Influence of Genetic Polymorphisms on Response to Biologics in Moderate-to-Severe Psoriasis

Abstract

Psoriasis is a chronic inflammatory skin pathology of autoimmune origin and unknown etiology. There are various therapies for treating it, including a wide range of biopharmaceuticals indicated in moderate-to-severe psoriasis. Depending on their therapeutic target, they are classified as tumor necrosis factor inhibitors (anti-TNF) or cytokine inhibitors (interleukin-12, 23, and 17 antagonists). Although they have proved effective and safe, in clinical practice, many patients show a short- and long-term suboptimal response and even varying degrees of toxicity. This variability in response may be influenced by genetic factors, such as polymorphisms in the genes involved in the pathological environment, metabolism or mechanism of action of the drug that could affect the effectiveness and toxicity of biological therapies. This review assesses pharmacogenetic studies of the impact of genetic factors on response to biopharmaceuticals and toxicity in patients diagnosed with moderate-to-severe psoriasis. The results suggest that polymorphisms detected in the HLA genes, in genes that encode cytokines (TNF, IL genes, TNFAIP3), transporters (PDE3A-SLCO1C1, SLC12A8), receptors (TNFRSF1B, CD84, FCGR2A and FCGR3A, IL17RA, IL23R, TLR genes, PGLYRP4) and associated proteins (TNFAIP3, LY96, TIRAP, FBXL19), as well as other genes implicated in the pathogenesis of psoriasis (CDKAL1, CARD14, PTTG1, MAP3K1, ZNF816A, GBP6, CTNNA2, HTR2A, CTLA4, TAP1) can be used in the future as predictive markers of treatment response and/or toxicity with biological therapies in patients diagnosed with moderate-to-severe psoriasis, tailoring treatment to the individual patient.

Dose Adjustment of Biologic Treatments for Moderate-to-Severe Plaque Psoriasis in the Real World: A Systematic Review

“…The frequent use of dose adjustment may also suggest a need to develop a more personalised therapeutic approach to the use of biologics, especially given the increasing number of treatment options. Several features have been shown to influence response to biologic therapy, including genetic, immune, and environmental factors [ 31 , 32 ]. In the future, it may be possible to assign patients with psoriasis to different anti-psoriatic drugs based on disease endotype and predictive biomarkers in order to reduce immunosuppressive-related side effects and maximise treatment efficacy.…”

Pharmacogenomics: An Update on Biologics and Small-Molecule Drugs in the Treatment of Psoriasis

“…However, the association studies reported conflicting results. In fact, the lack of association (p > 0.05) was described in Ps patients treated with ADA or ETN, whereas, the rs610604 and rs6920220 were associated (p = 0.041 and p = 0.025, respectively) with a good response to anti-TNF drugs [29,31].…”

“…ADA, INF, and CTL are indicated for the treatment of moderate-to-severe Ps. The efficacy of these monoclonal antibodies is influenced by different genetic variants located on the TNF-α gene [30,31]. To date, more than 200 genetic variants have been identified.…”

“…To date, more than 200 genetic variants have been identified. In particular, the polymorphisms TNF-308 (A/G, rs1800629), TNF-238 (G/A, rs361525), and TNF-857 (C/T, rs1799724) have been extensively investigated, either as risk or pharmacogenetic biomarkers [31]. The role of these SNPs has been evaluated in a meta-analysis that examined psoriatic patients treated with ETN, ADA, and INF, showing controversial results [32].…”

“…Another gene involved in the metabolism of anti-TNF drugs is IL-6 (7p15.3). The GG genotype of SNP rs1800795 (C/G/T) may influence the response to anti-TNF drugs, showing a worse response [29,31,33].…”