Research Results

Self-compassion and supporting adherence to topical therapies in people living with psoriasis

Dr Elaine Clarke - Centre for Behavioural Science and Applied Psychology, Sheffield Hallam University

This research was about self-compassion in people living with psoriasis. Self-compassion is an attitude that you take towards yourself in difficult times. It consists of being kind to yourself rather than judging yourself badly when things go wrong for you, understanding that difficulties are a normal part of life rather than feeling alone because of them, and being mindful of your distress rather than getting caught up in your feelings. There is lots of evidence that being self-compassionate is good for people’s health, including being linked with people using their medical treatments as prescribed, but this has not previously been explored in people living with psoriasis.

First, we carried out a survey of 131 people who had been prescribed a topical therapy for psoriasis. We found that people who were more self-compassionate tended to use their topical therapies in the way that they had been prescribed. In particular, people who reported greater self-kindness and mindfulness, fewer feelings of isolation, and less preoccupation with negative thoughts and feelings were more likely to report using their topical therapy as prescribed. These findings suggest that helping people living with psoriasis to be more self-compassionate would be beneficial, particularly in terms of supporting self-management of their psoriasis.

Next, we co-designed a self-help leaflet with six people who had psoriasis. The leaflet was designed to help people living with psoriasis learn how to be more self-compassionate. We held two co-design workshops, during which we discussed what needed to be included in such a leaflet and how it should be presented. We worked with a graphic designer to create the included images. The leaflet included an explanation of self-compassion and why this is important, exercises to help people become more self-compassionate, troubleshooting of potential problems, and quick tips for people to try. The final leaflet is freely available online from the authors’ research centre.

The research team are keen to receive feedback on leaflet, and for those interested in sharing their thoughts, a short (5 minute) online survey is available here.

The impact of psoriasis on wellbeing and clinical outcomes in juvenile psoriatic arthritis

Stephanie Shoop-Worrall - The University of Manchester

Juvenile psoriatic arthritis can have many different features affecting children and young people’s joints, skin, nails and scalp. One in three children will have psoriasis, and the rest a parent with this condition. This project explored how having psoriatic arthritis, and particularly having psoriasis within this disease, affects children’s quality of life and clinical picture. This could help pick treatments based on people’s type of disease. This study used information from 1653 children and young people with arthritis from the UK Childhood Arthritis Prospective Study. Information about their disease and its impact on daily life was collected at their hospital appointments from diagnosis to three years later. Of these, 111 had juvenile psoriatic arthritis. At diagnosis, children with juvenile psoriatic arthritis had similar impacts of disease across mood, wellbeing, pain, quality of life and disability compared with those with other types of juvenile arthritis.

This shows how important managing disease impacts are, across the spectrum of juvenile arthritis. Within juvenile psoriatic arthritis, those with psoriasis had significantly worse mood than those without psoriasis. This means that at a diagnosis of juvenile psoriatic arthritis, focus on treating psoriasis may be particularly important for managing mood. If poor mood carries on, other types of treatment, like psychology, might be helpful. We also found that children with psoriasis were more likely to have early remission, and less likely to have low-level grumbling disease, than those without psoriasis in juvenile psoriatic arthritis. This shows a positive picture of treatment for children and young people with psoriasis in juvenile psoriatic arthritis. Moving forward, the results of this project have led to a £1m MRC fellowship project starting in September 2022. This new 5-year project will understand which types of psoriatic arthritis, across children and adults, have different treatment needs, and in particular which will respond to the drug methotrexate. This will help in picking the right treatments based on type of psoriatic arthritis, right from diagnosis.

Demonstrating the benefits of smoking cessation in psoriasis, a molecular approach

Francesca Capon - King’s College London

The aim of this project was to investigate the effects of cigarette smoking on psoriasis. We specifically focused our attention on palmoplantar pustulosis (PPP), as this is a severe disease variant that mostly affects smokers.

During the first year of the study, our research activity was severely disrupted by the Covid-19 epidemic. Nonetheless, we were able to investigate whether genetic factors synergise with cigarette smoking in causing PPP. We first examined a gene called CARD14, which is known to malfunction in many skin diseases, including plaque psoriasis. We demonstrated that individuals who carry genetic defects in CARD14 are at increased risk of developing PPP, whether they smoke or not.

During the second and third year of the study, we expanded our analysis to include nearly 1,500 affected individual and cover 9 million DNA changes. This was the largest genetic study of PPP ever undertaken and identified two additional genes predisposing to the disease. Our analysis also showed a causal relationship between smoking initiation and PPP risk. Our lab is now working to identify the specific inflammatory molecules that mediate the effects of cigarette smoking. We will then seek to determine whether any of these molecules can be blocked by existing drugs.

Investigating the therapeutic benefits of exercise in patients with psoriasis

Dr Helen Young - University of Manchester

People with psoriasis are less physically active than those who do not have psoriasis, due to barriers caused by psoriasis. Psoriasis can also lead to conditions such as heart disease, which benefit from increased physical activity. Recognising this, we co-designed an exercise intervention with people with psoriasis and observed in a proof-of-concept study significantly: improved psoriasis control; reduced heart disease risk; enhanced wellbeing and improved functional capacity. These data suggest that further research including a controlled clinical trial to investigate whether physical activity can improve psoriasis and other health outcomes is important. Crucially our work has addressed the MOST important research priority identified by both the Psoriasis and Psoriatic Arthritis Priority Setting Partnerships.

