Role of autoimmunity in patients transplanted for acute liver failure of unknown origin: a clinical and graft-biopsy analysis

Abstract Background The etiology and prognosis of acute liver failure (ALF) remains unknown in a significant proportion of cases. Signs of autoimmunity may be present, but no consistent pattern has been observed. We aimed to analyse if pretransplant immunological findings, HLA haplotypes and clinical features among patients with unknown etiology differ from those of autoimmune or other known etiology. We also analysed whether such signs impact post-transplant biopsy findings or complications. Methods All adult ALF patients undergoing liver transplantation (LT) in Finland during 1987-2015 were followed to 2016. Data were from the LT registry, pathology database and patient records. 124 patients were included in the analysis. Study subgroups were acute autoimmune hepatitis (AIH) (n=25), known non-AIH etiology (n=54), and unknown etiology (n=45). Results The unknown etiology group differed from the known non-AIH group with regard to the following pretransplant autoimmunity-associated features: positive pANCA (35% vs 8%; P=0.02), higher mean IgA (3.2±1.7 vs 2.1±1.4, P=0.006) and IgG (12.7±4.3 vs 8.5±3.6, P=0.001). AIH-associated HLA haplotypes B8, DR3 and B8DR3 were more common in the AIH group (40%, 44% and 36%) and in the unknown group (29%, 33% and 29%) than in the known non-AIH group (11%, 17% and 11%) or in the Finnish general population (17%, 18% and 8%). However, these findings had no association with protocol biopsies, extrahepatic autoimmune diseases or survival. Patients with ≥1 rejection episode had higher pretransplant IgA (3.7±2.3 vs 2.6±1.2, P=0.02) and IgG (16.4±10.2 vs 12.4±6.8, P=0.03) than those without rejections. Conclusions Autoimmunity-associated pretransplant laboratory findings and HLA haplotypes were common in ALF of unknown etiology, but showed minimal predictive value for post-transplant biopsy findings, clinical complications or survival.Peer reviewe

Immune activation in the small intestine in patients with rheumatoid arthritis

Objectives: To determine whether inflammation in the gut associated immune system is activated in rheumatoid arthritis ( RA). The expression of chemokine receptor- (CCR4, CCR5) and cytokine- ( interleukin (IL) 2, IL10, interferon gamma (IFNgamma), tumour necrosis factor alpha (TNFalpha), and transforming growth factor beta (TGFbeta)) specific mRNA in intestinal biopsy samples from patients with RA was examined. Methods: Duodenal biopsy samples from 13 patients with RA and 15 control subjects were studied. The mRNA expression of CCR4, CCR5, IL2, IL10, IFNgamma, TNFalpha, and TGFb in intestinal biopsy samples was demonstrated by real time quantitative reverse transcriptase-polymerase chain reaction. Results: The mRNA expression of CCR4, CCR5, and IL10 in intestinal biopsy samples was increased in patients with RA in comparison with control subjects ( p = 0.001, p = 0.046, p = 0.019). No difference in the expression levels of IL2, IFNgamma, TNFalpha, or TGFbeta was seen between patients with RA and controls. Conclusions: The increased intestinal mRNA expression of IL10, CCR5, and CCR4 suggests that gut associated immune cells are activated in patients with RA.Peer reviewe

Multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis.

Objective: Interferon (IFN) beta has repeatedly shown benefit in multiple sclerosis (MS) in reducing the rate of relapse, the disease activity as shown with magnetic resonance imaging and, to some degree, the progression of disability; however, it is unknown how much the therapeutic response depends on the dose, the subgroup involved, and the disease stage. This multicentre, double blind, placebo controlled study explored the dose–response curve by examining the clinical benefit of low dose IFN beta-1a (Rebif®), 22 µg subcutaneously once weekly, in patients with secondary progressive MS. Methods: A total of 371 patients with clinically definite SPMS were randomised to receive either placebo or subcutaneous IFN beta-1a, 22 µg once weekly, for 3 years. Clinical assessments were performed every 6 months. The primary outcome was time to sustained disability, as defined by time to first confirmed 1.0 point increase on the Expanded Disability Status Scale (EDSS). Secondary outcomes included a sensitive disability measure and relapse rate. Results: Treatment had no beneficial effect on time to confirmed progression on either the EDSS (hazard ratio (HR) = 1.13; 95% confidence interval (CI) 0.82 to 1.57; p = 0.45 for 22 µg v placebo) or the Regional Functional Status Scale (HR = 0.93; 95% CI 0.68 to 1.28; p = 0.67). Other disability measures were also not significantly affected by treatment. Annual relapse rate was 0.27 with placebo and 0.25 with IFN (rate ratio = 0.90; 95% CI 0.64 to 1.27; p = 0.55). The drug was well tolerated with no new safety concerns identified. No significant gender differences were noted. Conclusions: This patient population was less clinically active than SPMS populations studied in other trials. Treatment with low dose, IFN beta-1a (Rebif®) once weekly did not show any benefit in this study for either disability or relapse outcomes, including a subgroup with preceding relapses. These results add a point at one extreme of the dose–response spectrum of IFN beta therapy in MS, indicating that relapses in this phase may need treatment with higher doses than in the initial phases

