Long-term outcomes of noninfectious uveitis treated with systemic immunomodulatory therapy: a retrospective case series.

OBJECTIVE: To study the clinical characteristics and long-term outcomes of patients with noninfectious uveitis (NIU) who are treated with systemic immunomodulatory therapy (IMT). DESIGN: Retrospective case series. PARTICIPANTS: All consecutive cases of adults with NIU under the care of 5 uveitis subspecialty tertiary care clinics between 2010 to 2021 were included. METHODS: Patient outcomes were assessed at initial presentation and at the latest available follow-up. RESULTS: A total of 418 NIU patients receiving IMT therapy with a median age of 46.0 years and 59.3% female were identified. Each patient required an average of 1.4 agents until achieving an optimal response. Following initial treatment with prednisone, patients were most commonly initiated on methotrexate. The top 3 treatments with the highest proportion of optimal treatment response when taken alone or in combination with other agents were infliximab (79.3%), cyclosporine (75%), and adalimumab (70%). The strongest predictors for requiring a greater number of IMTs trialed were younger age, panuveitis, and a chronic or recurrent disease course. Multivariable linear regression analysis suggested that baseline visual acuity at diagnosis was the only significant predictor of final visual acuity (p < 0.001). CONCLUSIONS: NIU patients on IMT are often trialed on multiple therapeutic agents before achieving an optimal treatment response. Visual acuity at diagnosis is a predictor of final visual outcomes, whereas chronic or recurrent disease course, younger age, and panuveitis are predictors of requiring multiagent treatment regimens.

Characteristics of ocular hypertension and uveitic glaucoma among patients with noninfectious uveitis.

OBJECTIVE: Ocular hypertension and uveitic glaucoma are important downstream sequela of noninfectious uveitis (NIU). Herein, we describe the clinical outcomes of NIU cases with ocular hypertension and uveitic glaucoma. DESIGN: Retrospective cohort study. PARTICIPANTS: All adults (≥18 years) with NIU under the care of uveitis subspecialty tertiary care clinics between 2010 and 2021 were included. METHODS: The primary outcomes were baseline and final visual acuity. RESULTS: A total of 216 patients out of 914 (23.6%) cases with NIU had ocular hypertension or uveitic glaucoma over the study period. Of all patients with ocular hypertension or uveitic glaucoma, 46% were corticosteroid responders. Baseline and last median visual acuities were better for the ocular hypertension patients compared with patients with uveitic glaucoma (p < 0.001). A higher proportion of patients with uveitic glaucoma than patients with ocular hypertension required glaucoma surgery (p < 0.001). The regression analyses suggested that baseline visual acuity and anatomical classification are significant predictors of last visual acuity, whereas diagnosis of ocular hypertension versus uveitic glaucoma were significant predictors of requirement for glaucoma surgery (p < 0.001). CONCLUSION: A quarter of patients with NIU in this study developed ocular hypertension or uveitic glaucoma. Approximately half of the patients with ocular hypertension or uveitic glaucoma were deemed to be corticosteroid responders. Baseline and last visual acuity outcomes are better amongst ocular hypertension patients compared with those with uveitic glaucoma. Poor baseline visual acuity and panuveitis are predictors of worse vision at last follow-up. Additionally, diagnosis of uveitic glaucoma was a significant predictor of requirement for glaucoma surgery.

Functional variants of OCTN cation transporter genes are associated with Crohn disease.

Crohn disease is a chronic, inflammatory disease of the gastrointestinal tract. A locus of approximately 250 kb at 5q31 (IBD5) was previously associated with susceptibility to Crohn disease, as indicated by increased prevalence of a risk haplotype of 11 single-nucleotide polymorphisms among individuals with Crohn disease, but the pathogenic lesion in the region has not yet been identified. We report here that two variants in the organic cation transporter cluster at 5q31 (a missense substitution in SLC22A4 and a G-->C transversion in the SLC22A5 promoter) form a haplotype associated with susceptibility to Crohn disease. These variants alter transcription and transporter functions of the organic cation transporters and interact with variants in another gene associated with Crohn disease, CARD15, to increase risk of Crohn disease. These results suggest that SLC22A4, SLC22A5 and CARD15 act in a common pathogenic pathway to cause Crohn disease.

Clinical characteristics of non-infectious uveitis treated with and without systemic immunomodulatory therapy.