Investigation of the prevalence of liver fibrosis in patients with psoriasis using Transient Elastography and evaluation of the relationship between liver fibrosis and risk factors for liver fibrosis including methotrexate

Parastoo Babakinejad - Dermatology Outpatients Department New Victoria Wing, Royal Victoria Infirmary

Liver scarring has been shown to be common in patients with moderate to severe psoriasis. Known risk factors for liver scarring include obesity, alcohol, and diabetes. However there have been concerns that methotrexate which is a common systemic therapy used to treat psoriasis, has been associated with liver scarring.  In this study we confirmed that liver scarring is prevalent in patients with moderate to severe psoriasis. Liver scarring was not shown to be associated with cumulative methotrexate dose. Our findings showed that Body Mass Index (BMI) ≥28, diabetes and metabolic syndrome (a group of health problems leading to increased risk of heart disease and stroke), are important risk factors which can be useful in identifying patients requiring a more detailed liver health assessment. 

Identifying immune determinants of clinical response to ustekinumab in psoriasis

Dr Di Meglio - University of Manchester

In this project, we have identified a biological marker that could predict whether people with psoriasis will improve on ustekinumab before it is even prescribed. We analysed how white blood cells behave in a group of people who improved after 12 weeks of taking ustekinumab compared to a group who didn’t improve. Doing this, we discovered that a certain type of white blood cell behaves much differently in people who improved with ustekinumab compared to those who didn’t improve. To confirm that our findings are specifically related to the effects of ustekinumab, we analysed the sensitivity of this type of white blood cell in people who are on other psoriasis drugs such as adalimumab and secukinumab. Interestingly, we observed that these white blood cells are not sensitive to the effects of adalimumab, but are sensitive to secukinumab. Our data suggests that people who have more reactive white blood cells may be more sensitive to drugs that work in a similar way like ustekinumab and secukinumab, and this may relate to why they do well on treatment.

To validate our findings, we analysed these white blood cells in an independent group of people with psoriasis who were receiving ustekinumab from a different project. In this independent group, we also observed that the white blood cells are more active in people who respond well to ustekinumab compared to people who don’t. This reaffirms our original discovery. We also carried out further analysis by measuring the frequency of these specific white blood cells and the amount of pro-inflammatory mediators they release. But we observed no major difference in the frequency of white blood cells and pro-inflammatory mediators between people who improved with ustekinumab compared to those who didn’t improve. Taken together, we have identified a promising biological marker in blood which is able to predict how well people will do on ustekinumab and that may be useful to identify people that will benefit from this drug before commencing the therapy.

The impact of flare-ups on psychological wellbeing, treatment adherence, and life engagement in people living with psoriasis

Ella Guest - University of the West of England

Researchers at the Centre for Appearance Research at the University of the West of England in Bristol explored the impact flare-ups can have on the people with psoriasis. They interviewed 18 Psoriasis Association members about their experiences. They found that as well as the physical aspects of psoriasis (i.e. itching, redness), flare-ups had a significant impact on psychological wellbeing and how they felt about their appearance, which influenced their engagement in activities and relationships with others. In parallel, psychological wellbeing and lifestyle factors, such as stress and diet influenced the severity of their psoriasis. Some participants found it difficult to manage their condition, due to treatments being time consuming, messy, or unpleasant, and difficulties accessing dermatology support. Many believed health professionals did not fully understand how to treat psoriasis and did not acknowledge the wider impact on wellbeing. Despite some ongoing struggles, participants believed that having psoriasis helped them to be more empathetic and had given them opportunities to connect and support others. The findings show that psoriasis is more than just a skin condition and can affect individuals in different ways. It is important for health professionals to consider the influence of psychological and lifestyle factors when offering treatments for psoriasis and to acknowledge the impact flare-ups can have on wellbeing and quality of life. Further, people with psoriasis need to feel listened to and involved in decisions about their treatment to help them manage their condition around their everyday life and to help to prevent flare-ups.

In future, they would like to better understand what people with psoriasis think health professionals should know about their condition and its impact on wellbeing. An aim would be to inform the development of resources that highlight the wide-ranging impact psoriasis and flare-ups have on physical and psychological wellbeing and appearance-concerns. They would also like to explore how to include patients in the decision-making process around their treatment and receive more support relating to the psychological impact of psoriasis. The findings of this research will be shared at conferences, with the Psoriasis Association in an infographic, and in reports and academic papers.

Building a social prescribing pathway for patients with psoriasis in Salford to enable access to community-based lifestyle and wellbeing support

Angela Eden - Salford City Council

This project aimed to develop a social prescribing pathway for patients who are accessing the Psoriasis Rapid Access Clinic (P-RAC), affiliated with Salford Royal Foundation Trust. This builds on work that has already been established within primary care in Salford.

The project placed a dedicated member of Health Improvement staff alongside the Psoriasis Rapid Access Clinic to provide one to one coaching, goal setting, motivational interviewing and behaviour change techniques to support patients to make significant improvements to their health and wellbeing. Through the programme, patients were supported to access groups, activities and interventions based within their local community to sustain any behaviour change. This related to diet, physical activity, smoking cessation, mental wellbeing, or social support. This is highly relevant to psoriasis patients because behavioural factors, known to exacerbate psoriasis and increase the risk of CVD, are significantly increased in this population. This novel pathway integrated a validated psoriasis psychoeducational intervention with social prescribing to optimise patient care.

