Anti-retinal Antibodies in Sarcoidosis.

PURPOSE: To measure, characterize, and evaluate the clinical significance of anti-retinal antibodies in patients with sarcoid uveitis. SUBJECTS/METHODS: Prospective study of anti-retinal antibodies in 45 patients with biopsy-proven sarcoidosis (25 with and 20 without uveitis). Results were compared with patients with confirmed infectious uveitis (n = 40) and non-infectious uveitis (n = 40). RESULTS: Among sarcoidosis patients, anti-retinal antibodies were positive in 23/25 patients with uveitis and in 15/20 without uveitis [P = ns]. The most common antigens recognized were carbonic anhydrase II (14/23) and α-enolase (6/23). Anti-carbonic anhydrase II autoantibodies were infrequently detected in sarcoidosis patients without uveitis (2 out 15, P < .001), in patients with infectious uveitis (1 out 18, P < .001), and in patients with non-infectious uveitis (8 out 37, P < .001). CONCLUSIONS: Anti-retinal antibodies recognizing carbonic anhydrase II are common in sarcoid uveitis. Although not fully sensitive and specific, they might be a useful non-invasive diagnostic tool for the diagnosis of sarcoid uveitis.

Immune responses to mRNA vaccines against SARS-CoV-2 in patients with immune-mediated inflammatory rheumatic diseases.

BACKGROUND: Patients with immune-mediated rheumatic diseases (IMRDs) are commonly treated with immunosuppressors and prone to infections. Recently introduced mRNA SARS-CoV-2 vaccines have demonstrated extraordinary efficacy across all ages. Immunosuppressed patients were excluded from phase III trials with SARS-CoV-2 mRNA vaccines. AIMS: To fully characterise B-cell and T-cell immune responses elicited by mRNA SARS-CoV-2 vaccines in patients with rheumatic diseases under immunotherapies, and to identify which drugs reduce vaccine's immunogenicity. METHODS: Humoral, CD4 and CD8 immune responses were investigated in 100 naïve patients with SARS-CoV-2 with selected rheumatic diseases under immunosuppression after a two-dose regimen of SARS-CoV-2 mRNA vaccine. Responses were compared with age, gender and disease-matched patients with IMRD not receiving immunosuppressors and with healthy controls. RESULTS: Patients with IMRD showed decreased seroconversion rates (80% vs 100%, p=0.03) and cellular immune responses (75% vs 100%, p=0.02). Patients on methotrexate achieved seroconversion in 62% of cases and cellular responses in 80% of cases. Abatacept decreased humoral and cellular responses. Rituximab (31% responders) and belimumab (50% responders) showed impaired humoral responses, but cellular responses were often preserved. Antibody titres were reduced with mycophenolate and azathioprine but preserved with leflunomide and anticytokines. CONCLUSIONS: Patients with IMRD exhibit impaired SARS-CoV-2 vaccine immunogenicity, variably reduced with immunosuppressors. Among commonly used therapies, abatacept and B-cell depleting therapies show deleterious effects, while anticytokines preserved immunogenicity. The effects of cumulative methotrexate and glucocorticoid doses on immunogenicity should be considered. Humoral and cellular responses are weakly correlated, but CD4 and CD8 tightly correlate. Seroconversion alone might not reflect the vaccine's immunogenicity.

Adalimumab for Treatment of Noninfectious Uveitis: Immunogenicity and Clinical Relevance of Measuring Serum Drug Levels and Antidrug Antibodies.

