Catherine O'Doherty

Folate and methionine metabolism in autism: a systematic review

BACKGROUND Autism is a complex neurodevelopmental disorder that is increasingly being recognized as a public health issue. Recent evidence has emerged that children with autism may have altered folate or methionine metabolism, which suggests the folate-methionine cycle may play a key role in the etiology of autism. OBJECTIVE The objective was to conduct a systematic review to examine the evidence for the involvement of alterations in folate-methionine metabolism in the etiology of autism. DESIGN A systematic literature review was conducted of studies reporting data for metabolites, interventions, or genes of the folate-methionine pathway in autism. Eighteen studies met the inclusion criteria, 17 of which provided data on metabolites, 5 on interventions, and 6 on genes and their related polymorphisms. RESULTS The findings of the review were conflicting. The variance in results can be attributed to heterogeneity between subjects with autism, sampling issues, and the wide range of analytic techniques used. Most genetic studies were inadequately powered to provide more than an indication of likely genetic relations. CONCLUSIONS The review concluded that further research is required with appropriately standardized and adequately powered study designs before any definitive conclusions can be made about the role for a dysfunctional folate-methionine pathway in the etiology of autism. There is also a need to determine whether functional benefits occur when correcting apparent deficits in folate-methionine metabolism in children with autism.

The potential role of the antioxidant and detoxification properties of glutathione in autism spectrum disorders: a systematic review and meta-analysis

BackgroundGlutathione has a wide range of functions; it is an endogenous anti-oxidant and plays a key role in the maintenance of intracellular redox balance and detoxification of xenobiotics. Several studies have indicated that children with autism spectrum disorders may have altered glutathione metabolism which could play a key role in the condition.MethodsA systematic literature review and meta-analysis was conducted of studies examining metabolites, interventions and/or genes of the glutathione metabolism pathways i.e. the γ-glutamyl cycle and trans-sulphuration pathway in autism spectrum disorders.ResultsThirty nine studies were included in the review comprising an in vitro study, thirty two metabolite and/or co-factor studies, six intervention studies and six studies with genetic data as well as eight studies examining enzyme activity.ConclusionsThe review found evidence for the involvement of the γ-glutamyl cycle and trans-sulphuration pathway in autistic disorder is sufficiently consistent, particularly with respect to the glutathione redox ratio, to warrant further investigation to determine the significance in relation to clinical outcomes. Large, well designed intervention studies that link metabolites, cofactors and genes of the γ-glutamyl cycle and trans-sulphuration pathway with objective behavioural outcomes in children with autism spectrum disorders are required. Future risk factor analysis should include consideration of multiple nutritional status and metabolite biomarkers of pathways linked with the γ-glutamyl cycle and the interaction of genotype in relation to these factors.

Pharmacogenomics of interferon beta and glatiramer acetate response: A review of the literature

Multiple sclerosis (MS) is one of the most common inflammatory and degenerative autoimmune diseases of the central nervous system with considerable heterogeneity in all aspects, including response to therapy. A number of disease modifying drugs, including traditional first line agents such as, interferon-beta (IFN-β) and glatiramer acetate (GA) are available for disease management. However, a considerable number of patients fail to achieve adequate response at therapeutic doses of IFN-β or GA. This variability in response to treatment has prompted the search for prognostic markers in order to personalize and optimize therapy so as to treat MS more efficiently. This review will summarize the existing literature examining the pharmacogenomics of IFN-β and GA response in MS patients.

Polymorphisms in cytochrome P450 2C19 enzyme and cessation of leflunomide in patients with rheumatoid arthritis

