Advancing Psoriasis Treatment : Clinical drug evaluation of fumaric acid esters and TLR-antagonists

textabstractPsoriasis is a common immune-mediated inflammatory skin disease that can elicit a significant high burden of disease on patients, theirs families, and society. In the last two decades significant advances have been made in the treatment of psoriasis, but psoriasis remains a challenging and difficult-to-treat disease. In this thesis, the focus was set on advancing psoriasis treatment by undertaking a clinical drug evaluation approach of two different systemic psoriasis treatments. The first studied therapy is fumaric acid esters (FAEs), which are an established classical systemic treatment for psoriasis, but important questions regarding their efficacy, safety, and mechanism of action remain unanswered. We undertook a systematic literature search to assess the evidence on the efficacy and safety of FAEs in psoriasis treatment (Chapter 2). In two randomized controlled trials, we assessed the therapeutic benefit of combining FAE treatment with the TNF-alpha antagonist etanercept (Chapter 3) and the histamine-1 receptor antagonist cetirizine (Chapter 4). Furthermore, we performed a descriptive case series of two rare but clinically important side effects associated with FAEs: first, progressive multifocal leuko-encephalopathy, an opportunistic viral infection of the central nervous system; and second, Fanconi syndrome, which is characterized by proximal renal tubular dysfunction (Chapter 5). In a gene expression profiling study using lesional psoriasis skin samples we identified several pathways and mechanisms affected by FAE treatment (Chapter 6). The second drug assessed in this thesis is a novel oligonucleotide-based antagonist of toll-like receptor (TLR) 7, 8 and 9, which is a potential targeted biologic treatment for psoriasis. Aberrant TLR 7, 8, and 9 activation by self-nucleic acids is implicated in the initiation of immune-mediated inflammatory diseases (IMIDs) such as psoriasis. In multiple IMID models, blockage of TLR-activation reduced disease severity. In chapter 7 we describe the results of a first-in-patient phase 2 randomized placebo-controlled trial of a novel TLR-antagonist in patients with moderate-to-severe plaque psoriasis. In the concluding chapter of this thesis, results of each of the studies are put into context, potential implications of the main findings are discussed, and some perspectives on the future care for individuals with psoriasis are explored (Chapter 8)