B27 associated AAU. METHODS: The study group comprised 114 patients with HLA-B27 associated AAU. One hundred and eleven healthy HLA-B27 positive individuals served as the HLA-B27 positive control group, whereas 81 healthy HLA-B27 negative individuals served as a HLA-B27 negative control group. Genotyping for the CCL2 -2518A>G polymorphism was performed by polymerase chain reaction. RESULTS: Carriers of a CCL2 -2518G allele were found significantly more often in patients with HLA-B27 associated AAU than among HLA-B27 positive controls (49.2% and 31.5%, respectively; odds ratio 2.1; 95% confidence interval 1.2-3.6; p=0.007). CONCLUSIONS: Our data suggest that the CCL2 -2518A>G polymorphism may play a role in HLA-B27 associated acute anterior uveitis.

Five-year results of prognostic value of tyrosinase in peripheral blood of uveal melanoma patients.

Tyrosinase-based reverse transcriptase-polymerase chain reaction (RT-PCR) is a method for the detection of circulating melanoma cells in peripheral blood. To our knowledge, no long-term studies on the prognostic impact of tyrosinase PCR in uveal melanoma have yet been reported. In this prospective, non-randomized, observational cohort study, we included 41 patients with uveal malignant melanoma. RT-PCR for tyrosinase was performed in each patient before and after treatment. A clinical follow-up was performed for each patient for at least 5 years, including chest X-ray, serum liver enzyme determination, ultrasound of the liver and bone scintigraphy. The PCR results, age of the patients, tumour size, tumour location, tumour therapy, internal reflectivity, histology, development of distant metastasis and survival rate during follow-up were analysed. At the time of diagnosis, tyrosinase messenger RNA (mRNA) in peripheral blood, suggesting the presence of circulating melanoma cells, was detected in 16 of the 41 patients. Sixty-nine percent of the PCR samples with a positive result prior to therapy revealed a negative result after therapy. The internal reflectivity of the tumour (P=0.021) and the 5-year survival (P=0.023) showed a statistically significant association with positive PCR. It can be concluded that tyrosinase RT-PCR is a sensitive method for the detection of melanoma cells in peripheral blood. This study indicates that the presence of tumour cells in peripheral blood correlates with 5-year survival. Our results suggest a prognostic value of this method. Nevertheless, prospective analysis of a larger cohort is needed to determine the ultimate value of RT-PCR for tyrosinase in blood testing.

Prognostic value of keratin subtyping in transitional cell carcinoma of the upper urinary tract.

To investigate the prognostic value of keratin subtyping in invasive transitional cell carcinomas (TCCs), we performed a systematic study applying 15 different monoclonal keratin antibodies on 53 upper urinary tract TCCs using a tissue microarray technique. Immunoreactivity was correlated with pT stages and tumour grades using the Fisher's exact test. Impact on disease-free survival was analysed using the Kaplan-Meier method and compared by the log-rank test. Immunoreactivity for keratins 5/6, 6, 7, 8, 13, 14, 17, 18, 19, 20, low molecular weight (LMW) keratins (8, 18) and high molecular weight (HMW) keratins (1, 5, 10, 14) was detected in varying quantities. Regarding semi-quantitative assessment, a prognostic impact was found for keratins 5/6, 7, 8, 13, 17, 20 and HMW keratins, with reduced expression or loss of immunoreactivity being significantly associated with disease progression. With respect to analysis of staining patterns, the retention of a basally accentuated labelling for keratin 5/6 and HMW keratin as well as a superficially accentuated labelling for keratin 20 was significantly associated with a favourable outcome. In conclusion, this investigation is the first to demonstrate a possible prognostic value for keratin subtyping in invasive (upper urinary tract) TCCs with respect to metastasis-free survival. Further studies, however, are needed to substantiate our results.

Keratin immunohistochemistry in renal cell carcinoma subtypes and renal oncocytomas: a systematic analysis of 233 tumors.

Keratin immunohistochemistry represents a widely applied differential diagnostic tool in surgical pathology. To investigate the value of keratin subtyping for the diagnosis among histological subtypes of renal cell carcinoma and oncocytomas, we performed a detailed immunohistochemical study, applying 22 different monoclonal keratin antibodies on a large series of 233 renal tumors [125 conventional, 22 chromophobe, and 20 papillary (12 type-1, 8 type-2 tumors) cancers and 66 oncocytomas] using a tissue microarray technique. Immunoreactivity for keratin 7, 8, 18, and 19 was present in all tumor entities, albeit in varying quantities. With antibodies directed against keratins 8 and 18, oncocytomas showed a distinct perinuclear and punctate dot-like pattern, which was not observed in renal cancer specimens. The only tumors showing immunoreactivity for keratin 20 were two type-2 papillary cancers. All other monospecific keratin antibodies yielded consistently negative results. Overall, in contrast to some recent publications, keratin subtyping generally appeared to be of additional value only for the differentiation of renal epithelial tumors. Hence, with respect to differential diagnostic value, Hale's colloidal iron stain and vimentin immunostaining are still the most useful tools in renal tumor pathology.