Clinical, genetic and immune determinants of drug immunogenicity in psoriasis

Why is research needed in this area?
Psoriasis is common, affecting around 2 in every 100 people. In this condition, skin cells grow and shed more rapidly than usual. Patients may have red scaly patches of skin that they find embarrassing, itchy and painful. This can hugely affect quality of life - as much as having heart disease or cancer.
Severe psoriasis can now be treated using powerful injectable biologics (costing around £10,000 per year, per patient). Although many people at first respond well to biologic treatment, some unfortunately see their skin worsen again. In fact, almost a third of patients discontinue biologics within 3 years because they no longer work. We believe that this is mostly due to a patient's immune system attacking the drug molecules (an anti-drug response), which reduces the drug's effect over time. The anti-drug response is a common problem affecting people taking biologics for many different conditions, but we know surprisingly little about it. In particular, it is unclear why some people's immune systems launch an attack on biologic drugs, whereas others do not.

What does this research aim to achieve?
We aim to identify specific factors that could help predict which patients are at increased risk of developing an anti-drug response. This knowledge would allow us to take steps to reduce the risk as much as possible, whilst weighing up other factors to consider when choosing the best biologic for each patient. Taking this personalised approach would maximise patients' chances of having lasting benefit from treatment. For instance, if a patient is at high risk of an anti-drug response, their doctor could suggest starting biologics that appear to result in anti-drug responses in fewer people. Doctors could also consider giving a tablet alongside the biologic that settles the immune system, or changing the dose and frequency of the biologic itself. On the other hand, if a patient is at low risk of an anti-drug response, doctors could reassure them that the biologic will likely continue to work. The high cost of biologics makes it especially important to understand which patients will have lasting benefit from their use.
Although this research focuses on people with psoriasis, the potential impact is widespread. Prescribing biologics is currently based on trial and error, but using a personalised approach would help patients with many different conditions maintain better control of their health, as well as saving money for the NHS. On a fundamental level, we may gain basic insight into how and why the anti-drug response develops, and more generally into how the immune system works.

How will this research be conducted?
Using a unique UK database of more than 3000 people with psoriasis, we plan to test whether or not the following factors differ between those who develop an anti-drug response to the commonest biologic adalimumab (brand name Humira), compared to those who do not:
- Clinical factors, by analysing information about participants such as age and gender
- Genetic factors, by analysing DNA samples
- Immune factors, by analysing white blood cells
In the first stage, we will combine important clinical and genetic factors into a risk score to predict whether someone is likely to develop an anti-drug response. We will also test this risk score in people taking a different biologic called ustekinumab (brand name Stelara), and in people on biologics for other immune-related conditions such as rheumatoid arthritis and inflammatory bowel disease.
In the second stage, we will study white blood cells in great detail, looking for differences between people who develop an anti-drug response, compared to those who do not.

Who will carry out the research and where will it take place?
This project will be led by Dr Teresa Tsakok, a dermatologist and researcher at King's College London. Her work will be supported by a team of experts in psoriasis, genetics, and the immune system.

Management of psoriasis has been transformed by biologics. However, 30% of patients stop these drugs due to ineffectiveness within 3 years. A major cause of loss of response to treatment is drug immunogenicity, but this is poorly understood and has been identified by the BAD (British Association of Dermatologists) as a research priority.

Aim 1: Develop and validate a drug immunogenicity risk prediction score by integrating clinical and genetic determinants
A case-control design within the BADBIR (BAD Biologics Intervention Register) Bioresource will compare 800 patients with detectable anti-drug antibodies (ADA) to 1200 patients with undetectable ADA, taking first-line anti-TNF inhibitor adalimumab as the exemplar drug. Impact of clinical variables on drug immunogenicity will be modelled, and genetic variables will be identified via a genome-wide association study with human leukocyte antigen imputation. Clinical and genetic variables will be integrated into a risk prediction score. This will be validated in psoriasis, then tested in patients on a different biologic (ustekinumab), and in rheumatoid arthritis (RA)/inflammatory bowel disease (IBD).