Defining Primary Sclerosing Cholangitis : Results From an International Primary Sclerosing Cholangitis Study Group Consensus Process COMMENT

Peer reviewe

Accumulation of 99mTc-low-density lipoprotein in human malignant glioma.

Low-density lipoprotein (LDL) uptake in gliomas was studied to find out if LDL has potential as a drug carrier of boron, especially for boron neutron capture therapy. Single photon emission tomography (SPET) was performed 2 h and 20 h after intravenous injection of autologous 99mTc-labelled LDL in four patients with untreated and five patients with recurrent glioma. 99mTc-LDL uptake was compared with the uptake of 99mTc-labelled human serum albumin (HSA), an established blood pool marker. The intra- and peritumoral distributions of radioactivity in the SPET images were not identical for radiolabelled LDL and HSA. The mean LDL tumour to brain ratio, determined from transversal SPET slices at 20 h post injection, was 1.5 in untreated and 2.2 in recurrent gliomas; the corresponding ratios for HSA were 1.6 and 3.4. The brain to blood ratio remained constant at 2 h and 20 h in both types of tumours. These data are not consistent with highly selective, homogeneous uptake of LDL in gliomas. However, the different tumoral distribution and rate of uptake of 99mTc-LDL, as compared with 99mTc-HSA, indicate that the uptake of LDL is different from that of HSA and that further studies on the mechanism of LDL uptake in glioma are warranted

A placebo-controlled randomised trial of budesonide for PBC following an insufficient response to UDCA

Background & Aims: In patients with primary biliary cholangitis (PBC), the efficacy of budesonide, a synthetic corticosteroid displaying high first-pass metabolism, is unresolved. In a placebo-controlled, double-blind trial, we evaluated the added-value of budesonide in those with PBC and ongoing risk of progressive disease despite ursodeoxycholic acid (UDCA) treatment. Methods: We evaluated 62 patients with PBC who had histologically confirmed hepatic inflammatory activity, according to the Ishak score, and an alkaline phosphatase (ALP) >1.5x upper limit of normal (ULN), after at least 6 months of UDCA therapy. Participants were randomly assigned 2:1 to receive budesonide (9 mg/day) or placebo once daily, for 36 months, with UDCA treatment (12-16 mg/kg body weight/day) maintained. Primary efficacy was defined as improvement of liver histology with respect to inflammation and no progression of fibrosis. Secondary outcomes included changes in biochemical markers of liver injury. Results: Recruitment challenges resulted in a study that was underpowered for the primary efficacy analysis. Comparing patients with paired biopsies only (n = 43), the primary histologic endpoint was not met (p>0.05). The proportion of patients with ALP = 15% decrease in ALP and normal bilirubin was higher in the budesonide group than in the placebo group at 12, 24, and 36 months (p Conclusion: Budesonide add-on therapy was not associated with improved liver histology in patients with PBC and insufficient response to UDCA; however, improvements in biochemical markers of disease activity were demonstrated in secondary analyses. Lay summary: Around one-third of patients with primary biliary cholangitis (PBC) needs additional medical therapy alongside ursodeoxycholic acid (UDCA) treatment. In this clinical trial, the addition of the corticosteroid budesonide did not improve liver histology; there were however relevant improvements in liver blood tests. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V.Peer reviewe

Early and accurate detection of cholangiocarcinoma in patients with primary sclerosing cholangitis by methylation markers in bile

