Humoral autoimmune response heterogeneity in the spectrum of primary biliary cirrhosis

To compare autoantibody features in patients with primary biliary cirrhosis (PBC) and individuals presenting antimitochondria antibodies (AMAs) but no clinical or biochemical evidence of disease.A total of 212 AMA-positive serum samples were classified into four groups: PBC (definite PBC, n = 93); PBC/autoimmune disease (AID; PBC plus other AID, n = 37); biochemically normal (BN) individuals (n = 61); and BN/AID (BN plus other AID, n = 21). Samples were tested by indirect immunofluorescence (IIF) on rat kidney (IIF-AMA) and ELISA [antibodies to pyruvate dehydrogenase E2-complex (PDC-E2), gp-210, Sp-100, and CENP-A/B]. AMA isotype was determined by IIF-AMA. Affinity of anti-PDC-E2 IgG was determined by 8 M urea-modified ELISA.High-titer IIF-AMA was more frequent in PBC and PBC/AID (57 and 70 %) than in BN and BN/AID samples (23 and 19 %) (p < 0.001). Triple isotype IIF-AMA (IgA/IgM/IgG) was more frequent in PBC and PBC/AID samples (35 and 43 %) than in BN sample (18 %; p = 0.008; p = 0.013, respectively). Anti-PDC-E2 levels were higher in PBC (mean 3.82; 95 % CI 3.36-4.29) and PBC/AID samples (3.89; 3.15-4.63) than in BN (2.43; 1.92-2.94) and BN/AID samples (2.52; 1.54-3.50) (p < 0.001). Anti-PDC-E2 avidity was higher in PBC (mean 64.5 %; 95 % CI 57.5-71.5 %) and PBC/AID samples (66.1 %; 54.4-77.8 %) than in BN samples (39.2 %; 30.9-37.5 %) (p < 0.001). PBC and PBC/AID recognized more cell domains (mitochondria, nuclear envelope, PML/sp-100 bodies, centromere) than BN (p = 0.008) and BN/AID samples (p = 0.002). Three variables were independently associated with established PBC: high-avidity anti-PDC-E2 (OR 4.121; 95 % CI 2.118-8.019); high-titer IIF-AMA (OR 4.890; 2.319-10.314); antibodies to three or more antigenic cell domains (OR 9.414; 1.924-46.060).The autoantibody profile was quantitatively and qualitatively more robust in definite PBC as compared with AMA-positive biochemically normal individuals.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Research and Development Department of Fleury Medicine and HealthConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo, UNIFESP, Div Rheumatol, BR-04023900 São Paulo, BrazilFleury Med & Hlth Labs, Div Res & Dev, São Paulo, BrazilUniv São Paulo, Sch Med, Dept Gastroenterol, São Paulo, BrazilUniv São Paulo, Inst Trop, Lab Med Invest LIM 06, São Paulo, BrazilUniversidade Federal de São Paulo, UNIFESP, Hosp Servidor Publ Estadual Francisco Morato Oliv, São Paulo, BrazilUniversidade Federal de São Paulo, UNIFESP, Dept Stat, São Paulo, BrazilUniversidade Federal de São Paulo, UNIFESP, Div Rheumatol, BR-04023900 São Paulo, BrazilUniversidade Federal de São Paulo, UNIFESP, Hosp Servidor Publ Estadual Francisco Morato Oliv, São Paulo, BrazilUniversidade Federal de São Paulo, UNIFESP, Dept Stat, São Paulo, BrazilFAPESP: 2009/51887-0CNPq: 476356/2008-3Web of Scienc

Fibrates for the Treatment of Primary Biliary Cholangitis Unresponsive to Ursodeoxycholic Acid: An Exploratory Study