Individual outcomes for psoriasis patients

Fewer patients have been recruited to the Psoriasis Wellbeing Pathway than was initially planned. There have been a number of reasons for this, but principally this was due to it taking much longer to establish the community based clinic than anticipated, meaning there were much fewer opportunities to identify patients who could benefit, shortly followed by the outbreak of the pandemic. Nine patients were referred and received holistic person-centred lifestyle coaching and behaviour change support. Outcomes for these patients have included support to stop smoking, reduce BMI and/or improve their self-reported emotional wellbeing.

If this support was provided routinely across a wide range of long-term conditions there could be a significant impact for society and the health and social care economy more widely as evidence demonstrates that individuals and community become better able to manage their own health and conditions and feel confident and empowered to make changes that can significantly impact upon their life expectancy and mortality. Preventative services help to reduce the need for patients to access higher level acute services which are often the most expensive and resource intensive. Preventative service, delivered at a neighbourhood level, would help to bring about a change in culture whereby people feel that they are equipped and able to take control over their own health and wellbeing.

PhD Studentship - An attentional bias approach to understanding and reducing the psychosocial burden of psoriasis

Sarah Etty, supervised by Dr Henning Holle - University of Hull

Attentional bias is the tendency for visual attention to be drawn either towards or away from threatening information as compared to more neutral information. We know from previous research that people with anxiety show an attentional bias for anxiety-specific threatening information. As people with psoriasis often struggle with anxiety, it follows that they may also demonstrate a similar attentional bias.

In this PhD research project, we first examined attentional bias for itch related information in healthy participants who were experiencing experimentally induced itch and compared this with a control group who were not itching. We found that people experiencing acute itch showed an avoidance of itch-related words, but not itch-related images. The full study report can be accessed free of charge here. We then examined attentional bias for psoriasis-related information in people with psoriasis and compared this with a control group of people that do not have psoriasis. The results of this were much more complex. The task we used to measure attentional bias in the previous itch experiments showed that attentional bias in people with psoriasis did not differ from control participants. However, as previous research has shown that there is a difference between these two populations, we further investigated this using a simpler procedure known as the Stroop task. Using this simpler task revealed a difference in attentional processing of threat-related words between those with psoriasis and healthy participants.

This could be interpreted as the simpler Stroop task being better able to detect small attentional biases, or that it is measuring something else entirely, such as delayed processing due to emotional reactions to psoriasis-related threatening words. This is one of the open questions we want to answer next.

PhD Studentship - Investigating genetic control of the psoriasis transcriptome to define and validate drug and disease endotypes

Ashley Rider, supervised by Professor Nick Reynolds - University of Leeds

In the past decade a new class of psoriasis treatments have emerged called “biologics.” Several different biologics are available and currently we have no way of knowing which will work best for each patient. This means that biologics are prescribed in a “trial-and-error” manner, which is detrimental to patient wellbeing and also wasteful of NHS resource. Therefore, an important goal in psoriasis treatment is for each patient to be prescribed the right biologic for them straight away. This will not only require deeper understanding of psoriasis and its molecular subgroups (“disease endotypes”) but also the mechanisms by which these drugs work (“drug endotypes”).

In order to investigate these disease and drug endotypes, a multi-centre consortium was established called PSORT (Psoriasis Stratification to Optimise Relevant Therapy). The ultimate aim of PSORT is to develop tests based on blood samples or a small skin biopsy that predict individual patient responses to biologic drugs. In order to achieve this PSORT has recruited a cohort of patients commencing treatment with either adalimumab or ustekinumab, two commonly prescribed biologics. Skin and blood samples were collected from these patients before commencing treatment, and one week and twelve weeks after commencing treatment. The messenger RNA (mRNA) in these samples was then sequenced, providing us with data indicating the levels of gene expression in these patients at each of these time points. This has allowed us to identify a number of gene expression patterns that not only describe the biological mechanisms by which these drugs work, but also predict clinical response to these drugs. Genetic data from these patients has also allowed us to identify genetic variants that influence gene expression in psoriasis.

In summary, this studentship has demonstrated the power of bioinformatics methods when creatively combined with the impressive data sets within PSORT. Together these analyses have demonstrated the proof of principle for the personalisation of biologic therapy for psoriasis. Further work is required to develop scalable tests. However the linkage of genetic and gene expression data suggests that simple blood tests could be developed with the potential for positive clinical impact in psoriasis.

PhD Studentship - The role of abnormal IL-36/IL-1 in palmar plantar pustulosis (PPP)

Athanasios Niaouris, supervised by Professor Francesca Capon - King's College London

The focus of this project is on palmar plantar pustulosis (PPP), a severe variant of psoriasis that manifests with the appearance of painful skin pustules on the hands and feet. The hypothesis driving our study is that PPP is caused by the excessive accumulation of two related proteins called IL-1 and IL-36. To demonstrate that this is the case, we are examining the DNA of affected individuals, looking for changes in genes that influence IL-1 and IL-36 production.

In the final 12 months of the study, we have examined the impact of mutations affecting CARD14, a gene that has been linked to IL-36 synthesis. We found that most CARD14 changes seen in people with PPP cause the gene to produce an abnormally active CARD14 protein. Of note, excessive CARD14 activity has also been observed in common plaque psoriasis, erythrodermic psoriasis and pityriasis rubra pilaris (a disease that is sometimes mistaken for plaque psoriasis, as it also presents with reddish, well-demarcated lesions).

These observations suggest that CARD14 abnormalities represent a common mechanism contributing to different forms skin inflammation, including common and rare variants of psoriasis.

