Biomarcadores predictores de respuesta y toxicidad al tratamiento con terapias biológicas en pacientes diagnosticados con enfermedad psoriásica

Abstract

Psoriasis is an autoimmune skin disease with a prevalence between 2-4%. It is characterized by the development of lesions in the form of erythematous plaques with whitish scales on the scalp, elbows, knees and back, mainly. In addition, it is associated with other potentially disabling pathologies. Consequently, psoriasis is considered a systemic pathology with a great impact on the quality of life of patients and generates high health costs. Genetic, immunological and environmental factors can trigger psoriatic lesions, which are maintained by alterations in cutaneous immune responses. In this process, dendritic cells activated by Toll-like receptors interfere, producing a cytokine cascade [TNF and interleukins (IL) IL-12, IL-17 and IL-23] that activates the hyperproliferation of keratinocytes in the epidermis and leads to the appearance of epidermal hyperplasia, typical of psoriasis lesions. The treatment of moderate-severe psoriasis is based mainly on biological therapies (BT). The first-line biologicals are inhibitors of tumor necrosis factor, known as “anti-TNF” [infliximab (INF), etanercept (ETN), adalimumab (ADA) and certolizumab (CTL)] and the inhibitor of the p40 subunit of IL12 and IL23 [ustekinumab (UTK)]. In addition, as a last option of treatment there are drugs inhibiting IL17 and IL23, authorized more recently. Anti-TNF and UTK drugs have proven to be highly effective and safe. However, not all patients achieve good results, loss of efficacy is the main reason for change or “switching” of BT (in the long term, especially). This implies a great economic burden for health systems, hindering medical decision-making and worsening the quality of life of patients. Genetic factors may be involved in the variability of pharmacological survival of BT in psoriatic patients. Numerous pharmacogenetic studies in patients with psoriasis treated with BT (specifically, anti- TNF and UTK) have been carried out to find biomarkers predicting efficacy and/or toxicity. So far it has been found that allelic variants and single nucleotide polymorphisms (SNPs) in human leukocyte antigen (HLA) genes, which collaborate identifying exogenous proteins and can trigger the immune response, could be associated with the response to BT. Likewise, SNPs in genes encoding proteins directly involved in the cytokine cascade (TNF and IL-1, IL-6, IL-12 and IL-17) or receptors that regulate or trigger this cytokine cascade, typical of psoriasis (CD84, FCGR, IL17RA, IL23R, SLC and TLR) have been shown to have an impact on the response of BT. Despite knowing the possible impact of the biomarkers mentioned above, it is currently not possible to translate this information into routine clinical practice of psoriasis due to the lack of scientific evidence. Therefore, it is necessary to study and confirm the effect of functional genetic polymorphisms in more studies so that they can be established as biomarkers predicting response to BT indicated in moderate-severe psoriasis. HYPOTHESIS Certain genetic polymorphisms involved in the pathogenesis of psoriasis and the target of biologic drugs that inhibit TNF or IL12 and 23 may influence the interindividual variability in response to these drugs in patients with moderate-severe psoriasis. Therefore, it is essential to study and validate the utility of these genetic polymorphisms as predictive biomarkers of drug retention in psoriasis, enabling the implementation of personalised medicine. OBJECTIVES Main objective To assess the impact of immunogenetic factors as prognostic and predictive biomarkers of response to biologic therapy in patients with moderate-severe psoriasis, specifically anti-TNF and IL12/23 inhibitors. Specific objectives • To determine the role of genetic polymorphisms involved in the response of patients diagnosed with moderate-severe psoriasis treated with anti-TNF and UTK drugs. • To assess drug survival of anti-TNF and UTK in Caucasian patients diagnosed with moderate-severe psoriasis, and the reasons for discontinuing TB therapy. • To evaluate the association between functional genetic polymorphisms and the longterm efficacy of biological treatment, as measured by pharmacological survival of anti- TNF and UTK. MATERIALS AND METHODS We conducted an ambispective cohort study of 379 therapeutic lines [anti-TNF (n = 247) and UTK (n = 132)] from 198 Caucasian patients with moderate-severe psoriasis in southern Spain and Italy [Hospital Universitario Virgen de las Nieves (HUVN) and Centro Hospitalario- Universitario Policlínico Umberto I (PUI)]. Sociodemographic and clinical variables were obtained from the review of patients' medical records and personal