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.

Putting recommendations into practice: Australian rheumatologists' opinions on leflunomide use in rheumatoid arthritis.

Leflunomide is the most recently introduced conventional disease-modifying anti-rheumatic drugs in Australia. It has several unique methods for initiation, unique monitoring recommendations and a distinctive cessation protocol in the event of serious toxicity. The aim of this study was to evaluate initiation and monitoring practices of Australian rheumatologists using leflunomide. A survey was emailed twice, approximately 3 months apart to 332 rheumatologist members of the Australian Rheumatology Association. Wave analysis was used to assess evidence of non-response bias. The response rate to the survey was 20% and there was no difference between the responses of waves 1 and 2. Fifty percent of the respondents indicated that 20 mg once daily was the initial dose of leflunomide that they most commonly prescribed, 45% indicated 10 mg once daily, whilst only 3% preferred to initiate leflunomide at 100 mg daily for 2-3 days followed by 10 mg once a day as recommended when first marketed. Of the responders, 12% had used doses above 20 mg daily and 70% had used alternate daily dosing with leflunomide. In a patient taking leflunomide with an ALT or AST >3 times the ULN on two or more blood tests, 75% of responders indicated they would stop leflunomide immediately and 20% would follow cessation by administering a cholestyramine washout. The choice of initial leflunomide dose among responding Australian rheumatologists varied considerably, although most preferred not to use the loading dose. Despite the recommendation of clinical guidelines, the use of a cholestyramine washout procedure for hepatic toxicity is not universal.

Individualization of leflunomide dosing in rheumatoid arthritis patients.

Leflunomide is largely considered to be a second-line treatment option for rheumatoid arthritis (RA). Those who fail to respond, tend to progress to treatment with expensive biological agents, which can also be associated with serious toxicities. Optimizing leflunomide treatment to meet the needs of individuals would hence be beneficial in terms of patient outcomes and health care expenditure. In this respect, therapeutic drug monitoring (TDM) may be useful, as plasma concentrations of leflunomide's active metabolite, teriflunomide, correlate with response to treatment, but are highly variable between patients. A number of pharmacogenetic markers have also been identified that influence response and toxicity. Incorporation of these findings into clinical practice could facilitate more efficient use of leflunomide.

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

BACKGROUND: Glutathione 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. METHODS: A 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. RESULTS: Thirty 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. CONCLUSIONS: The 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.

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.