PhD Studentship - Mutation burden of narrowband UVB
Noeline Nadarajah, supervised by Professor Eugene Healey - University of Southampton

Ultraviolet radiation (UV), including narrowband UVB (NBUVB), is used as treatment for psoriasis, but UV can cause mutations in the DNA of skin cells and potentially lead to skin cancer development.

We have conducted a study to look at the amount of DNA mutations that occur from a course of NBUVB to try to estimate how many courses of NBUVB a patient could receive over their lifetime without being at significant increased risk of skin cancer. DNA from skin biopsies, taken from uninvolved skin of patients with psoriasis before and after a course of NBUVB treatment, have been sequenced and are currently being comprehensively analysed using a process called ‘bioinformatics’ and it is anticipated that this analysis will be completed in the next several months. The project also involved bioinformatics work by a PhD student looking at the different gene mutations in skin cancers from people where DNA from their skin cancers had been sequenced in order to allow us to understand the importance of DNA mutations in various genes in skin cells, principally which gene mutations do or do not promote skin cancer development.

The student has submitted her thesis and has been successfully awarded a PhD degree. The final results of the study will inform on exactly how much DNA damage a course of NBUVB causes in uninvolved skin of patients with psoriasis with the aim that it will allow us to mathematically model how many courses of NBUVB treatment it would take to reach the same number of mutations that are present in chronically exposed skin of patients with skin cancer, so that we can then estimate a safe limit of NBUVB over a patient’s lifetime

PhD Studentship - Characterisation of novel pathogenic pathways for generalised pustular psoriasis
Marika Catapano, supervised by Professor Francesca Capon - King's College London

The aim of this project was to achieve a better understanding of generalised pustular psoriasis (GPP). This is a rare, but potentially life-threatening variant of psoriasis, manifesting with the appearance of painful pustules on inflamed skin. Disease episodes require immediate hospitalisation, as they are often accompanied by high fever and a sharp increase in the number of white blood cells. As GPP symptoms are very difficult to manage, there is a clear need to identify disease mechanisms that can be targeted for effective treatment.

The study of GPP has also the potential to shed new light on the causes of common plaque psoriasis (Ps), as people affected by GPP often suffer from Ps as well.

Here, we investigated the possibility that a protein called interleukin-36 (IL-36) may play a key role in both GPP and Ps.

We found that treating normal epidermal cells with IL-36 induced several changes that were also observed in the skin of GPP and Ps patients. This prompted us to use an IL-36 inhibitor on skin samples donated by Ps patients. The experiment demonstrated that blocking IL-36 markedly reduced epidermal thickness and inflammation, supporting the notion that IL-36 antagonists could be used for the treatment of plaque and pustular psoriasis.

These exciting results have now been published on a prestigious scientific journal (Science Translational Medicine).

Next, we sought to determine whether IL-36 also contributes to other symptoms of psoriasis, beyond skin inflammation. By examining affected individuals and healthy volunteers, we found that IL-36 is abnormally active in the bloodstream of GPP and Ps patients. We further demonstrated that this causes the over-production of a protein called IFN-a. While healthy IFN-a levels help the immune system to fight viral infections, excessive production of this protein can cause the inflammation of joints (arthritis) and blood vessels (atherosclerosis). Given that the latter are often observed in psoriatic patients, our work suggests that IL-36 blockade might reduce IFN-a levels and improve the disease manifestations that affect other organs beyond the skin.

PhD Studentship - Not just skin deep: circulating lipids in a 'localised' disease
Jemma Paterson, supervised by Dr Timothy M Millar - Southampton General Hospital

Many people with psoriasis also have a high body mass index (BMI). Sometimes, there can by high levels of cholesterol in the blood too. In psoriasis, blood vessels grow too quickly and change the skin, causing the plaques. We thought that there might be a link between too much fat in the blood and how quickly blood vessels grow. In tests with blood vessels, we showed that the bad version of cholesterol changes how blood vessels grow. This bad cholesterol works by making the blood vessel cells grow more quickly and forget when to stop growing. It looks like this happens through another fat in the blood for which there are experimental drugs. If we increase good cholesterol, we can also control this blood vessels growth. Together, it might be possible to slow down the blood vessels and so reduce plaques in the skin. We aim to continue this research and will look at white cells and how they might also be affected by fats in the blood. This research is at a very early stage and we thank the Psoriasis Association for their support.

PhD Studentship - The role of mast cell tryptase in psoriatic itch
Haris Atmoko, supervised by Professor Silvia Bulfone-Paus - University of Manchester

Approximately 70-80% of individuals with psoriasis also suffer from itch. Psoriatic itch can be intense and detrimental to patients’ quality of life. However, there are currently no treatments that consistently alleviate psoriatic itch, and the mechanisms behind psoriatic itch still need further clarification. Mast cells are immune cells that can release itch-inducing mediators and are known to communicate with nerve fibres. Some nerve fibres are believed to transmit signals to the brain, which induces the sensation of itch. Both mast cells and nerve fibres are increased in psoriatic skin, which may suggest a role for them in psoriatic itch. This project aims to identify potential mechanisms of itch that mast cells contribute to through interaction with nerve fibres.