IntroductionRational selection of disease modifying anti-rheumatic drugs in the treatment of rheumatoid arthritis (RA) has many potential advantages, including rapid disease control, reduced long-term disability and reduced overall cost to the healthcare system. Inter-individual genetic differences are particularly attractive as markers to predict efficacy and toxicity, as they can be determined rapidly prior to drug selection. The aims of this study, therefore, were to investigate the association between differences in genes associated with the metabolism, clearance and efficacy of leflunomide with its cessation in a group of rheumatoid arthritis patients who were treated with an intensive contemporary, treat-to-target approach.MethodsThis retrospective cohort study identified all individuals who received leflunomide and were enrolled in the Early Arthritis inception cohort at the Royal Adelaide Hospital between 2001 and July 2011. Inclusion criteria were age (>18) and a diagnosis of rheumatoid arthritis. Patients were excluded if a DNA sample was not available, if they withdrew from the cohort or if clinical data were insufficient. Subjects were followed for 12 months or until either another disease modifying antirheumatic drug was added or leflunomide was ceased. The following single nucleotide polymorphisms (SNPs) were determined: CYP2C19*2 (rs4244285), CYP2C19*17 (rs12248560), ABCG2 421C>A (rs2231142), CYP1A2*1F (rs762551) and DHODH 19C>A (rs3213422). The effects of variables on cessation were assessed with Cox Proportional Hazard models.ResultsThirty-three of 78 (42.3%) patients ceased leflunomide due to side effects. A linear trend between cytochrome P450 2C19 (CYP2C19) phenotype and leflunomide cessation was observed, with poor and intermediate metabolizers ceasing more frequently (adjusted Hazard Ratio = 0.432 for each incremental change in phenotype, 95% CI 0.237 to 0.790, P = 0.006). Previously observed associations between cytochrome P450 1A2 (CYP1A2) and dihydro-orotate dehydrogenase (DHODH) genotype and toxicity were not apparent, but there was a trend for ATP-binding cassette sub-family G member 2 (ABCG2) genotype to be associated with cessation due to diarrhea.ConclusionsCYP2C19 phenotype was associated with cessation due to toxicity, and since CYP2C19 intermediate and poor metabolizers have lower teriflunomide concentrations, it is likely that they have a particularly poor risk:benefit ratio when using this drug.

IL7RA polymorphisms and chronic inflammatory arthropathies.

The C allele of a single nucleotide polymorphism (SNP), rs6897932, located in the interleukin-7 receptor alpha chain (IL7RA) was recently found to be associated with multiple sclerosis and Type I diabetes. We analysed 13 SNPs in the IL7RA gene in a combined cohort of patients with chronic inflammatory arthropathies (rheumatoid arthritis and juvenile idiopathic arthritis; 368 patients and 532 unaffected subjects). No significant associations with disease were found with the exception of the non-synonymous SNP rs6897932. This SNP showed modest enrichment of the TT genotype in arthritic patients compared with controls [P = 0.02; OR 1.72 (95% CI 1.08-2.75)]. Our data are suggestive for a role of rs6897932 in predisposition to chronic inflammatory arthropathies.

Pharmacokinetic evaluation of teriflunomide for the treatment of multiple sclerosis

Introduction: Teriflunomide is an immunomodulatory drug that received FDA approval for the treatment of relapsing forms of multiple sclerosis (MS) in September 2012. Its primary mode of action is inhibition of dihydroorotate dehydrogenase which inhibits the proliferation of activated T cells, but it also has a number of other actions that may be important contributors to its efficacy in MS. Areas covered: This review covers a basic pathophysiology of MS and the current treatment options, including a discussion of the needs for additional treatments. The main focus of the review is the pharmacokinetics and pharmacodynamics of teriflunomide, including a brief comparison with the disease-modifying antirheumatic drug leflunomide. The authors discuss the clinical efficacy and toxicity profile of teriflunomide and make some comparisons with treatments that are currently, or soon to be available. Expert opinion: While teriflunomide is no more effective than a number of other agents that are used in the treatment of MS, it has a favorable side-effect profile and the convenience of once a day oral administration. As such, it is likely to be a popular agent in the treatment of MS over the next 5 years.