PURPOSE: To evaluate the rate of immunogenicity induced by adalimumab and its relationship with drug serum levels and clinical responses in patients with noninfectious uveitis. DESIGN: Prospective observational study. PARTICIPANTS: Consecutive patients from 1 referral center who initiated treatment with adalimumab for active noninfectious uveitis resistant to conventional therapy. METHODS: All patients received 40 mg adalimumab every other week. Patients were evaluated clinically and immunologically before and after 4, 8, and 24 weeks of treatment. MAIN OUTCOME MEASURES: Clinical evaluation included assessment of changes in visual acuity, degree of inflammation in the anterior chamber and vitreous cavity, central macular thickness, and retinal angiographic leakage. Immunologic evaluation included assessment of serum trough adalimumab and antibodies against adalimumab (AAA) levels and class II HLA typing. RESULTS: Twenty-five patients were enrolled. Overall, 18 of 25 patients (72%) showed a favorable clinical response to adalimumab therapy. Eleven patients (44%) achieved a complete response and 7 (28%) achieved a partial response. However, 7 of 25 patients (28%) were considered nonresponders. Median trough adalimumab serum levels were higher in responders than in nonresponders (P < 0.001). We observed AAA positivity (AAA+) at least 1 time point in 8 of 25 patients (32%), including 4 with transitory AAA and 4 with permanent AAA. In all patients with permanent AAA+, trough adalimumab levels became undetectable (P < 0.001). However, in patients who demonstrated transitory AAA+, no correlation was observed between AAA titers and adalimumab trough levels (P = 0.2).Concomitant immunosuppression did not show any protective effect on adalimumab immunogenicity in our cohort. An association between the presence of AAA+ and a worse uveitis outcome was observed only in patients with permanent AAA+, which correlated with undetectable adalimumab trough levels (P = 0.014). CONCLUSIONS: Treatment of noninfectious uveitis with adalimumab is associated with high rates of favorable clinical response. Overall, adalimumab trough levels were higher in responder patients. Development of permanent AAA was associated with undetectable trough adalimumab levels and worse uveitis outcome. Immunogenicity was more common in patients in whom uveitis was associated with a systemic disease and was not influenced by concomitant immunosuppressors.

Insulin resistance and metabolic syndrome are related to non-alcoholic fatty liver disease, but not visceral adiposity index, in severely obese patients.

The visceral adiposity index (VAI) is a marker of visceral fat distribution and dysfunction. Visceral adiposity is related to nonalcoholic fatty liver disease (NAFLD); however, there is some controversy regarding the association between VAI and NAFLD.The aim of this study was to analyse the relationship between VAI and NAFLD and to describe the related factors in severely obese patients. A total of 139 patients who underwent bariatric surgery were included in this cross-sectional study. Liver biopsy was performed during surgery. Univariate and multivariate analysis were conducted to study the features related to VAI. A univariate analysis was conducted to identify which factors were associated with liver histology. In the univariate analysis, steatosis, liver inflammation, non-alcoholic steatohepatitis (NASH) and fibrosis were associated with VAI. In the multivariate analysis, only HOMA (Beta: 0.06; p < 0.01) and metabolic syndrome (Beta: 1.23; p < 0.01) were related to VAI. HOMA, the presence of metabolic syndrome, and waist circumference (WC) were statistically related to the NAFLD activity score (NAS score): HOMA: 0-2: 5.04; 3-4: 7.83; > or = 5: 11,32; p < 0.01; MS: 0-2: 37 %; 3-4: 33.3 %; > or = 5: 76%; p < 0.01; WC: 0-2: 128.7 cm; 3-4: 130.7; > or = 5: 140.6; p < 0.01). For the prediction of NASH (NAS score > or = 5), the AUROC curve were 0.71 (CI 95 %: 0.63-0.79) for VAI and 0.7 (CI 95 %: 0.62-0.78) for WC. In conclusion, HOMA, WC and metabolic syndrome are related to liver histology in patients with severe obesity. In the multivariate analysis, VAI was associated with HOMA and metabolic syndrome, but not with liver histology.

Vitamin D levels and bone turnover markers are not related to non-alcoholic fatty liver disease in severely obese patients / Los niveles de vitamina D y marcadores de recambio óseo no se encuentran relacionados con el hígado graso no alcóholico en obesos mórbidos

Background: Morbidly obese patients usually present vitamin D deficiency or secondary hyperparathyroidism. Low vitamin D levels have been recently related to non-alcoholic fatty liver disease (NAFLD). The aim of this study was to analyse the relationship between vitamin D, bone turnover markers and non-alcoholic fatty liver disease and metabolic syndrome in severely obese patients. Methods: One hundred and ten patients who underwent bariatric surgery were included. Liver biopsy was taken during surgery. Two univariate analyses were carried out in order to i) analyse the relationship between liver histology and vitamin D-bone turnover markers (intact parathyroid hormone (PTH), osteocalcin and Carboxy-terminal collagen crosslinks) and ii) establish the association between metabolic syndrome components-insulin resistance (HOMA) and vitamin D-bone turnover markers. Results: 70% of the patients had lower levels of vitamin D or secondary hyperparathyroidism. None of the components of liver histology were associated with levels of vitamin D or with bone turnover parameters. Patients with metabolic syndrome showed lower levels of PTH and osteocalcin (72,42 (29,47) vs 61.25(19.59) p-Value: 0.022; 19.79 (10.43) vs 16.87(10.25) p-Value: 0,028, respectively). HOMA was not related to Vitamin D or bone turnover markers. Conclusion: Low levels of vitamin D or hyperparathyroidism are common in severely obese patients. Vitamin D and bone metabolism markers were associated neither to NAFLD nor with metabolic syndrome in our series of obese morbid patients (AU)