Aim 2: Investigate early B cell mechanisms underlying development of drug immunogenicity by using a tailored immune marker panel
Mass cytometry (CyTOF) will be used to study immune phenotypes pre- and post-biologic initiation, in patients with detectable ADA compared to those with undetectable ADA. Standard flow cytometry will be used to replicate resulting candidate markers before testing them in RA and IBD.

Identifying psoriasis patients at increased risk of drug immunogenicity would allow us to take steps to minimize this risk, thus reducing loss of response to treatment. This may have wide applicability to diverse conditions treated with biologics. Fundamentally, we may uncover mechanistic insights into the development of drug immunogenicity, as well as predictors of antibody responses in humans per se.

Short-term impact (1-2 years)
Professional bodies and national institutions (eg. BAD and NICE) responsible for developing clinical guidelines will benefit from increased understanding of determinants of drug immunogenicity; this will provide an evidence base to guide patient pathways and advice on starting/switching biologics. My findings will inform the next national biologic guideline in psoriasis, with resulting international impact (the first BAD guideline for use of biologics in psoriasis was pioneering worldwide and is highly cited).
Increased recognition that drug immunogenicity is a major driver of loss of response to biologics will inform future teaching and learning, especially as this concept is not yet integrated into clinical practice in dermatology.
My work will benefit health economists by stratifying the population of patients on biologics, as therapy may be more cost-effective in those at low risk of drug immunogenicity.
Upon completion of my fellowship, I will be immediately equipped to progress my career towards becoming an independent researcher. I am committed to helping train more junior academics and clinicians, whilst continuing to generate high-quality research.

Medium-term impact (3-5 years)
The main beneficiaries will be people with psoriasis (>1 million in the UK alone). 75% develop the condition before turning 35, and biologic treatment can be lifelong. Losing response to these drugs is common and debilitating, resulting in loss of sleep, time off school/work, difficulty with relationships, and exclusion from public-facing employment. Minimizing loss of response would thus increase quality of life for people with psoriasis and their carers, and may impact on comorbidities eg. depression, cardiovascular disease. Drug immunogenicity as a mechanism of loss of response will also relate to patients with other diseases such as RA and IBD, allowing these impacts to benefit an even greater number of patients.
This project will provide insight into how drug immunogenicity can be estimated and then minimized eg. by choosing less immunogenic biologics initially, modifying baseline risk factors such as smoking or weight, and adjusting aspects of treatment such as dosing regimen or giving concomitant methotrexate. Those losing response due to immunogenicity will be recognized more quickly, progressing to more suitable treatment with less exposure to ineffective treatment. Conversely, patients at low risk of drug immunogenicity can be reassured, and may be deemed eligible for dose minimization strategies to reduce exposure to biologics and overall cost (see below).
Closing the knowledge gap on drug immunogenicity is an area of critical importance to drug developers, as discontinuation of early phase biologics due to unforeseen immunogenicity issues represents huge wasted investment. My real-world findings will be reported to PSORT's industry partners, to complement and build on clinical trial data.
The four high-cost drugs most commonly prescribed by the NHS are TNF inhibitors, contributing to an 11% increase in drug spend between 2015-2016. My work will inform more effective and efficient use of biologics across multiple diseases, by minimizing loss of response. This will feed into evidence-based policy making, and holds potential for major healthcare gains as well as cost savings. For example, implementation of dose minimization/drug discontinuation in patients achieving remission has been hampered by concerns that such strategies increase risk of drug immunogenicity. However, it is possible that patients with a low predicted risk of drug immunogenicity would be more suitable for such approaches.
My work will help generate wider public understanding and interest in psoriasis. This will benefit charities eg. the Psoriasis Association, for instance by increasing donations from the public. In turn this will benefit skin researchers and ultimately people with skin conditions.