ECZEMA, EPIGENETICS AND THE POWER TO REPROGRAM .ECZEMA, EPIGENETICS AND THE POWER TO REPROGRAM .

As industry moves toward disease-modifying treatments in atopic dermatitis (AD), its focus is broadening beyond inflammation and immune targets. In our last article we explored how JAK inhibitors, by modulating multiple cytokine pathways, have the potential to transform the treatment landscape. But what if the future of AD treatment lies not just in blocking inflammatory signals – but in rewiring the instructions themselves?

In this follow-up, we examine the underexplored role of epigenetics in AD:

Why is eczema on the rise — and what role does epigenetics play?

The incidence of AD and related conditions such as food allergies, hay fever and asthma (atopic conditions), has steadily increased in industrialised countries in recent decades. AD now affects approximately 15–20% of children and up to 10% of adults worldwide.¹ This upward trend is now occurring in developing countries too, pointing to environmental factors underpinning the rise; urbanisation, pollution, poor diet, reduced exposure to microbes and lower socio-economic status have all been associated with AD.¹ There is also a strong genetic component. Those with a family history of atopic conditions are more likely to get it, and it is associated with several genes involved in inflammation and the immune system, and in skin barrier function, such as filaggrin.¹ So, as usual, the nature vs nature argument is not clear cut.

What links our biology to our environment?

It is clear that our bodies are responding to the world around us, but how is nature affecting nurture when it comes to AD? The answer lies in epigenetics; chemical tags on DNA. Epigenetic marks tell ‘readers’ of the tags when and how the associated genes on the DNA should be expressed (turned ‘on’ or ‘off’). If genes associated with AD are tagged with epigenetic marks, such as genes instructing immune responses, subsequent alterations in gene expression can lead to disease. Importantly, unlike disease-causing mutations in genes, epigenetic modifications do not affect the DNA itself.²

Epigenetics are influenced by environmental factors. For example, air pollution, pesticides, stress, diet, alcohol consumption and exercise are just some of the factors that have been linked to epigenetic changes.³ Scientists are becoming increasingly aware of the influence of environmental-mediated epigenetic changes on several AD genes. Factors such as exposure to pollutants and allergens and maternal diet can influence how genes associated with atopic diseases are expressed.⁴ For example, a recent cohort study found that prenatal exposure to smoking led to epigenetic changes in the inflammation gene NLRP2, and reduced gene expression at birth and was associated with childhood AD.⁵

How close are we to epigenetic treatments for AD?

Just as epigenetic modifications can be added, they can also be removed, reversing altered gene expression. This offers an opportunity to ameliorate AD symptoms through lifestyle changes, as well as medications that target epigenetic marks. Such medications are creeping from the experimental setting to the clinic in other disease areas,⁶ offering a potential future therapeutic avenue in AD. Hinting at this potential, belinostat may be able to treat AD through two epigenetic mechanisms – both by restoring MIR-335 and by acting as an HDAC inhibitor.⁷ It is also possible that existing AD medications control symptoms through epigenetic modification unknowingly. For example, JAK inhibitors like abrocitinib have been shown to influence histone modifications at inflammatory gene promoters in other inflammatory diseases,⁸ potentially contributing to their therapeutic efficacy.

Given our growing understanding of the role of epigenetics, does the pharmaceutical industry need to pay more attention to the role of epigenetics in modulating patient response to treatment? Could epigenetic-based treatments provide synergistic effects when combined with immunomodulation?

In an effort to understand how epigenetic changes influence treatment response, one ongoing study is investigating the effects of topical retinoids on epigenetic markers and gene expression in AD (NCT06658847).

The role of epigenetics in AD is increasingly recognised and warrants further attention. Further research may reveal new options for prevention and treatment, easing the burden of those living with AD.

By Nicola Joseph

References:

1. Savva A, et al. Front Biosci (Landmark Ed). 2024 Feb 22;29(2):84. doi:10.31083/j.fbl2902084.
2. Dupont C, Armant DR, Brenner CA. Epigenetics: definition, mechanisms and clinical perspective. Semin Reprod Med. 2009 Sep;27(5):351–7. doi:10.1055/s-0029-1237423.
3. Alegría-Torres JA, Baccarelli A, Bollati V. Epigenetics and lifestyle. 2011;3(3):267-77. doi: 10.2217/epi.11.22.
4. Bin L, Leung DYM. Genetic and epigenetic studies of atopic dermatitis. Allergy Asthma Clin Immunol. 2016;12(52):52. doi:10.1186/s13223-016-0158-5.
5. Thürmann L, et al. Early-onset childhood atopic dermatitis is related to NLRP2 repression. J Allergy Clin Immunol. 2018;141(4):1482–1485.e16.
6. Fardi M, Solali S, Farshdousti Hagh M. Epigenetic mechanisms as a new approach in cancer treatment: An updated review. Genes Dis. 2018 Jun 18;5(4):304–11. doi:10.1016/j.gendis.2018.06.003.
7. Buckley MT, Yoon J, Yee H, Chiriboga L, Liebes L, Ara G, et al. The histone deacetylase inhibitor belinostat (PXD101) suppresses bladder cancer cell growth in vitro and in vivo. J Transl Med. 2007;5:49.
8. Tsuchiya H, Ota M, Takahashi H, Hatano H, Ogawa M, Nakajima S, et al. Epigenetic targets of Janus kinase inhibitors are linked to genetic risks of rheumatoid arthritis. Inflamm Regen. 2024;44(1):29.