Antecedentes: los pacientes con obesidad mórbida presentan frecuentemente déficit de vitamina D o hiperparatiroidismo secundario. Presentar niveles bajos de vitamina D se ha asociado recientemente con el hígado graso no alcohólico (EHNA). El objetivo de este estudio fue analizar la relación de la vitamina D y los marcadores de recambio óseo con el hígado graso no alcohólico y el síndrome metabólico, en pacientes con obesidad mórbida. Métodos: Ciento diez pacientes sometidos a cirugía bariátrica fueron incluidos, obteniéndose una biopsia hepática durante la cirugía. Dos análisis univariados se llevaron a cabo con el fin de: i) analizar la relación de la histología hepática con la vitamina D y marcadores de recambio óseo (hormona paratiroidea intacta (PTH), osteocalcina y enlaces cruzados de colágeno carboxi-terminal) y ii) establecer la asociación de los componentes del síndrome metabólico y resistencia a la insulina (HOMA) con los marcadores de recambio óseo y vitamina D. Resultados: El 70% de los pacientes presentaron niveles bajos de vitamina D o hiperparatiroidismo secundario. Ninguno de los componentes de la histología hepática resultó asociado con los niveles de vitamina D o con los parámetros de recambio óseo. Los pacientes con síndrome metabólico mostraron un nivel menor de PTH (72,42 (29,47) vs 61,25 (19,59) Valor p: 0.022) y de osteocalcina 19,79 (10,43) vs 16,87 (10,25) p-valor: 0.028). El HOMA no resultó relacionado con la vitamina D o con los marcadores de recambio óseo. Conclusión: Niveles bajos de vitamina D e hiperparatiroidismo secundario son hallazgos frecuentes en pacientes con obesidad mórbida en nuestro medio. Los marcadores de la vitamina D y recambio óseo no resultaron asociados con el hígado graso no alcohólico, ni con el síndrome metabólico en nuestra serie de pacientes obesos mórbidos (AU)

Insulin resistance and metabolic syndrome are related to non-alcoholic fatty liver disease, but not visceral adiposity index, in severely obese patients / La resistencia a la insulina y el síndrome metabólico se relacionan con la enfermedad grasa del hígado pero no con el índice de adiposidad visceral en pacientes con obesidad severa

The visceral adiposity index (VAI) is a marker of visceral fat distribution and dysfunction. Visceral adiposity is related to nonalcoholic fatty liver disease (NAFLD); however, there is some controversy regarding the association between VAI and NAFLD. The aim of this study was to analyse the relationship between VAI and NAFLD and to describe the related factors in severely obese patients. A total of 139 patients who underwent bariatric surgery were included in this cross-sectional study. Liver biopsy was performed during surgery. Univariate and multivariate analysis were conducted to study the features related to VAI. A univariate analysis was conducted to identify which factors were associated with liver histology. In the univariate analysis, steatosis, liver inflammation, non-alcoholic steatohepatitis (NASH) and fibrosis were associated with VAI. In the multivariate analysis, only HOMA (Beta: 0.06; p < 0.01) and metabolic syndrome (Beta: 1.23; p < 0.01) were related to VAI. HOMA, the presence of metabolic syndrome, and waist circumference (WC) were statistically related to the NAFLD activity score (NAS score): HOMA: 0-2: 5.04; 3-4: 7.83; ≥ 5: 11,32; p < 0.01; MS: 0-2: 37 %; 3-4: 33.3 %; ≥ 5: 76%; p < 0.01; WC: 0-2: 128.7 cm; 3-4: 130.7; ≥ 5: 140.6; p < 0.01). For the prediction of NASH (NAS score ≥ 5), the AUROC curve were 0.71 (CI 95 %: 0.63-0.79) for VAI and 0.7 (CI 95 %: 0.62-0.78) for WC. In conclusion, HOMA, WC and metabolic syndrome are related to liver histology in patients with severe obesity. In the multivariate analysis, VAI was associated with HOMA and metabolic syndrome, but not with liver histology (AU)

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Vitamin D levels and bone turnover markers are not related to non-alcoholic fatty liver disease in severely obese patients.