The distance between mast cells and nerve fibres were found to decrease in psoriatic skin, which may suggest more communication between mast cells and nerve fibres in psoriatic skin, possibly in relation to itch. The itch-associated receptor proteinase activated receptor 2 (PAR2) was also found to increase in psoriatic skin, which may suggest a role for PAR2 in psoriasis. Meanwhile, published datasets of gene expression in psoriatic and healthy skin indicate an increase in expression of itch-associated genes that suggest a potential role for interleukin-4 (Il-4), prostaglandin E2 (PGE2), and leukotriene B4 (LTB4) in psoriatic itch. Furthermore, neurons have been shown to be stimulated by itch-associated mediators released by mast cells, including substance P, Il-4 and LTB4, which suggests that these molecules may be released by mast cells which could stimulate nerve fibres and contribute to itch-signal transmission.

PhD Studentship - A role for connexin-mediated signalling events in the pathogenesis of psoriasis
Erin O'Shaughnessy, supervised by Dr Patricia Martin - Glasgow Caledonian University

Psoriasis is associated with increased skin inflammation and skin cells that multiply and lose their ability to stick, resulting in ‘flaky’ skin. We investigated the role of Connexins in the development and progression of Psoriasis. Connexins are a family of proteins that form ‘channels’ between cells enabling the exchange of regulatory information. In keratinocytes, the cells that makeup the multiple upper layers of the skin, this is important as there is no direct blood supply. Biopsies of normal and psoriatic donated tissue were used to investigate tissue organisation and structure and skin cells (keratinocytes and fibroblasts) were isolated from the tissue to generate in vitro skin models to model disease progression. A panel of inhibitors of connexin channel function were also used.

Connexin26 was extensively upregulated in psoriatic plaques and in skin adjacent to the plaque borders. However, its sister protein Connexin43 was modified and likely targeted for degradation. Fibroblasts, express Connexin43 but not Connexin26 and those isolated from psoriatic patients had a higher ‘inflammatory index’ compared to fibroblasts from ‘normal’ donors. In co-cultures of psoriatic fibroblasts and normal keratinocytes the keratinocytes adopted of a ‘psoriatic phenotype’ and over-expressed Connexin26.

Signalling molecules released from connexin channels elicit events within the epidermis that promote inflammation and hence drive the altered formation of the outer layers of the skin. A range of connexin channel blockers can inhibit the release of pro-inflammatory markers in keratinocytes and fibroblasts. The triggers of enhanced Connexin26 expression are multifaceted. Our data indicate that changes in the external environment e.g. presence of bacterial components, can elicit acute signalling factors that enhance Connexin26 expression. These signals can be propagated via Connexin channels and promote pro-inflammatory pathways that subsequently trigger aberrant epidermal formation. However, internal factors, related to a sustained inflammatory index of underlying fibroblasts, are also involved in inducing ‘faulty’ Connexin behaviour and in so doing dysregulate specialised ‘cell to cell’ communication compartments.

We conclude that connexin signalling plays a critical role in the psoriatic phenotype and that developing compounds to specifically reduce Connexin26 signalling is of therapeutic value as a novel biologic in the control of Psoriasis.

Investigation of the roles of UV-induced nitric oxide and vitamin D in Narrow-band UVB phototherapy treated psoriasis patients.Dr Richard Weller - University of Edinburgh

Ultra Violet Phototherapy is one of the most effective treatments for psoriasis, but the mechanism by which it works is not fully understood.

We have previously shown that when ultraviolet hits the skin it releases nitric oxide (NO) gas into the circulation. In this work funded by the Psoriasis Association we were able to show that nitric oxide turns a form of white blood cell known as a T cell into an anti-inflammatory cell called a T-regulatory cell. We showed that these T regulatory cells are able to reduce inflammation and also that they change in a way that makes them more likely to enter the skin. We think that this is probably one of the means by which ultraviolet treatment reduces the inflammation in the skin, which is a hallmark of psoriasis. We plan to investigate this further as understanding how UV produces benefit offers the opportunity to improve the effectiveness of phototherapy or maybe even to develop a new treatments using the NO pathway without the need to attend hospital for phototherapy.

PhD Studentship - An investigation into genetic factors which discriminate psoriasis from psoriatic arthritis
Eftychia Bellou, supervised by Professor Richard Warren – University of Manchester

Approximately 1 in 3 people with psoriasis develop psoriatic arthritis (PsA), an inflammatory arthritis that causes pain, swelling and joint stiffness. Like psoriasis, PsA occurs as a result of the immune system mistakenly attacking healthy tissue, but it's not clear why some people with psoriasis develop psoriatic arthritis and others do not. However, psoriasis is not only linked to the joints, it is also known to be related to the presence of various other co-exisiting morbidities including cardiovascular disorders, depression, and diabetes, leading to a diminished health-related quality of life.

This study aims to search genetic and environmental factors such as smoking and obesity that discriminate psoriasis and PsA. Finding predictors of the development of PsA in people with psoriasis will help clinicians better diagnose patients according to their symptoms. They will also be able to intervene early on in the disease process thereby controlling joint damage. Finally, the discovery of specific genes that are responsible for the development of PsA can help in the development of more effective and stratified therapies. Apart from the main direction of this study, an additional objective is to investigate the prevalence of comorbidities with PsA, and psoriasis without arthritis, using the UK Biobank which contains data from approximately half a million people from across the UK.

During the past year a genetic study has been conducted using novel statistical methods and data from other musculoskeletal diseases (such as rheumatoid arthritis, lupus erythematosus, ankylosing spondylitis and juvenile arthritis) in order to identify novel genetic variants associated with PsA and potential genes that are associated with a sub-group of these disorders. The latter can help us understand the common biological pathways underlying PsA and the other musculoskeletal diseases. These diseases were chosen because they have a shared genetic basis with PsA and they could boost the possibilities of finding new genetic variants.