Background and Aims Primary sclerosing cholangitis (PSC) is associated with increased risk of cholangiocarcinoma (CCA). Early and accurate CCA detection represents an unmet clinical need as the majority of patients with PSC are diagnosed at an advanced stage of malignancy. In the present study, we aimed at establishing robust DNA methylation biomarkers in bile for early and accurate diagnosis of CCA in PSC. Approach and Results Droplet digital PCR (ddPCR) was used to analyze 344 bile samples from 273 patients with sporadic and PSC-associated CCA, PSC, and other nonmalignant liver diseases for promoter methylation of cysteine dioxygenase type 1, cannabinoid receptor interacting protein 1, septin 9, and vimentin. Receiver operating characteristic (ROC) curve analyses revealed high AUCs for all four markers (0.77-0.87) for CCA detection among patients with PSC. Including only samples from patients with PSC diagnosed with CCA 36 months) as controls, and remained high (83%) when only including patients with PSC and dysplasia as controls (n = 23). Importantly, the bile samples from the CCA-PSCPeer reviewe

Functional Profiling of FSH and Estradiol in Ovarian Granulosa Cell Tumors

Adult-type granulosa cell tumors (AGCTs) are sex-cord derived neoplasms with a propensity for late relapse. Hormonal modulators have been used empirically in the treatment of recurrent AGCT, albeit with limited success. To provide a more rigorous foundation for hormonal therapy in AGCT, we used a multi-modal approach to characterize the expressions of key hormone biomarkers in 175 tumor specimens and 51 serum samples using RNA sequencing, immunohistochemistry, RNA in situ hybridization, quantitative PCR, and circulating biomarker analysis, and correlated these results with clinical data. We show that FSH receptor and estrogen receptor beta (ER beta) are highly expressed in the majority of AGCTs, whereas the expressions of estrogen receptor alpha (ER alpha) and G-protein coupled estrogen receptor 1 are less prominent. ER beta protein expression is further increased in recurrent tumors. Aromatase expression levels show high variability between tumors. None of the markers examined served as prognostic biomarkers for progression-free or overall survival. In functional experiments, we assessed the effects of FSH, estradiol (E2), and the aromatase inhibitor letrozole on AGCT cell viability using 2 in vitro models: KGN cells and primary cultures of AGCT cells. FSH increased cell viability in a subset of primary AGCT cells, whereas E2 had no effect on cell viability at physiological concentrations. Letrozole suppressed E2 production in AGCTs; however, it did not impact cell viability. We did not find preclinical evidence to support the clinical use of aromatase inhibitors in AGCT treatment, and thus randomized, prospective clinical studies are needed to clarify the role of hormonal treatments in AGCTs. (C) Endocrine Society 2020.Peer reviewe

Aivojen magneettikuvaus MS-taudin immunologisen hoidon seurannassa

Aivojen magneettikuvaus (MK) osoittaa MS-taudin aktiivisuuden herkemmin kuin kliiniset relapsit, minkä vuoksi hoidossa käytettävän immunologisen hoitovasteen arvion tulee perustua kliiniseen taudinkuvaan ja aivojen kuvantamiseen. MK-seurantaan tarvitaan T2-, flair- ja T1-painotteiset kuvat, gadolinium-tehostaminen ja atrofian arviointi. Ensilinjan immunologisessa hoidossa ensimmäinen MK otetaan 6-12 kuukauden kuluttua lääkehoidon aloituksesta. Jos silloin havaitaan uusia muutoksia, seuraava kuvantaminen tehdään 1-2 vuoden kuluttua. Huonoa hoitovastetta vaikuttaa kuvaavan se, jos 6-12 kuukauden kuluttua hoidon aloituksessa tehdyssä magneettikuvassa esiintyy uusia (yli 4) tai kasvavia T2-painotteisia tulehduspesäkkeitä. Huonosta hoitovasteesta kertoo myös gadoliniumilla tehostuvien muutosten esiintyminen seurannan aikana. Tällöin suositellaan hoidon tehostamista, vaikka pahenemisvaiheita ei olisi esiintynyt. Fingolimodihoidossa seurantakuvaukset tehdään 6-12 kuukauden kuluttua hoidon aloituksesta ja 1-2 vuoden kuluttua tämän jälkeen. Alemtutsumabi- ja natalitsumabihoidossa kuvaukset ajoitetaan vuoden ja kahden vuoden päähän hoidon aloituksesta