BACKGROUND: Morbidly obese patients usually present vitamin D deficiency or secondary hyperparathyroidism. Low vitamin D levels have been recently related to non-alcoholic fatty liver disease (NAFLD). The aim of this study was to analyse the relationship between vitamin D, bone turnover markers and non-alcoholic fatty liver disease and metabolic syndrome in severely obese patients. METHODS: One hundred and ten patients who underwent bariatric surgery were included. Liver biopsy was taken during surgery. Two univariate analyses were carried out in order to i) analyse the relationship between liver histology and vitamin D-bone turnover markers (intact parathyroid hormone (PTH), osteocalcin and Carboxy-terminal collagen crosslinks) and ii) establish the association between metabolic syndrome components-insulin resistance (HOMA) and vitamin D-bone turnover markers. RESULTS: 70% of the patients had lower levels of vitamin D or secondary hyperparathyroidism. None of the components of liver histology were associated with levels of vitamin D or with bone turnover parameters. Patients with metabolic syndrome showed lower levels of PTH and osteocalcin (72,42 (29,47) vs 61.25(19.59) p-Value: 0.022; 19.79 (10.43) vs 16.87(10.25) p-Value: 0,028, respectively). HOMA was not related to Vitamin D or bone turnover markers. CONCLUSION: Low levels of vitamin D or hyperparathyroidism are common in severely obese patients. Vitamin D and bone metabolism markers were associated neither to NAFLD nor with metabolic syndrome in our series of obese morbid patients.

Antecedentes: los pacientes con obesidad mórbida presentan frecuentemente déficit de vitamina D o hiperparatiroidismo secundario. Presentar niveles bajos de vitamina D se ha asociado recientemente con el hígado graso no alcohólico (EHNA). El objetivo de este estudio fue analizar la relación de la vitamina D y los marcadores de recambio óseo con el hígado graso no alcohólico y el síndrome metabólico, en pacientes con obesidad mórbida. Métodos: Ciento diez pacientes sometidos a cirugía bariátrica fueron incluidos, obteniéndose una biopsia hepática durante la cirugía. Dos análisis univariados se llevaron a cabo con el fin de: i) analizar la relación de la histología hepática con la vitamina D y marcadores de recambio óseo (hormona paratiroidea intacta (PTH), osteocalcina y enlaces cruzados de colágeno carboxi-terminal) y ii) establecer la asociación de los componentes del síndrome metabólico y resistencia a la insulina (HOMA) con los marcadores de recambio óseo y vitamina D. Resultados: El 70% de los pacientes presentaron niveles bajos de vitamina D o hiperparatiroidismo secundario. Ninguno de los componentes de la histología hepática resultó asociciado con los niveles de vitamina D o con los parámetros de recambio óseo. Los pacientes con síndrome metabólico mostraron un nivel menor de PTH (72,42 (29,47) vs 61,25 (19,59) Valor p: 0.022) y de osteocalcina 19,79 (10,43) vs 16,87 (10,25) p-valor: 0.028). El HOMA no resultó relacionado con la vitamina D o con los marcadores de recambio óseo. Conclusión: Niveles bajos de vitamina D e hiperparatiroidismo secundario son hallazgos frecuentes en pacientes con obesidad mórbida en nuestro medio. Los marcadores de la vitamina D y recambio óseo no resultaron asociados con el hígado graso no alcohólico, ni con el síndrome metabólico en nuestra serie de pacientes obesos mórbidos.

Adjunctive globe magnetic resonance imaging in the diagnosis of posterior scleritis.

OBJECTIVE: To report 4 cases of posterior scleritis with unusually unremarkable ultrasonography findings in which diagnosis was based on magnetic resonance imaging (MRI) examination. DESIGN: Retrospective noncomparative case series. PARTICIPANTS: Four patients. METHODS: Patients suffering from suspected posterior scleritis and previously misdiagnosed with a range of conditions after an unremarkable B-scan ultrasonography. A new and thorough review of systems, including MRI examination of the eye/orbit, was carried out. RESULTS: All included patients were diagnosed with posterior scleritis based on MRI findings. Systemic treatment with immunosuppressors (2 patients), antibiotics (1 patient), or no treatment (1 patient) got their inflammatory condition under control. CONCLUSIONS: MRI may play a potential role in the diagnosis of posterior scleritis particularly in those clinically suspicious cases with nondefinitive ultrasonography. Further studies on this matter are warranted.

Preformed antibodies detected by cytotoxic assay or multibead array decrease liver allograft survival: role of human leukocyte antigen compatibility.