Finally, the project will explore the possibility of whether the risk factors (such as BMI), that were found to be associated with PsA during the epidemiological study earlier on in the project, are causes that could trigger the development of arthritis in patients with psoriasis. This will be investigated using the genetic data that was published by the UK Biobank. In previous epidemiological studies, the co-occurrence of psoriasis/PsA with a number of exposures such as smoking and increased obesity was shown, but this did not provide adequate evidence that these are risk factors for developing psoriasis and PsA. Using genetics rather than measured exposures has many advantages and could shed some light on the causes of the diseases of interest.

PhD Studentship - Functional characterisation of genetic susceptibility to psoriasis
Alicia Lledo Lara, supervised by Professor Julian Knight – Oxford University

The work of this PhD project aimed to build on previous genetic studies to identify the genetic variants that are causing psoriasis and to understand the way they alter the normal functioning of the immune system to lead to psoriasis. In order to answer this question we looked at four cell types from the immune system that have been identified by previous studies to be important in psoriasis. We obtained these cells from people with and without psoriasis and we looked at how open was the DNA at each position of the genome. The genome, in order to fit inside each of the cells of our body, needs to be tightly packed. When there is the need to read the message contained by a gene, the DNA unwinds and becomes more accessible. As a result, we defined and compared the accessibility of the different regions of the genome in the four cell types from people with and without psoriasis and we found differences at several positions in the genome. The cell type that showed the most differences is called CD8+ and they are seen as the foot soldiers of the immune system, in charge of attacking virus, bacteria or other cell types with various toxic compounds. We also measured the activity of each of the genes of the human genome in the same 4 type of cells and we found that the activity of genes in CD8+ cells were also the most different between people with and without psoriasis. It was very interesting to see that some of the regions that were differently open between the people with psoriasis and people without were located nearby genes whose activity was also altered. For example a gene called GRP56, which is involved in reducing the inflammatory ability of different immune cells, was found to be present in lower amounts in the CD8+ cells of people with psoriasis. This could explain the more powerful response of the immune system that contributes to developing psoriasis.

Measuring gene activity in the affected and non-affected skin of 3 people with psoriasis discovered several genes for which levels in the two types of skin were different. One of those genes, IFIH1, is regulated by a genetic variant that has been associated with psoriasis in previous studies. The genetic variant protects from psoriasis and seems to reduce the activity levels of this gene, IFIH1, which is involved in switching on the inflammatory response and could therefore also be a very interesting gene target for new treatments.

Overall, this research represents a step forward in how to study the function of particular genetic variants in the development of psoriasis. This study not only uses samples taken from people with psoriasis but also has generated different types of data from each of them. This will hopefully help to make complete the jigsaw of the genetic susceptibility in psoriasis and eventually will contribute to improve the quality of life for people with psoriasis through the development of more efficient and effective treatments.

PhD Studentship - Psoriasis and sleep deprivation
Alasdair Henry, supervised by Professor Chris Bundy - University of Manchester

Prior to starting this research, studies examining the extent, characteristics and factors associated with sleep disturbance in people living with psoriasis were relatively scarce. This was identified in study one which reviewed the literature, finding that current research demonstrated significant variation in the rates of sleep disturbance, limited use of sleep-specific assessment tools, and that current literature is typically of poor quality.

Given the current literature, a comprehensive investigation of sleep in psoriasis was warranted. In study two we showed that sleep disturbance was common, affecting more than 75% of participants. Poor sleep quality and obstructive sleep apnoea (OSA) were associated with more severe psoriasis, and poor sleep quality was independently associated with psychological (thoughts and worries at night, low mood,) and physical variables (itch and body not feeling ready for sleep at night). In addition, short sleep duration and difficulties initiating and maintaining sleep were documented. Finally, in agreement with other research, this study found an increased likelihood of OSA in those with psoriasis. This study highlighted that sleep disturbance is common in psoriasis, and that it is associated with both psychological and physical variables.

Study three investigated sleep disturbance in people with psoriasis, with a focus on the associated factors identified within study two.. Sleep difficulties appeared to be persistent and present for a number of years. Difficulties were associated with psoriasis-specific features including thoughts and worries about psoriasis and psoriasis symptoms. However, the thought processes (e.g. worry, rumination, uncontrollable thoughts) described were similar to those described in insomnia in general. Coping strategies were limited in their effectiveness at improving sleep, with many exacerbating sleep difficulties. Furthermore, psoriasis flares were described in the days following poor sleep, which could often negatively feedback on sleep. Importantly, participants reported a lack of attention provided to sleep by healthcare professionals, and that their concerns were often belittled or diminished when seeking help. This study indicated the significant influence persistent sleep disturbance has on the lives of people with psoriasis and that the links between psoriasis and sleep disturbance appear to be bi-directional.

The primary aim of study four was to examine the relationship between sleep and the next day experience of psoriasis. Results of this study indicated that daytime psoriasis symptoms predicted sleep fragmentation and that pre-sleep arousal predicted perceptions of sleep. In contrast to the findings of studies two and three, psoriasis symptoms did not emerge as robust predictors of sleep parameters. Nevertheless, relationships between sleep and next-day functioning were evident with both objective and subjective parameters significantly predicting next day fatigue, sleepiness and concentration. Findings from this study suggest that targeting pre-sleep arousal may confer improvements upon sleep and functioning the following day.