Aim: Up to 40% of patients with primary biliary cholangitis (PBC) will have a suboptimal biochemical response to ursodeoxycholic acid (UDCA), which can be improved by the addition of fibrates. This exploratory study aims to evaluate the long-term real-life biochemical response of different fibrates, including ciprofibrate, in subjects with UDCA-unresponsive PBC.Methods: The Brazilian Cholestasis Study Group multicenter database was reviewed to assess the response rates to UDCA plus fibrates in patients with UDCA-unresponsive PBC 1 and 2 years after treatment initiation by different validated criteria.Results: In total, 27 patients (100% women, mean age 48.9 +/- 9.2 years) with PBC were included. Overall response rates to fibrates by each validated criterion varied from 39 to 60% and 39-76% at 12 and 24 months after treatment combination, respectively. Combination therapy resulted in a significant decrease in ALT and ALP only after 2 years, while GGT significantly improved in the first year of treatment. Treatment response rates at 1 and 2 years appear to be comparable between ciprofibrate and bezafibrate using all available criteria.Conclusion: Our findings endorse the efficacy of fibrate add-on treatment in PBC patients with suboptimal response to UDCA. Ciprofibrate appears to be at least as effective as bezafibrate and should be assessed in large clinical trials as a possibly new, cheaper, and promising option for treatment of UDCA-unresponsive PBC patients

Response to Ursodeoxycholic Acid May Be Assessed Earlier to Allow Second-Line Therapy in Patients with Unresponsive Primary Biliary Cholangitis

Background Response to ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) has been traditionally assessed 1 to 2 years after treatment initiation. With the development of new drugs, some patients may benefit from an earlier introduction of second-line therapies. Aims This study aims to identify whether well-validated response criteria could correctly identify individuals likely to benefit from add-on second-line therapy at 6 months. Methods Analysis of a multicenter retrospective cohort which included only patients with clear-cut PBC. Results 206 patients with PBC (96.6% women; mean age 54 +/- 12 years) were included. Kappa concordance was substantial for Toronto (0.67), Rotterdam (0.65), Paris 1 (0.63) and 2 (0.63) criteria at 6 and 12 months, whereas Barcelona (0.47) and POISE trial (0.59) criteria exhibited moderate agreement. Non-response rates to UDCA was not statistically different when assessed either at 6 or 12 months using Toronto, Rotterdam or Paris 2 criteria. Those differences were even smaller or absent in those subjects with advanced PBC. Mean baseline alkaline phosphatase was 2.73 +/- 1.95 times the upper limit of normal (x ULN) among responders versus 5.05 +/- 3.08 x ULN in non-responders (p < 0.001). Conclusions After 6 months of treatment with UDCA, the absence of response by different criteria could properly identify patients who could benefit from early addition of second-line therapies, especially in patients with advanced disease or high baseline liver enzymes levels

UPDATE OF THE BRAZILIAN SOCIETY OF HEPATOLOGY RECOMMENDATIONS FOR DIAGNOSIS AND MANAGEMENT OF AUTOIMMUNE DISEASES OF THE LIVER

ABSTRACT New data concerning the management of autoimmune liver diseases have emerged since the last single-topic meeting sponsored by the Brazilian Society of Hepatology to draw recommendations about the diagnosis and treatment of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), overlap syndromes of AIH, PBC and PSC and specific complications and topics concerning AIH and cholestatic liver diseases. This manuscript updates those previous recommendations according to the best evidence available in the literature up to now. The same panel of experts that took part in the first consensus document reviewed all recommendations, which were subsequently scrutinized by all members of the Brazilian Society of Hepatology using a web-based approach. The new recommendations are presented herein. RESUMO Desde a publicação em 2015 das recomendações da Sociedade Brasileira de Hepatologia sobre a prevenção e tratamento de doenças hepáticas autoimunes, novos dados baseados em evidências científicas foram publicados na literatura, mudando o diagnóstico e tratamento da hepatite autoimune (HAI), colangite biliar primária (CBP), colangite esclerosante primária (CEP), síndromes de sobreposição de HAI, CBP e CEP e o manejo de complicações específicas além de outros tópicos relativos à HAI e doenças hepáticas colestáticas. Este manuscrito atualiza as recomendações anteriores de acordo com as melhores evidências disponíveis na literatura até o momento. O mesmo painel de experts que participou da primeira diretriz revisou todas as recomendações de acordo com os dados publicados na literatura e elaborou um manuscrito submetido subsequentemente à apreciação e revisão de todos os membros da Sociedade Brasileira de Hepatologia via homepage da sociedade. As recomendações finais atualizadas foram condensadas no presente documento