Pharmacogenomics of NAT2 and ABCG2 influence the toxicity and efficacy of sulphasalazine containing DMARD regimens in early rheumatoid arthritis

Sulphasalazine (SSA) is a disease modifying anti-rheumatic drug (DMARD) that is commonly used to treat rheumatoid arthritis (RA). Plasma levels of SSA and its metabolite sulphapyridine are influenced by common polymorphisms in genes that encode N-acetyl transferase 2 (NAT2) and ATP-binding cassette protein G2 (ABCG2). Study participants had early RA that was treated with a combination DMARD regimen that included SSA. Toxicity was defined by cessation of SSA due to adverse effects and response as remission after 12 months of treatment. The effect of variables on toxicity was assessed by a Cox-proportional Hazard model and response by logistic regression. After correction for conventional variables, toxicity in 229 participants was influenced by NAT2 phenotype (hazard ratio=1.74 (95% confidence interval (CI) 1.01–3.21), P=0.044) and remission in 141 participants was associated with ABCG2 genotype (odds ratio=3.34 (95% CI 1.18–9.50), P=0.024). In our sample of early RA patients who were primarily treated with a combination of DMARDs, common variants in genes that encode NAT2 and ABCG2 were associated respectively with toxicity and response to SSA.

Semiphysiologically Based Pharmacokinetic Model of Leflunomide Disposition in Rheumatoid Arthritis Patients

A semiphysiologically based pharmacokinetic (semi‐PBPK) population model was used to evaluate the influence of enterohepatic recycling and protein binding, as well as the effect of genetic variability in CYP1A2, CYP2C19, and ABCG2, on the large interindividual variability of teriflunomide (active metabolite) concentrations following leflunomide administration in rheumatoid arthritis (RA) patients. The model was developed with total and free teriflunomide concentrations determined in RA patients taking leflunomide, as well as mean teriflunomide concentrations following the administration of leflunomide or teriflunomide extracted from the literature. Once developed, the 15‐compartment model was able to predict total and free teriflunomide concentrations and was used to screen demographic and genotypic covariates, of which only fat‐free mass and liver function (ALT) improved prediction. This approach effectively evaluated the effects of multiple covariates on both total and free teriflunomide concentrations, which have only been explored previously through simplistic one‐compartment models for total teriflunomide.

The rheumatoid arthritis susceptibility polymorphism PTPN22 C1858T is not associated with leflunomide response or toxicity

A common polymorphism (C1858T) in the gene that encodes the protein tyrosine phosphatase non‐receptor type 22 (PTPN22) is associated with altered T‐cell responses and increased susceptibility to rheumatoid arthritis (RA) and other autoimmune diseases. Teriflunomide, the active metabolite of leflunomide, reduces T‐cell responses through inhibition of tyrosine kinase p56LCK. We examined a potential association between PTPN22 genotype and response or toxicity to leflunomide in Caucasian RA patients taking leflunomide in combination with other disease‐modifying antirheumatic drugs (DMARDs).

Genetic polymorphism of CYP1A2 but not total or free teriflunomide concentrations is associated with leflunomide cessation in rheumatoid arthritis.

AIM Leflunomide, via its active metabolite teriflunomide, is used in rheumatoid arthritis (RA) treatment, yet approximately 20 to 40% of patients cease due to toxicity. The aim was to develop a time-to-event model describing leflunomide cessation due to toxicity within a clinical cohort and to investigate potential predictors of cessation such as total and free teriflunomide exposure and pharmacogenetic influences. METHODS This study included individuals enrolled in the Early Arthritis inception cohort at the Royal Adelaide Hospital between 2000 and 2013 who received leflunomide. A time-to-event model in nonmem was used to describe the time until leflunomide cessation and the influence of teriflunomide exposure and pharmacogenetic variants. Random censoring of individuals was simultaneously described. The clinical relevance of significant covariates was visualized via simulation. RESULTS Data from 105 patients were analyzed, with 34 ceasing due to toxicity. The baseline dropout hazard and baseline random censoring hazard were best described by step functions changing over discrete time intervals. No statistically significant associations with teriflunomide exposure metrics were identified. Of the screened covariates, carriers of the C allele of CYP1A2 rs762551 had a 2.29 fold increase in cessation hazard compared with non-carriers (95% CI 2.24, 2.34, P = 0.016). CONCLUSIONS A time-to-event model described the time between leflunomide initiation and cessation due to side effects. The C allele of CYP1A2 rs762551 was linked to increased leflunomide toxicity, while no association with teriflunomide exposure was identified. Future research should continue to investigate exposure-toxicity relationships, as well as potentially toxic metabolites.