Taken together, the four studies provide a multi-dimensional and detailed understanding of sleep disturbance in psoriasis. Importantly, they highlight psoriasis-specific factors associated with sleep disturbance and document the significant detrimental impact sleep disturbance can have on the lives of those living with psoriasis. Based upon the findings of these studies it seems likely that currently available treatments for sleep disturbance, notably cognitive behavioural therapy for insomnia may be effective at improving sleep and daytime functioning in people with psoriasis.

PhD Studentship - Oxidised lipids and their role in the immunopathology of Psoriasis
Michael Olding, supervised by Dr Tim Millar, Dr Mike Arden-Jones and Professor Eugene Healy – University of Southampton

People with psoriasis have been found to have abnormal levels of lipids in their blood. While these waxy or fatty substances play a number of important roles in the body, abnormal lipid levels are known to be a key factor in other conditions such as heart disease. This project looked at whether different levels of lipids affected inflammation and blood vessel formation, and could therefore be playing a role in psoriasis.

It was found that lipids were important for maintaining immune cell proliferation and supporting new blood vessel formation. In addition, oxidation (the process that makes iron rust) of a lipid called LDL (low density lipoprotein) and the concentration of oxidised-LDL was found to be important in regulating inflammation. While further work is needed to understand how oxidised-LDL causes inflammation, this work may provide the basis for a new drug target to treat psoriasis.

PhD Studentship - The Genetic Basis of Pustular Psoriasis and its Overlap with Psoriasis VulgarisDorottya Maria Berki, supervised by Dr Francesca Capon, Professor Richard Trembath and Professor Jonathan Barker -King's College London   

Pustular Psoriasis (PP) is a rare and disabling inflammatory skin disorder that is associated with an increased risk of plaque psoriasis. While mutations in two genes (IL36RN and AP1S3) have been shown to cause PP, less than 30% of people with PP have these mutations. In addition, the main genetic mutation associated with plaque psoriasis has been shown to not to be associated with PP. As a result, the genetic causes of PP and the link with plaque psoriasis remain poorly understood. This project aimed to address this.

In the first part of the project, the possibility that the IL36RN gene may contribute to plaque psoriasis susceptibility was investigated. The results suggested that this important genetic factor of PP does not the increased risk of plaque psoriasis.

Next, the CARD14 gene, which had been previously associated with plaque psoriasis that runs in families, was looked at in people with PP. A mutation was found in a small number of people with PP, predominantly people of Asian descent with PP, which caused constant CARD14 activation.

PhD Studentship - The role of exercise on cardiovascular disease risk in psoriasisLisa Auker, supervised by Dr Helen Young, Professor Christopher Griffiths and Dr Lis Cordingley -University of Manchester

People with psoriasis have an increased risk of cardiovascular disease (CVD) and traditional CVD risk factors are highly prevalent in the psoriasis population. We hypothesised that individuals with psoriasis may avoid physical activity, which may contribute to their elevated CVD risk.

The aims of this PhD were to: i) identify the barriers to cardiorespiratory fitness; ii) determine whether physical activity influences arterial stiffness and cardiorespiratory fitness and iii) identify biomarkers of physical activity and arterial stiffness in patients with psoriasis.

In this study, over 50% of people with psoriasis failed to meet the recommended guidelines for exercise as provided by the American Heart Association. Psoriasis severity impacted on exercise behaviour and the DLQI (Dermatology Life Quality Index) identified six key psoriasis-specific barriers to physical activity, including: skin sensitivity, embarrassment, clothing choices, social/leisure activities, engagement in sport and treatment of psoriasis. Controlling blood sugar and lipid levels was found to have a significant impact on arterial stiffness, which is a preclinical indicator of future CVD risk. Importantly, we found that regulation of these biochemical parameters could be modulated by physical activity, thus providing a means to diminish the CVD risk of patients with psoriasis. Given the CVD risk in patients with psoriasis, these findings strengthen the need for intervention.

In addition, through arterial function assessment, we identified that measurement of the diastolic reflection area had utility as a bed-side measure of exercise profile which could provide a means to measure adherence to exercise in the psoriasis population.

Autophagy: a novel therapeutic target for psoriasis.
Professor Nick J Reynolds - Newcastle University

A number of effective psoriasis therapies are strong inducers of autophagy, which is a process of ‘self-eating’ where a cell will degrade or recycle damaged components. In contrast, drugs that make psoriasis worse block autophagy. This suggests that autophagy activation may play a role in the clearance of psoriatic plaques, which was investigated in this project.

Damage to a cell component called mitochondria is known to trigger autophagy. The topical treatment Dithranol can cause mitochondrial damage and cell death, but it wasn’t known if autophagy contributed to the clearance of psoriatic plaques by Dithranol treatment.

The study found that Dithranol activates autophagy in skin cells and that the damaged mitochondria are degraded by autophagy. The results also suggested that autophagy is needed to cause cell death in response to Dithranol treatment. This project also further clarified the signalling pathway that allows Dithranol to cause skin cell death. These findings not only support the hypothesis that autophagy is potential therapeutic target for psoriasis, but the further understanding of the mechanism behind Dithranol could lead to the development of new avenues for potential treatments.

Cochrane Review update: Topical Treatments for Chronic Plaque Psoriasis                                                               Dr Anne Mason - University of York

This review describes average benefits of different topical treatments (i.e. treatments applied to the skin), while recognising that individual patients will vary in their experiences of each treatment.