Risk factors for cancer in patients with primary biliary cholangitis and autoimmune hepatitis and primary biliary cholangitis overlap syndrome

Introduction and objectives: Primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) and PBC overlap syndrome (AIH/PBC) have been associated with a higher risk of hepatocellular carcinoma (HCC) and extra-hepatic malignancy (EHM). This study aims to assess potential risk factors associated with cancer development in PBC and AIH/PBC. Materials and methods: The Brazilian Cholestasis Study Group database was reviewed to compare clinical and laboratory features of PBC patients with HCC and EHM with those without cancer. Results: Among the 752 PBC patients enrolled, 64 of them with AIH/PBC, 87 cancers were identified in 72 patients, including 20 cases of HCC and 67 of EHM. Patients with HCC had a higher prevalence of cirrhosis (95% vs. 32.5% of those subjects without cancer, p≤0.001), smoking (55% vs. 12.3%, p≤0.001), CREST syndrome (30% vs 7.6%, p=0.003) and prior azathioprine (30% vs 8%, p= 0.005) and prednisone (35% vs 14%, p= 0.018) use, whereas patients with EHM had a higher prevalence of smoking (42.3% vs 12.4% of those subjects without cancer, p= <0.001), AMA positivity (96.6% vs 80.1%, p≤0.001), azathioprine therapy (21% vs 7.9%, p= 0.01) and concurrent other autoimmune diseases. In multivariate analysis, cirrhosis, obesity and prior azathioprine therapy were independent risk factors for HCC, while Sjogren syndrome and psoriasis were associated with EHM. Fibrates reduced EHM risk. Conclusions: The prevalence of EHM is higher when compared to HCC in PBC patients. Cirrhosis, obesity, prior azathioprine use, and concurrent autoimmune diseases were significantly associated with cancer in PBC

Clinical features and treatment outcomes of primary biliary cholangitis in a highly admixed population

Introduction and objectives: Little is known about primary biliary cholangitis (PBC) in non-whites. The purpose of this study was to evaluate clinical features and outcomes of PBC in a highly admixed population. Material and methods: The Brazilian Cholestasis Study Group multicentre database was reviewed to assess demographics, clinical features and treatment outcomes of Brazilian patients with PBC. Results: 562 patients (95% females, mean age 51 ± 11 years) with PBC were included. Concurrent autoimmune diseases and overlap with autoimmune hepatitis (AIH) occurred, respectively, in 18.9% and 14%. After a mean follow-up was 6.2 ± 5.3 years, 32% had cirrhosis, 7% underwent liver transplantation and 3% died of liver-related causes. 96% were treated with ursodeoxycholic acid (UDCA) and 12% required add-on therapy with fibrates, either bezafibrate, fenofibrate or ciprofibrate. Response to UDCA and to UDCA/fibrates therapy varied from 39%-67% and 42-61%, respectively, according to different validated criteria. Advanced histological stages and non-adherence to treatment were associated with primary non-response to UDCA, while lower baseline alkaline phosphatase (ALP) and aspartate aminotransferase (AST) levels correlated with better responses to both UDCA and UDCA/fibrates. Conclusions: Clinical features of PBC in highly admixed Brazilians were similar to those reported in Caucasians and Asians, but with inferior rates of overlap syndrome with AIH. Response to UDCA was lower than expected and inversely associated with histological stage and baseline AST and ALP levels. Most of patients benefited from add-on fibrates, including ciprofibrate. A huge heterogeneity in response to UDCA therapy according to available international criteria was observed and reinforces the need of global standardization