OBJECTIVE: To compare the patient characteristics and long-term outcomes for those treated with and without systemic immunomodulatory therapy (IMT) for non-infectious uveitis (NIU). DESIGN: Retrospective cohort study. PARTICIPANTS: All consecutive adults with NIU receiving care at 5 uveitis subspecialty tertiary care clinics between 2010 and 2021. METHODS: Clinical outcomes were evaluated on initial presentation and at the last available follow-up. The main outcome measures were baseline characteristics and final visual acuity. RESULTS: A total of 914 NIU patients (418 IMT, 496 non-IMT) with a median age of 51.0 years and 57.4% female were identified. Over half the patients had bilateral disease, with a significantly higher proportion of bilateral cases in the IMT group compared with the non-IMT group (p < 0.001). The IMT group was more likely to have chronic uveitis (p < 0.001), with a higher proportion of patients experiencing cataracts and cystoid macular edema (p < 0.001 for both). A significantly higher proportion of non-IMT patients had anterior uveitis and an idiopathic etiology (p < 0.001). Overall, visual acuity improved significantly from baseline to last follow-up in the entire cohort (p < 0.001), with a slightly better improvement in the IMT group. Multivariable linear regression analysis suggested that baseline visual acuity and panuveitis were significant predictors of final visual acuity (p < 0.001 for both). CONCLUSIONS: NIU patients on IMT are often younger, suffer from bilateral and chronic uveitis, and are more likely to have ocular complications. Those in the non-IMT group are more likely to have anterior idiopathic NIU. Baseline visual acuity and panuveitis are the main predictors of final vision outcomes among patients with NIU.

Flow diversion in vasculitic intracranial aneurysms? Repair of giant complex cavernous carotid aneurysm in polyarteritis nodosa using Pipeline embolization devices: first reported case.

Intracranial aneurysms in polyarteritis nodosa (PAN) are exceedingly rare lesions with unpredictable behavior that pose real challenges to microsurgical and endovascular interventions owing to their inflammatory nature. We introduce a safe and effective alternative for treating these aneurysms using Pipeline embolization devices (PEDs). A 20-year-old man presented with diplopia, headaches, chronic abdominal pain, and weight loss. Diagnostic evaluations confirmed PAN, including bilateral giant cavernous carotid aneurysms. Cyclophosphamide and steroids achieved significant and sustained clinical improvement, with a decision to follow the aneurysms serially. Seven years later the left unruptured aneurysm enlarged, causing a sudden severe headache and a cavernous sinus syndrome. Treatment of the symptomatic aneurysm was pursued using flow diversion (PED) and the internal carotid artery was successfully reconstructed with a total of four overlapping PEDs. At 6 months follow-up, complete exclusion of the aneurysm was demonstrated, with symptomatic recovery. This is the first description of using a flow-diverting technique in an inflammatory vasculitis. In this case, PEDs not only attained a definitive closure of the aneurysm but also reconstructed the damaged and fragile arterial segment affected with vasculitis.

Transforming growth factor beta-1 (TGFB1) and peak bone mass: association between intragenic polymorphisms and quantitative ultrasound of the heel.

BACKGROUND: Variance of peak bone mass has a substantial genetic component, as has been shown with twin studies examining quantitative measures such as bone mineral density (BMD) and quantitative ultrasound (QUS). Evidence implicating single nucleotide polymorphisms (SNPs) of the transforming growth factor beta-1 (TGFB1) gene is steadily accumulating. However, a comprehensive look at multiple SNPs at this locus for their association with indices of peak bone mass has not been reported. METHODS: A cohort of 653 healthy Caucasian females 18 to 35 years old was genotyped for seven TGFB1 SNPs. Polymorphisms were detected by restriction endonuclease digestion of amplified DNA segments. RESULTS: The frequencies of the least common allele at G-800A, C-509T, codon 10 (L10P), codon 25 (R25P), codon 263 (T263I), C861-20T, and 713-8 delC loci were 0.07, 0.33, 0.41, 0.08, 0.04, 0.25 and 0.01, respectively. A significant association was seen between QUS Stiffness Index (QUS-SI) and the SNP at codon 10 and the linked promoter SNP, C-509T. This association remained significant after multiple regression was used to incorporate important clinical covariates--age, BMI, level of activity, family history, and caffeine intake--into the model. CONCLUSION: The association of QUS-SI with -509T is consistent with a gene-dose effect, while only individuals homozygous for the codon 10P allele showed a significant increase. In this cohort of young healthy Caucasian females, the T allele at position -509 is associated with greater bone mass as measured by calcaneal ultrasound.

Flow diversion in vasculitic intracranial aneurysms? Repair of giant complex cavernous carotid aneurysm in polyarteritis nodosa using Pipeline embolization devices: first reported case.

Intracranial aneurysms in polyarteritis nodosa (PAN) are exceedingly rare lesions with unpredictable behavior that pose real challenges to microsurgical and endovascular interventions owing to their inflammatory nature. We introduce a safe and effective alternative for treating these aneurysms using Pipeline embolization devices (PEDs). A 20-year-old man presented with diplopia, headaches, chronic abdominal pain, and weight loss. Diagnostic evaluations confirmed PAN, including bilateral giant cavernous carotid aneurysms. Cyclophosphamide and steroids achieved significant and sustained clinical improvement, with a decision to follow the aneurysms serially. Seven years later the left unruptured aneurysm enlarged, causing a sudden severe headache and a cavernous sinus syndrome. Treatment of the symptomatic aneurysm was pursued using flow diversion (PED) and the internal carotid artery was successfully reconstructed with a total of four overlapping PEDs. At 6 months follow-up, complete exclusion of the aneurysm was demonstrated, with symptomatic recovery. This is the first description of using a flow-diverting technique in an inflammatory vasculitis. In this case, PEDs not only attained a definitive closure of the aneurysm but also reconstructed the damaged and fragile arterial segment affected with vasculitis.