The evidence was based on 175 studies that included 34,808 people. Studies were typically about 7 weeks long, but ranged from 1 to 52 weeks. Vitamin D products were found to work better than placebo (the base cream or ointment). Potent (strong, e.g. betamethasone dipropionate) and very potent (very strong, e.g. clobetasol propionate) topical corticosteroids were also effective.

Some studies compared vitamin D products directly with potent or very potent corticosteroids. These products had similar effects when applied to the body, but corticosteroids worked better than vitamin D for scalp psoriasis. Treatment that combined vitamin D with a corticosteroid was more effective than vitamin D alone and more effective than the topical corticosteroid alone. Vitamin D products generally performed better than coal tar, but studies found conflicting results when comparing vitamin D with dithranol.

Whether applied to the body or to the scalp, potent corticosteroids were less likely than vitamin D to cause ‘local adverse events’, such as skin irritation or burning, and people were therefore more likely to stop using vitamin D products. When studies examined whether topical treatments had effects within the body (‘systemic adverse events’), we found no difference between placebo and any other treatment. However, this may be because many trials did not properly assess systemic adverse events rather than because there really was no difference.

More long-term studies would help doctors and people with psoriasis decide on the best way to treat this chronic condition.

A multi-centre, prospective, cohort study to establish clinically relevant pharmaco-genetic markers of systemic treatment outcomes in patients with severe Psoriasis.
Dr Catherine Smith - St. John's Institute of Dermatology, London

This study has led to the development of one of the largest psoriasis bio-resources of DNA, RNA (the molecule produced from DNA) and blood serum in the UK. Over 2,000 people with psoriasis were recruited, all of whom are also taking part in the BADBIR study. This means that the collection of biological samples have corresponding clinical data available from BADBIR, allowing future studies to compare biological differences with clinical outcomes.

In addition, the development of this bio-resource proved to be fundamental to the successful bid to the MRC to build the Psoriasis Stratification to Optimise Relevant Therapy (PSORT) Consortium. PSORT will provide ongoing funding to the bio-resource, as well as providing £7 million of investment to bring personalised medicine to people with psoriasis.

Signal transduction of mechanical stress in normal and psoriatic skin.Dr Julia Reichelt - Newcastle University

This study found that psoriatic skin reacts differently to non-psoriatic skin in response to mechanical stress (stretching). A number of different signalling proteins were investigated and it was found that proteins that were activated in non-psoriatic skin following stretching were not activated, or only weakly activated, in psoriatic skin.

In particular, p38 MAP kinase signalling which, though found to be activated in psoriatic skin, was significantly weaker than the activation seen in non-psoriatic skin. This activation was so weak that proteins which are normally activated by p38 were not activated upon stretching of psoriatic skin. One of these proteins, MSK1 (mitogen and stress-activated kinase 1) is known to stimulate the production of anti-inflammatory signalling proteins called cytokines and can therefore act as a negative regulator of inflammation. This data suggests that the regulation of MSK1 may play a role in psoriasis and MSK1 may be a new therapeutic target.

PhD Studentship – The role of genes predisposing to epithelial inflammation in the pathogenesis of psoriasis.
Maria Quaranta, supervised by Dr Francesca Capon, Professor Richard Trembath and Professor Jonathan Barker – King’s College London.

It has long been recognised that subtle genetic defects can make some individuals especially vulnerable to inflammatory diseases. Prior to the onset of this study, our group had identified alterations in two particular genes (known as IL12B and IL23R), that had been previously shown to malfunction in inflammatory bowel disease (IBD). Thus, the aim of this study was to investigate whether psoriasis sufferers also carried defects in other IBD genes.

We investigated a total of 29 IBD genes, which were examined in more than 1,200 psoriatic patients. This systematic analysis identified alterations in a third CD gene, known as CDKAL1. Of note, CDKAL1 defects had also been found in patients suffering from type II diabetes. This is of great interest, as it might explain why diabetes occurs at a higher frequency among psoriasis sufferers, compared to the rest of the population.

In the second phase of the research, we investigated how CDKAL1 defects might contribute to disease onset and used genetic engineering techniques to switch off the gene, in cells grown in a culture dish. The analysis of these cells revealed significant alterations in the production of molecules that contribute to inflammation, suggesting that this might be the mechanism whereby CDKAL1 contributes to CD, psoriasis and diabetes susceptibility. More broadly, these results indicate that some disease processes can lead to the onset of different clinical conditions. This notion, which is supported by the results obtained by other groups, has important therapeutic implications, as it implies that similar agents could be used for the treatment of inflammatory diseases such as psoriasis and CD.

A study to investigate self management practices and their development in adult patients with mild to moderate psoriasis.
Dr Steven Ersser – University of Bournemouth.

The main treatment for mild to moderate psoriasis is the regular application of topical medication by the individual. At present little is known about how people with psoriasis self-manage and how they may best be supported in this. This study aimed to explore how adults with mild to moderate psoriasis manage their condition and to identify strategies that can support people to help them self-manage effectively.

The study found that people with mild to moderate psoriasis do not always achieve what they perceive to be optimal self-management. They often do not use topical therapy systematically and frequently abandon it if rapid improvements are not seen. Providing individualised education about improving effective adherence techniques was identified by the patients as one of the factors that would be likely to improve self-management.

In conclusion, people with mild to moderate psoriasis continue to find self-management problematic; however, they can identify strategies that could enable them to become more effective in self-managing. There is a need to incorporate these strategies in “self-management plans” in order to support individuals to self-manage as effectively as possible to help improve their skin condition and quality of life.