Do genetics contribute to TNF inhibitor response prediction in Psoriatic Arthritis?

Abstract

Psoriatic arthritis (PsA) is a heterogeneous chronic musculoskeletal disease, affecting up to 30% of people with psoriasis. Research into PsA pathogenesis has led to the development of targeted therapies, including Tumor Necrosis Factor inhibitors (TNF-i). Good response is only achieved by ~60% of patients leading to ‘trial and error’ drug management approaches, adverse reactions and increasing healthcare costs. Robust and well-validated biomarker identification, and subsequent development of sensitive and specific assays, would facilitate the implementation of a stratified approach into clinical care. This review will summarise potential genetic biomarkers for TNF-i (adalimumab, etanercept and infliximab) response that have been reported to date. It will also comment upon the importance of managing clinical confounders when understanding drug response prediction. Variants in multiple gene regions including TNF-A, FCGR2A, TNFAIP3, TNFR1/TNFR1A/TNFRSF1A, TRAIL-R1/TNFRSF10A, FCGR3A have been reported to correlate with TNF-i response at various levels of statistical significance in patients with PsA. However, results were often from heterogenous and underpowered cohorts and none are currently implemented into clinical practice. External validation of genetic biomarkers in large, well-documented cohorts is required, and assessment of the predictive value of combining multiple genetic biomarkers with clinical measures is essential to clinically embed pharmacogenomics into PsA drug management.

Psoriatic arthritis: the role of self-reported non-adherence, non-trough drug levels, immunogenicity and conventional synthetic DMARD co-therapy in adalimumab and etanercept response

“…Further work is needed to establish the full impact of smoking, and meanwhile clinicians should use interventions to encourage patients to stop smoking, with the aim of optimizing drug levels and response. In the present analysis, co-morbidities, including increased BMI, asthma and liver disease, in addition to disease duration and severity at baseline, were associated with decreased drug response, decreased drug levels and increased ADAb levels, as supported by previous rheumatic disease studies [ 8 , 14 , 30 , 36–38 ]. Of note, patients with liver disease might be more likely to develop ADAb owing to MTX being contraindicated in these individuals.…”

“…Up to 40% of patients experience a failure of first-line TNF-i therapy, increasing the risk of disease progression and health-care costs [ 6 , 7 ]. It is not currently possible to predict TNF-i response in PsA accurately, but it is thought to be multifactorial [ 8 ]. The identification and validation of robust biomarkers of response would be a major scientific breakthrough, paving the way to precision medicine approaches.…”

Response to anti-IL17 therapy in inflammatory disease is not strongly impacted by genetic background

“… 1 A common hypothesis is that heterogeneity in response reflects genetic differences between individuals or, relatedly, genetically distinct disease subtypes with different molecular etiologies. 2 If this hypothesis is true and genetic biomarkers for drug response can be identified, this could lead to new understanding of the biology of drug response or discovery of biomarkers to stratify subgroups of participants to specific treatments to increase response rates. 3 , 4 , 5 …”

Molecular profiling of clinical remission in psoriatic arthritis reveals dysregulation of FOS and CCDC50 genes: a gene expression study

“…To date, no successful models of TNFi prediction in PsA are available clinically ( 38 ), and the research field of biomarker discovery related to molecular remission achievement is only at an early stage ( 39 – 41 ). Whole-blood transcriptomic profiling performed in this study suggests that TNFi-induced clinical remission in PsA is similar to a healthy condition, but not identical, differing for a list of 125 transcripts and particularly for the FOS and CCDC50 gene expression amount.…”