Effects of Tildrakizumab on Epigenetic Age

• Introduction

Psoriasis is a common, chronic, inflammatory disorder that affects millions of individuals worldwide.1,2 Although psoriasis etiology is still largely unknown and its precision management remains to be improved, advances in understanding the pathogenic cytokine network of psoriasis have led to the development of biologic therapy, such as FDA-approved on-label indication for moderate-to-severe psoriasis of tildrakizumab-asmn (ILUMYA, Sun Pharma Global, Princeton, NJ), an injectable monoclonal antibody that inhibit interleukin (IL)-23, a pro-inflammatory cytokine. Epidemiologic studies have promoted the recognition of psoriasis as a systemic disorder.3 Associations between psoriasis and incident risk of diabetes, cardiovascular disease, Crohn's disease, and gout have been reported in prospective studies.4-7 However, the mechanism underlying the systemic manifestations has been a knowledge gap for research on psoriasis.8

• Epigenetic aging (DNA methylation)

The complex interplay of genetic and environmental factors in psoriasis may occur through the epigenetic mechanisms. DNA methylation of cytosine followed by guanine residues (CpG dinucleotides), the epigenetic process that participates in the transcriptional regulation and gene expression, has been linked to psoriasis.9 As the precise pathogenesis underlying the development of psoriasis remains largely undefined, further exploration of the role of epigenetics would offer a biologically plausible perspective to clarify psoriasis etiology. Epigenetic epidemiology would serve as a tool to elucidate the susceptibility and to identify novel biomarkers for psoriasis.10 The epigenetic clock is a novel biomarker of aging, developed based on DNA methylation.11-13 The epigenetic clock may capture aspects of "biological age" and older epigenetic age of blood has been associated with all-cause mortality,14,15 obesity,16 and many diseases.17-20 Although whether epigenetic age is associated with psoriasis is not yet known, previous research from our group recently found that average epigenetic age in psoriasis patients was 5 years higher than their corresponding chronological age (data not published), suggesting possible epigenetic age acceleration in psoriasis. Therefore, epigenetic age acceleration may serve as a novel biomarker for psoriasis and its systemic manifestations. It may also potentially be used as an intermediate biomarker assessing the systemic effects of tildrakizumab.

Blood-based measures of epigenetics have the advantage of interrogating the systemic health status or treatment responses and assessing biomarkers across a large variety of disease domains.10,21

Rationale for the study:

Although epigenetic changes are tissue-specific, the connections between epigenetic epidemiology and psoriasis in blood-based epigenetic studies would decipher novel systemic inflammation and immune states of psoriasis and elucidate the effect of tildrakizumab use on the epigenetic age acceleration. Comprehensive assessment of epigenetic age acceleration in blood leukocytes between psoriasis and controls, and the change in epigenetic age acceleration after tildrakizumab initiation may lead to the identification of methylation markers for predicting the systemic risk of psoriasis and the effect of tildrakizumab on psoriasis. If confirmed to be an intermediate marker for the effect of psoriasis therapy with tildrakizumab, epigenetic age may be used to better profile the beneficial role of immunomodulation, promoting the management of psoriasis and its systemic comorbidities.

Psoriasis is an inflammatory disease of the skin and joints and has been recognized as a systemic disorder. In this proposed study, the investigators hypothesize that epigenetic age acceleration may be associated with psoriasis, and tildrakizumab may be able to affect the epigenetic age acceleration associated with psoriasis.

• Objective

To determine the association between epigenetic age acceleration and risk of psoriasis, and also to evaluate if tildrakizumab can reverse peripheral blood leukocyte DNA methylation (epigenetic aging) associated with chronic psoriasis.

Specific Aim 1: To examine the association between epigenetic age acceleration and psoriasis: by comparing the baseline samples of peripheral blood leukocyte genome-wide DNA methylation assay collected at screening for psoriasis patients and controls.

Specific Aim 2: To evaluate dynamic changes in epigenetic age of the on-label use of tildrakizumab (week 28 vs screening visit). And upon discontinuation (week 28 vs week 52). Assess if epigenetic age could be a marker for the effect of tildrakizumab on psoriasis through psoriasis severity scores.

Specific Aim 3: We will evaluate the transcriptomic impact of ILUMYA therapy in patients with psoriasis and possible correlation/association with Epigenetic changes, psoriasis severity scores, the presence of systemic comorbidities.

Inclusion criteria

• Age: 35 years of age or older.
• Psoriasis subjects: moderate-to-severe psoriasis: PASI (Psoriasis Area and Severity Index ≥12) and a minimum Body Surface Area (BSA) involvement of 10%.
• Control Subjects: other skin diseases without psoriasis.

Exclusion criteria

• Patients aged less than 35 years.
• Patients with previous skin cancer or other cancers.
• Women of childbearing potential without effective contraceptive method, or lactating women.
• Prisoners.
• Psoriasis patients who have had a severe allergic reaction to ILUMYA or any of its ingredients.
• Psoriasis patients who have chronic or recurring infections. Positive QuantiFERON upon screening will be exclusionary for this trial (latent tuberculosis).
• Any condition that, in the opinion of the investigator, may interfere with patient's ability to participate in the study, such as severe cognitive impairment or other comorbidities that would, in the opinion of the investigator, predictably limit compliance with the study plan.