Pharmacogenetics of Patients Treated by Biologics Pilot Study

Introduction: The aim of the study is to evaluate influence of genetic variability in some proinflammatory genes on efficacy of adalimumab therapy in patients of psoriasis and on psoriasis development in patients with other autoimmune diseases treated by different biologics. Methods: In the study, three patients with biologics were compared: 11 patients with psoriasis with finished treatment with adalimumab (A), 14 patients with psoriasis successfully treated by adalimumab (B), and 12 patients with other diagnosis treated by biologics with development of psoriasis (group C, 1 patient with hidradenitis suppurativa, 4 patients with m. Crohn, 3 patients with ulcerative colitis, 3 cases with ankylosing spondylitis, 1 patient with rheumatoid arthritis). These patients were treated by different biologics. In all patients, several polymorphisms in proinflammatory genes (I/D ACE, MMP-2, MMP-9, and in MDR1) were examined. Results: Significantly lower effect of adalimumab treatment in 3 months in the A group compared to B group was observed (P=0.009), more frequently in women. In A group, a significant association of I/D ACE genotype with PASI and BSA before onset of adalimumab treatment and with positive family history of psoriasis at the first-degree relatives (parents, children, siblings) with MMP-9 -1575 T/C genotype. In B group, a longer successful treatment by adalimumab in GG genotype carriers in TNF alpha – 308 A/G (P=0.03), better treatment effect in the TT genotype of MMP-2 -790T/G (p=0.04) and in the CC genotype of MMP- 9 -1575 T/C (P=0.04) were found. In the heterogeneous C group, duration of biologics treatment correlated with onset of psoriasis from the beginning of the therapy by biologics and was significantly associated with the MDR1 polymorphism. Conclusion: Finally, it is possible to conclude that success of biologics therapy is associated with some germ line genotypes in especially proinflammatory genes. different autoimmune diseases seems to be related to MDR1 gene variability which can responsible for many pharmacokinetic and pharmacodynamics aspects of therapy.


Introduction
Autoimmune disease, characterized by the host's immune response against self-antigens, manifests in more than 100 different types and affects more than 10% of the world's population, causing significant morbidity. Psoriasis is amongst the most common autoimmune diseases affecting approximately 2% of people globally. The disease is a result of the net outcome of genetic and environmental factors whose multilevel interaction is not fully understood yet. Intense research efforts to date, had focused on examining these factors in isolation, resulting in hundreds of genetic risk loci identified, many of which are shared between the members of the autoimmune disease spectrum, such as psoriatic arthritis, Crohn´s disease and others. This genetic overlap seems DOI: 10.26717/BJSTR.2020.24.004022 to be an indication of overlap of common causal pathways [1] [3].
Because psoriasis has commonly higher prevalence in many other diseases with autoimmune features, biologics therapy potentially can improve or deteriorate clinical manifestation of psoriasis. This could be individually influenced by gene polymorphisms forming genetic predisposition to chronic inflammatory diseases. Although these therapies are very efficient, around 30-50% of patients have inadequate response. Ustekinumab is a monoclonal antibody that targets interleukin (IL)-12 and IL-23 and is used for moderate-tosevere psoriasis. New drugs (apremilast, brodalumab, guselkumab, ixekizumab, and secukinumab) have recently been approved for psoriasis. However, response rates to systemic treatments for moderate-to-severe psoriasis range from 35 to 80%, so it is necessary to identify non-invasive biomarkers that could help predict treatment outcomes of these therapies and individualize care for patients with psoriasis. These biomarkers could improve patient quality of life and reduce health costs and potential side effects [1,2]. However, very few pharmacogenetic studies have examined the relationship between germline gene polymorphisms and the response to biologicals [3,4]. Aim of the pharmacogenetic pilot study was to compare three different groups of patients with biologics treatment in genotype distributions and/ or allelic frequencies of some germline polymorphisms in gene participating on immunomodulation during chronic inflammatory state [5].

Material and Methods
a) Group A: 11 psoriatic patients treated by adalimumab for three months when the treatment was stopped due to insufficient efficacy of disease (Table 1) b) Group B: 14 psoriatic patients with efficient continuous therapy by adalimumab (Table 1) Table 4: Differences in genotype distribution in -1562 T/C MMP-9 polymorhisms in family history of psoriasis in Group A.  Table 6).   for adalimumab, from 61% to 42% for infliximab, and from 82% to 56% for ustekinumab [6]. Certainly, individual genome variability must be to some extent responsible for these results. But, so far, pharmacogenetic studies in psoriasis have generated divergent results. Replication of findings in larger cohorts is required [7] Our pilot study tries to accent the importance of knowledge of interindividual variability in the main inflammatory genes which can substantially influence all pharmacological aspects of systemic therapy of psoriasis. According to our results, an association of duration of biologic treatment with genotypes of TNF-α -308

MMP-9 -1562 T/C -genotypes N Parents/siblings/children have not psoriasis Parents/siblings/children have psoriasis
A/G was found. Patients with another polymorphic TNF-α-238 GG genotype treated by biologics more frequently achieved a PASI75 at 6 months and those with the TNF-α-857CT/TT genotypes showed greater improvements in PASI score and BSA and more frequently achieved PASI75 in the study of Gallo et all. [5] Several studies evaluated changing levels of TNF-α and MMP-9 in tissue and/or serum of psoriasis patients treated with biologics but without genetic variability of susceptible genes [6,7]. We can conclude that efficacy of biological treatment is associated with some germ cell (innate) genotypes in genes contributing to inflammation and wound healing (TNF alpha, matrix metalloproteinases).
Besides duration of treatment, clinical manifestation of psoriasis in patients with other autoimmune diagnosis treated by biologics seems to be associated with genotype in MDR-1 gene. Our pilot results support necessity of evaluation of interindividual genome variability in clinical studies which can support further introducing of personalized medicine during development of new drugs for (not only) psoriasis treatment [8,9].