The significance of human leukocyte antigen (HLA) compatibility and preformed antibodies in liver transplantation remains unclear. The objectives of this study were to evaluate, in a single-center cohort comprising 896 liver transplants, whether the degree of donor-recipient compatibility and preformed antibodies modified graft survival. Univariate Kaplan-Meier analysis demonstrated that donor-recipient HLA compatibility had a marginal impact on allograft survival. As for compatibility at individual antigen loci, 2 mismatches at HLA-A conferred a survival advantage in retransplanted allografts (P = 0.011). HLA-B and HLA-DR loci did not play a significant role in outcome in any pathology. The concordance of results on preformed antibodies detected by complement-dependent cytotoxicity (CDC) and a multiple bead assay (Luminex xMAP) showed a strong correlation between both techniques (P < 0.0001). Both CDC-detected and Luminex-detected antibodies were associated with shorter graft survival within the first year post-transplant (P = 0.01 and P = 0.016, respectively). Positive CDC T crossmatches and Luminex-detected HLA class II antibodies played a significant role in decreasing graft survival (P = 0.043 and P = 0.0019 at 1 year, respectively, and P = 0.005 and P = 0.038 at 5 years, respectively). A correlation was also observed between the presence of preformed Luminex-detected class II or Luminex I and II antibodies and allograft rejection (P = 0.001 and P = 0.042, respectively). In conclusion, although HLA typing is not a prerequisite for transplantation, screening of HLA antibodies with Luminex techniques and CDC crossmatch may be useful in the detection of at-risk patients that could benefit from increased surveillance and tailored therapy following transplantation.

Gly111Ser mutation in CD8A gene causing CD8 immunodeficiency is found in Spanish Gypsies.

We describe the second case of CD8 immunodeficiency. It confirms the pathogenic effect of p.Gly111Ser, leading to complete deficit of CD8+ lymphocytes, although the clinical manifestations may vary in severity. Similarly to the first case reported, our patient is also from Spanish Gypsy origin and homozygous for the p.Gly111Ser mutation in CD8alpha chain. The patient has suffered repeated respiratory infections from childhood but with conservation of her pulmonary parenchyma, on the contrary to the first patient, who died because of his respiratory injury. We developed an AluI-PCR-RFLP assay to screen a total of 1127 unrelated control individuals: 734 subjects of Gypsy ancestry from different sub-isolates and geographic locations in Europe, and 393 of Spanish (non-Gypsy) ethnicity. The results indicate that p.Gly111Ser is confined to the Spanish Gypsy population, where it occurs at a carrier rate of 0.4%. Analysis of microsatellite markers flanking the CD8A mutated gene revealed a shared polymorphic haplotype suggesting a common founder for p.Gly111Ser mutation that causes CD8 deficiency in the Spanish Gypsy population. CD8 immunodeficiency should be given diagnostic consideration in Spanish Gypsies with recurrent infections. Our findings may also have implications for these patients in terms of specific recommendations in vaccination and healthy habits and for genetic counseling of affected families.

Peripheral blood lymphocyte populations in end-stage liver diseases.

GOALS/BACKGROUND: The aim of this study was to decipher whether end-stage liver failure modifies peripheral blood lymphocytes (PBL) in a homogeneous manner, independently of the base pathology, or, if on the contrary, PBL subsets show a different profile in each hepatic disease. METHODS: We studied PBL subsets in 71 patients with end-stage liver disease, before liver transplant, and 74 healthy controls by flow cytometry. The results were statistically compared between patients and controls, and cohorts of patients classified according to their base pathology. RESULTS: We observed lower absolute numbers in all lymphocyte populations in patients compared with controls. We found an increment of CD3+ activated cells (P<10) and CD45RO+CD4+ (P<10) in chronic hepatitis C virus versus controls; hepatitis B virus showed high TCRgammadelta+ and CD8+ T cells with respect to controls (P=0.008 and P=0.029, respectively); alcoholic cirrhotic patients showed low CD8+, mainly CD45RA+CD8+ (P=0.007) and high CD45RO+CD4+ (P<10) compared with the normal population; autoimmune diseases showed lower CD3+ and TCRalphabeta+ (P=0.002 and P=0.0001) than controls. CONCLUSIONS: Regardless of the base pathology, patients with end-stage liver disease show a low absolute number of lymphocyte populations compared with controls. However, PBL profiles are different, characteristic, and specific of every disease causing chronic liver failure.