interviews. DNA samples were collected by buccal swab or blood and extracted using a DNA extraction kit from saliva or blood. Subsequently, 29 genetic polymorphisms were analysed by real-time PCR with TaqMan® probes: HLA-B/MICA (rs13437088), HLA-C (rs12191877), TNF-238 (rs361525), TNF-857 (rs1799724), TNF-308 (rs1800629), TNF-1031 (rs1799964), TNFRSF1B (rs1061622), TNFAIP3 (rs610604), IL1B (rs1143623 and rs1143627), IL6 (rs1800795), IL12B (rs3213094 and rs2546890), TIRAP (rs8177374), PGLYR4-24 (rs2916205), CDKAL1 (rs6908425), CD84 (rs6427528), IL17RA (rs4819554), IL23R (rs11209026), TLR2 (rs4696480 and rs11938228), TLR5 (rs5744174), TLR9 (rs352139), PDE3A (rs11045392), SLCO1C1 (rs3794271), FCGR2A (rs1801274), FCGR3A (rs396991), LY96 (rs11465996) and BCL2 (rs59532114). The effect of these functional genetic polymorphisms on anti-TNF and UTK drug survival was evaluated using R 3.5 software by applying the following statistical methods: chi-square test, Fisher's test and survival analysis by Cox regression and Kaplan-Meier regression method. RESULTS Multivariate Cox regression analysis showed that patients carrying the T allele of the HLA-C polymorphism rs12191877 (HR=0.560; 95%CI=0.40-0.78; p=0.0006) and the C allele of the TNF- 1031 polymorphism rs1799964 (HR=0.707; 95%CI=0.50-0.99; p=0.048) are associated with longer survival to anti-TNF drugs in our population (Table 1). In contrast, patients carrying the G allele of the TLR5 rs5744174 polymorphism (HR=0.589; 95%CI=0.37-0.92; p=0.02), the GG genotype for the CD84 rs6427528 polymorphism (HR=0.557; 95%CI=0.35-0.88; p=0. 013), and the T allele of the PDE3A rs11045392 polymorphism, which is in linkage disequilibrium with the SLCO1C1 rs3794271 polymorphism (HR=0.508; 95%CI=0.32- 0.79; p=0.002), had increased drug survival to UTK (Table 2). However, we observed no association between CDKAL1 (rs6908425), FCGR2A (rs1801274), FCGR3A (rs396991), HLA B/MICA(rs13437088), IL1B (rs1143623), IL6 (rs1800795), IL12B (rs3213094 and rs2546890) genetic polymorphisms, IL17RA (rs4819554), IL23R (rs11209026), PGLYR4-24 (rs2916205), TIRAP (rs8177374), TLR2 (rs4696480 and rs11938228), TLR9 (rs352139), TNF-857 (rs1799724), TNFAIP3 (rs610604), TNFRSF1B (rs1061622) and TB survival included in this study. In addition, the median TB duration was 24 months (9-51.5), with UTK showing the longest survival (Plong rank=0.07, 36 months vs. 24). Specifically, patients treated with anti-TNF had 1.32 higher risk of discontinuation than those treated with UTK (HR=1.32; 95%CI=1.02-1.7; p=0.0316). Loss of efficacy was the main reason for discontinuation (n=188; 67.14%), followed by the adverse events (n=55; 19.64%). Patients treated with UTK had 1.9 higher risk of discontinuation due to lack of efficacy (OR=1.895; 95%CI=1.05-3.52; p=0.024) than patients treated with anti- TNF drugs. CONCLUSIONS I. The median TB duration in the study was 24 months (9-51.5), with UTK showing the longest survival and anti-TNF-treated patients having the highest risk of biologic therapy discontinuation. The main reason for TB discontinuation or switching was loss of efficacy, followed by adverse events. II. The T allele of the HLA-C rs12191877 polymorphism and the C allele of the TNF-1031 rs1799964 polymorphism were associated with longer survival to anti-TNF drugs. This suggests that variants of the wild-type alleles in the HLA-C rs12191877 (C>T) and TNF- 1031 rs1799964 (T>C) genetic polymorphisms may modify these proteins, and thus reduce cytokine production and monocyte or T-cell activation, enhancing the effect of anti-TNF drugs and improving drug survival. III. We observed an association between UTK survival and the TLR5 rs5744174-G, CD84 rs6427528-A and PDE3A rs11045392 gene polymorphisms, along with SLCO1C1 rs3794271-T. Therefore, variations in the genes encoding receptors involved in the activation or signalling of the immune response typical of psoriasis may decrease the cytokine cascade and reinforce the effect of the IL-12/23 inhibitor drug, UTK, improving its survival. IV. No association was found between the genetic polymorphisms CDKAL1 (rs6908425), FCGR2A (rs1801274), FCGR3A (rs396991), HLA-B/MICA(rs13437088), IL1B (rs1143623), IL6 (rs1800795), IL12B (rs3213094 and rs2546890), IL17RA (rs4819554), IL23R (rs11209026), PGLYR4-24 (rs2916205), TIRAP (rs8177374), TLR2 (rs4696480 and rs11938228), TLR9 (rs352139), TNF-857 (rs1799724), TNFAIP3 (rs610604), TNFRSF1B (rs1061622) and TB survival included in this study. Overall conclusion, these results identify potential predictive biomarkers of pharmacological survival to different TBs in patients with moderate-severe psoriasis, useful for personalised medicine, allowing appropriate decision-making for each patient, saving healthcare costs and improving disease progression and patient quality of life.