HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1.

The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.

Plant functional trait response to environmental drivers across European temperate forest understorey communities.

Functional traits respond to environmental drivers, hence evaluating trait-environment relationships across spatial environmental gradients can help to understand how multiple drivers influence plant communities. Global-change drivers such as changes in atmospheric nitrogen deposition occur worldwide, but affect community trait distributions at the local scale, where resources (e.g. light availability) and conditions (e.g. soil pH) also influence plant communities. We investigate how multiple environmental drivers affect community trait responses related to resource acquisition (plant height, specific leaf area (SLA), woodiness, and mycorrhizal status) and regeneration (seed mass, lateral spread) of European temperate deciduous forest understoreys. We sampled understorey communities and derived trait responses across spatial gradients of global-change drivers (temperature, precipitation, nitrogen deposition, and past land use), while integrating in-situ plot measurements on resources and conditions (soil type, Olsen phosphorus (P), Ellenberg soil moisture, light, litter mass, and litter quality). Among the global-change drivers, mean annual temperature strongly influenced traits related to resource acquisition. Higher temperatures were associated with taller understoreys producing leaves with lower SLA, and a higher proportional cover of woody and obligate mycorrhizal (OM) species. Communities in plots with higher Ellenberg soil moisture content had smaller seeds and lower proportional cover of woody and OM species. Finally, plots with thicker litter layers hosted taller understoreys with larger seeds and a higher proportional cover of OM species. Our findings suggest potential community shifts in temperate forest understoreys with global warming, and highlight the importance of local resources and conditions as well as global-change drivers for community trait variation.

Long-term follow-up of antiviral combination therapy in chronic hepatitis B.

For patients with chronic hepatitis B e (HBe)-positive hepatitis, long-term results of pilot studies with lymphoblastoid interferon-alpha, acyclovir, or a combination, and of a randomized controlled trial of interferon/desciclovir combination therapy are presented. HBe seroconversion was observed in more than 40 percent of patients treated with combination therapy, 30 percent with interferon therapy, 18 percent with acyclovir, and 0 percent with no treatment. HBe reactivation occurred in two patients with cirrhosis. Hepatitis B surface seroconversion followed HBe seroconversion in 11 to 30 percent of treated patients. HBe seroconversion was significantly related to initial low levels of viral replication and to transient aminotransferase elevation during the second half of the interferon treatment of 16 weeks. Clinical improvement and persistent normalization of aspartate aminotransferase was observed in all patients with HBe seroconversion. Conversion to a state of virus latency (HBe negative) mostly occurred after therapy, suggesting that the specific immunologic host response had been brought about by the suppression of virus replication through antiviral agents. Recommendations for selection of patients for antiviral combination therapy are made on the basis of these long-term results.

Wood structural differences between northern and southern beech provenances growing at a moderate site.

Planting provenances originating from southern to northern locations has been discussed as a strategy to speed up species migration and mitigate negative effects of climate change on forest stability and productivity. Especially for drought-susceptible species such as European beech (Fagus sylvatica L.), the introduction of drought-tolerant provenances from the south could be an option. Yet, beech has been found to respond plastically to environmental conditions, suggesting that the climate on the plantation site might be more important for tree growth than the genetic predisposition of potentially drought-adapted provenances. In this study, we compared the radial growth, wood-anatomical traits and leaf phenology of four beech provenances originating from southern (Bulgaria, France) and northern locations (Sweden, the Netherlands) and planted in a provenance trial in the Netherlands. The distribution of precipitation largely differs between the sites of origin. The northern provenances experience a maximum and the southern provenances experience a minimum of rainfall in summer. We compared tree productivity and the anatomy of the water-conducting system for the period from 2000 to 2010, including the drought year 2003. In addition, tree mortality and the timing of leaf unfolding in spring were analysed for the years 2001, 2007 and 2012. Comparison of these traits in the four beech provenances indicates the influence of genetic predisposition and local environmental factors on the performance of these provenances under moderate site conditions. Variation in radial growth was controlled by environment, although the growth level slightly differed due to genetic background. The Bulgarian provenance had an efficient water-conducting system which was moreover unaffected by the drought in 2003, pointing to a high ability of this provenance to cope well with dry conditions. In addition, the Bulgarian provenance showed up as most productive in terms of height and radial growth. Altogether, we conclude that the similarity in ring-width variation among provenances points to environmental control of this trait, whereas the differences encountered in wood-anatomical traits between the well-performing Bulgarian provenance and the other three provenances, as well as the consistent differences in flushing pattern over 3 years under various environmental conditions, support the hypothesis of genetic control of these features.

The role of mycophenolate mofetil in the management of autoimmune hepatitis and overlap syndromes.