SLC22A4 polymorphisms implicated in rheumatoid arthritis and Crohn's disease are not associated with rheumatoid arthritis in a Canadian Caucasian population.

OBJECTIVE: Single-nucleotide polymorphisms (SNPs) in the SLC22A4 gene encoding the organic cation transporter OCTN1 have been associated with rheumatoid arthritis (RA) in the Japanese population and with Crohn's disease in a Canadian cohort. The RA-associated and Crohn's disease-associated SNPs include, respectively, an intronic variant (slc2F2) and an exonic variant (1672T). We used a case-control approach to investigate the prevalence of these variants in a Canadian RA cohort and to determine whether RA and Crohn's disease share SLC22A4 susceptibility alleles. METHODS: Nine hundred eighteen unrelated patients with RA, 507 patients with Crohn's disease, and 623 healthy controls were genotyped for the putatively RA-associated slc2F1 and slc2F2 variants and the Crohn's disease-associated SLC22A4 1672T variant. RESULTS: Neither slc2F1 nor slc2F2 showed evidence for association with RA, the allele frequencies of these variants being significantly different in the Canadian population compared with those reported in the Japanese population, but not significantly different between patients with RA and controls. In addition, associations between the 1672T Crohn's disease risk allele and RA or between the slc2F1-A and slc2F2-T risk alleles and Crohn's disease were not detected in this study cohort, and the latter 2 alleles were not in linkage disequilibrium with the 1672T variant. CONCLUSION: These observations do not support roles for any of the previously identified SLC22A4 disease risk alleles in RA susceptibility in the Canadian population. The slc2F1/slc2F2 risk alleles were not associated with Crohn's disease nor in linkage disequilibrium with the Crohn's disease-associated 1672T variant, and accordingly, also appear to be irrelevant to Crohn's disease susceptibility in the population under study.

Association of the lymphoid tyrosine phosphatase R620W variant with rheumatoid arthritis, but not Crohn's disease, in Canadian populations.

OBJECTIVE: A single-nucleotide polymorphism in the PTPN22 gene encoding the lymphoid protein tyrosine phosphatase (Lyp) has recently been identified as a functional variant associated with susceptibility to rheumatoid arthritis (RA), type 1 diabetes, and systemic lupus erythematosus. To determine whether association of this variant (PTPN22 1858T) with RA is reproducible and is also observed in another autoimmune condition, Crohn's disease, we investigated the association between the PTPN22 1858T allele and RA and Crohn's disease in a Canadian population. METHODS: Two RA case-control cohorts representing a total of 1,234 patients and 791 healthy controls as well as a cohort of 455 patients with Crohn's disease and 190 controls were genotyped for the PTPN22 C1858T polymorphism, and genotype frequencies were compared between patients and controls. RESULTS: Significant association of the PTPN22 1858T allele with RA was detected in both the Toronto-based RA cohort (P = 1.6 x 10(-6), odds ratio [OR] 1.8) and the Halifax-based RA cohort (P = 9.4 x 10(-4), OR 1.94). Association of the risk allele with RA was not affected by sex, age at disease onset, or the presence of either rheumatoid factor or rheumatoid nodules. No association between the PTPN22 risk allele and Crohn's disease was detected. CONCLUSION: These observations confirm the association of RA susceptibility with the PTPN22 1858T allele. However, the data also reveal a lack of association between this variant and Crohn's disease, suggesting that the PTPN22 1858T allele is a risk allele for multiple, but not all, autoimmune diseases.

NOD2/CARD15 gene mutation is not associated with susceptibility to Wegener's granulomatosis.

OBJECTIVE: Polymorphisms and mutations in the NOD2/CARD15 gene have been reported to increase susceptibility to Crohn's disease (CD) and the rare Blau syndrome, respectively. Both conditions are characterized by granuloma formation. We assessed the influence of variants in the CARD15 gene in another disorder characterized by granuloma, Wegener's granulomatosis (WG). METHODS: Direct DNA sequencing of the CARD15 gene was performed on 25 patients with WG, and an additional 73 patients were genotyped for the 3 CD associated variants, R702W, G908R, and fs1007. RESULTS: In the WG patients, 10 previously reported single nucleotide polymorphisms (SNP) were identified. No SNP were present in the WG patients at significantly different frequencies than the control population. CONCLUSION: Our data provide no evidence to support an association between CARD15 and WG.