Genetic variants contribute to differences in response and toxicity to drugs used in autoimmune diseases: Rheumatoid arthritis and systemic lupus erythematosus

Dávila Fajardo, C.L. (2020)

Doctoral Thesis

The primary objective of this thesis is to investigate the role of pharmacogenetics in predicting drug response in treatments for the autoimmune diseases: RA and SLE. For this reason, this thesis is divided in two parts: pharmacogenetics related with drugs used in RA and pharmacogenetics of rituximab used in SLE and other autoimmune diseases. Part 1: Pharmacogenetics of drugs used in RA MTX is the most common DMARD used in RA. However, its use is hampered by frequent adverse drug events among which gastrointestinal toxicity is most frequent. Hepatotoxicity is a relatively rare but serious adverse event related to the use of MTX and is largely unpredictable. In chapter 2 an overview is presented of the previously performed studies concerning pharmacogenetic predictive biomarkers for MTX-induced hepatotoxicity. Treatment with anti-TNF agents results in a reduction of disease activity in most RA patients. However, a substantial part of patients does not respond to this therapy for unknown reasons. It would be highly beneficial to be able to predict whether or not an individual patient responds to treatment. Chapters 4 and 5 describe the investigations on the role of different candidate SNPs related to the efficacy of the treatment with different anti-TNFs in RA. In addition, in chapter 3 a replication study is presented based on 4 polymorphisms that were found associated with anti-TNF response in RA in a previously published genomewide association study. Part 2: Pharmacogenetics of rituximab used in SLE and other autoimmune diseases In chapters 6–8 the role of different genetic variants related to the pharmacodynamics of the drug or of the diseases are evaluated to study the contribution to differences in the response to rituximab in patients with SLE and other systemic autoimmune diseases. In chapter 6, the possible involvement of the -174 IL-6 polymorphism in the clinical response to rituximab in different systemic autoimmune diseases is assessed. In chapter 7, the aim is to investigate the possible involvement of the FCGR3A-158F/V polymorphism in the clinical response to rituximab in Spanish patients with different systemic autoimmune diseases. In chapter 8, the role of G/T polymorphism at the IL2–IL21 region in the rituximab response in a cohort of SLE patient and different autoimmune disorders is analyzed. Chapter 9 provides a summary of this thesis, chapter 10 the Dutch summary (Nederlandse samenvatting), and chapter 11 the general discussion and future perspective of this thesis.

• Response to drugs
• Pharmacogenetics
• Autoimmune diseases
• Rheumatoid arthritis
• Systemic lupus erythematosus

• All authors: Dávila Fajardo, C.L.
• Supervisor: Guchelaar, H.-J.
• Co-supervisor: Swen, J.J.
• Committee: Helm-van Mil, A.H.M. van der; Burggraaf, J.; Wilffert, B.; Bemt, B.W.F. van den
• Qualification: Doctor (dr.)
• Awarding Institution: Faculty of Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2020-09-29
• ISBN (print): 9789492026163
• Sponsorship: Financial support for publication of this thesis was provided by departmental funds from the department of Clinical Pharmacy & Toxicology of the Leiden University Medical Center, Leiden, the Netherlands.