BACKGROUND: Treatment failure occurs in 20% of autoimmune hepatitis patients on prednisolone and azathioprine (AZA). There is no established second line treatment. AIM: To assess the efficacy of mycophenolate mofetil as second line treatment after AZA-intolerance or AZA-nonresponse in autoimmune hepatitis and overlap syndromes. METHODS: Consecutive patients from the Dutch Autoimmune Hepatitis Group cohort, consisting of 661 patients, with autoimmune hepatitis or overlap syndromes, AZA-intolerance or AZA-nonresponse and past or present use of mycophenolate mofetil were included. Primary endpoint of mycophenolate mofetil treatment was biochemical remission. Secondary endpoints were biochemical response (without remission), treatment failure and prevention of disease progression. RESULTS: Forty-five patients treated with mycophenolate mofetil were included. In autoimmune hepatitis remission or response was achieved in 13% and 27% in the AZA-nonresponse group compared to 67% and 0% in the AZA-intolerance group (P = 0.008). In overlap-syndromes remission or response was reached in 57% and 14% in the AZA-nonresponse group and 63% and 25% of the AZA-intolerance group (N.S.); 33% had side effects and 13% discontinued mycophenolate mofetil. Overall 38% had treatment failure; this was 60% in the autoimmune hepatitis AZA-nonresponse group. Decompensated liver cirrhosis, liver transplantations and death were only seen in the autoimmune hepatitis AZA-nonresponse group (P < 0.001). CONCLUSIONS: Mycophenolate mofetil induced response or remission in a majority of patients with autoimmune hepatitis and azathioprine-intolerance and with overlap syndromes, irrespective of intolerance or nonresponse for azathioprine. In autoimmune hepatitis with azathioprine nonresponse mycophenolate mofetil is less often effective.

Cyclical etidronate in the prevention of bone loss in corticosteroid-treated primary biliary cirrhosis. A prospective, controlled pilot study.

BACKGROUND: Recently, promising disease modifying effects of low dose corticosteroid treatment in primary biliary cirrhosis have been reported. However, steroid-induced bone loss constitutes a potential drawback of this treatment option. AIM: To assess whether etidronate can reduce bone loss during corticosteroid treatment. METHODS: Twelve primary biliary cirrhosis patients (all Child-Pugh Class A), treated with prednisone in the context of a 1-year placebo-controlled pilot study with prednisone (maintenance dose 10 mg daily), and azathioprine (50 mg daily), were randomized to receive either cyclical etidronate (400 mg daily, during 2 weeks) alternated with calcium 500 mg daily during 11 weeks or calcium alone. All patients had been receiving ursodeoxycholic acid during at least 1 year and this treatment was continued. Bone mass was measured in the lumbar spine and the femoral neck by dual energy X-ray absorptiometry before and after 3 and 12 months of treatment. Markers of bone formation (serum osteocalcin, procollagen-I-propeptide) and bone resorption (urinary deoxypyridinoline and calcium) were also monitored. RESULTS: The mean lumbar bone mineral density did not significantly change in the patients taking etidronate + calcium, in contrast to patients treated with calcium alone (+0.4 vs. -3.0%; p = 0.01). Changes in femoral bone mineral density and markers of bone turnover did not significantly differ between both groups. No adverse effects of etidronate were noted. CONCLUSIONS: Cyclical etidronate appears to prevent bone loss associated with prednisone treatment in patients with primary biliary cirrhosis. These preliminary results encourage the further evaluation of long term prednisone treatment and concurrent bisphosphonate therapy in primary biliary cirrhosis.

Triple therapy with ursodeoxycholic acid, prednisone and azathioprine in primary biliary cirrhosis: a 1-year randomized, placebo-controlled study.

BACKGROUND/AIMS: Treatment with ursodeoxycholic acid has been shown to decrease the rate of disease progression in patients with primary biliary cirrhosis, although the effect is modest. Since primary biliary cirrhosis has many features of an autoimmune disorder, immunosuppressives added to ursodeoxycholic acid may be of value in the treatment of primary biliary cirrhosis. METHODS: A 1-year randomized, double-blind, placebo-controlled trial was carried out in 50 patients with primary biliary cirrhosis, who had already been treated with ursodeoxycholic acid for at least 1 year, but had not achieved complete disease remission. Patients were randomized to additional prednisone (30 mg per day initially, tapered to 10 mg daily after 8 weeks) and azathioprine (50 mg daily) or placebo. A subgroup of patients received cyclical etidronate and calcium. The principal aim of the study was to assess the short-term benefits and risks of the combined bile acid and low-dose immunosuppressive regimen. Primary endpoints were effects on symptoms, liver biochemistry, liver histology, bone mass and the occurrence of adverse events. RESULTS: Pruritus (p=0.02), alkaline phosphatase, aspartate aminotransferase, IgM and procollagen-III-propeptide improved significantly (all p<0.002) in the combined treatment group as compared to the placebo group. Histological scores for disease activity and disease stage decreased significantly within the combination treatment group (p<0.001). CONCLUSIONS: In patients with primary biliary cirrhosis receiving ursodeoxycholic acid, there is an additional beneficial effect of 1-year treatment with prednisone and azathioprine on symptoms and biochemical, fibrogenetic and histological parameters. These results strongly encourage the evaluation of this triple treatment regimen in long-term controlled trials of adequate size to document its effect on clinical events.