Providing new hope to patients with difficult-to-treat Rheumatoid Arthritis

Neutrophil Group photo

Our hands do a lot of work for us on a daily basis, from tying our shoe laces to typing emails. We may take the work done by our hands for granted, but imagine if moving your hands and fingers was so painful that even the simplest task, such as getting dressed or making a cup of tea, felt impossible. This is what every day feels like for people living with rheumatoid arthritis. While there are medications available to treat some forms of the disease, occasionally patients won’t respond well to these treatments and find themselves unable to do even the easiest tasks. Dr. Helen Wright, a research fellow here at IIB as part of our  research theme, is focused on learning more about this disease and developing new ways to screen patients. This research will better enable doctors to work with individual patients in order to find their best treatment options available.

Helen has been here at the University of Liverpool since earning her PhD in 2009. Her research focuses on the role of neutrophils in autoimmune diseases, including rheumatoid arthritis. Neutrophils are the most abundant type of white blood cells, with billions of these cells circulating in our blood stream. They are the blood cells that provide us with fast, ‘first-line’ protection against infection. When these cells are working normally, neutrophils patrol the blood stream and when they come across any bacteria, fungus, or other ‘foreign’ invader, they secrete toxic chemicals that can break down and kill the infecting agent. This attack causes the inflammation and red colouring that you’ll see on your own skin when you get a small cut or scrape.

However neutrophils sometimes don’t attack just foreign invaders: in autoimmune diseases, there is a widespread activation of neutrophils, and they’ll attack your own cells with these toxic chemicals in the same way that they attack an infection. Rheumatoid arthritis happens when these hyper-active neutrophils get into joints and cause inflammation and a break-down of cartilage. “Patients with arthritis have many joints – including hands, feet and knees – that are in a lot of pain, and even basic things like brushing their hair become very painful and difficult. Many people with manual jobs, or any sort of work that involves using their hands or having to stand for long periods of time, will have to quit their jobs”, Helen commented. Over 500,000 adults in the UK live with the disease, and in general many people do well with standard drug treatments, with only occasional disease flare-ups. But a small yet significant number of patients have extreme forms of the disease and don’t respond at all to standard treatments. These patients find it difficult to complete simple tasks such as cooking or getting dressed without significant help.

Learning how drugs work

Helen’s research group is studying how autoimmune diseases manifest and how diseases like arthritis can be better treated for the patients that don’t respond well to a typical drug regimen. One of their approaches is to focus on how arthritis drugs target neutrophils. “We know that these drugs work in reducing inflammation and arthritic symptoms, but we don’t know exactly how a lot of these drugs work, or how these drugs specifically alter neutrophil activation”, Helen said. Having a better understanding of how these drugs work and what properties allow them to target neutrophils can allow for the design of better and more effective drugs in the future.

While Helen’s group is very active and focused on a diverse set of topics, one of her most exciting projects is in finding out ways to tell if a person will respond well to a typical arthritis drug regimen or not. Helen’s approach – an example of personalised medicine – is to use gene expression differences between patients who responded well to drugs and those who didn’t. This data is then used to see what biomarkers could be developed as a way to screen patients before therapeutic treatments begin.

By looking at differences in gene expression, Helen has been able to find out what genes are more prevalent in patients that respond well to drugs and those that don’t. Using a method called RNA-seq, Helen’s group has taken RNA (the form that expressed genes take after they are copied from the genomic DNA) from patients who respond well to treatment and those who don’t. Her group has identified which genes are expressed at higher or lower levels in patients who do or don’t respond to therapy. This allowed Helen’s group to identify two separate groups of genes that are only expressed in responders (10 genes) or non-responders (13 genes) to treatment and these genes are able to distinguish the two groups of patients.

What next?

The next step of Helen’s work is to develop these biomarkers as a tool that can be used by clinicians to predict if a patient will or won’t respond to a drug therapy. “By doing these predictive screens, you can save time and money by not giving a standard drug to someone it won’t work for, and you can focus that time and energy on getting them on a treatment that will work better for them” says Helen on the importance of being able to use these screening tools in the clinic.

The next step is also one that will require a new set of collaborations and experiences: setting up a full clinical trial. Helen is currently working on grant proposals to get the trial off the ground, one that will involve over 200 patients, at least six collaborating research centres and medical clinics, and patient follow-throughs of up to 12 months after the trial. The clinical study in its entirety will take almost 3 years from start to finish.

“This is my first time being involved with a project as big as this, and I’ve realised that scaling up this project into a national study will take a lot of time and energy. In this field, you go from the science to the clinical aspects and then into the legal and business side of things, and I’m completely new to the legal and business aspects of this work” said Helen.

Working with patients

When Helen isn’t busy analysing data or writing grants for the clinical trial, she can be found either in the lab or in the hospital working with patients, doctors, and researchers. She and her group members are all trained to take blood on healthy individuals and can be found regularly recruiting fellow staff at IIB for blood donations. “We need to have fresh neutrophils for our experiments in the lab,” Helen said, and admitted that she and other members of the group have had their fair share of blood drawn from themselves to get enough samples to work with.

In the hospital, Helen and her team visit arthritis clinics to collect blood from patients, with all collections done on a volunteer basis. They work with clinical specialists to identify patients with rheumatoid arthritis who have varying responses to drugs and then Helen and her research team will talk with each patient about the work they are doing and what its impact will be. Since blood is already taken as part of a normal screen, it usually takes very little additional time to provide a research sample by filling an extra couple of collection tubes with blood.

Helen has found that most patients are generally interested in what her group is doing and are happy to help. “You have to say that the work you’re doing won’t directly impact the patient themselves but could instead help a future patient. So when you talk to patients, you have to have an altruistic angle in how you talk about the work.” Helen said. “The only reason we have so many drugs to treat rheumatoid arthritis now is because some patients in the past donated their blood for research, to benefit the patients of today.  Someone diagnosed with rheumatoid arthritis today has a much better chance of being treated in a way that prevents serious damage to their joints than someone diagnosed, say, 30 years ago. But we still have a lot of work to do, particularly for those patients with very severe, hard-to-treat, rheumatoid arthritis.”

Mature student

While Helen’s career is driven by her degree and background in molecular biology and biochemistry, her passion comes from having a connection to people and patients in her work. “I spent a lot of time studying signalling pathways in university but I was always more of a people-person, and I wanted my work to focus on treating human diseases. I like my job because it feels satisfying to have this balance between science and connecting with people,” Helen said. Helen received her undergraduate degree from the University of Central Lancashire as a mature student and was 35 years old when she completed her PhD at the University of Liverpool. She transitioned into research with more direct clinical applications by collaborating with doctors in the rheumatology clinics at the Royal Liverpool and Broadgreen Hospital and University Hospital Aintree. She is very passionate about her research and at the end of her PhD was awarded an Arthritis Research UK Foundation Fellowship to support her work.

Helen enjoys that each day is very different, with time spent analysing data, working with students and postdocs, and visiting hospitals and clinics to talk to patients. “By far the best part of my job is talking to patients, explaining the science of what we do, and convincing patients and clinicians to help us out. I’m really driven by the human side of research. There are so many patients with rheumatoid arthritis that are so hard to treat, but if we can find a better way to find out who these patients are, it can help doctors find better treatments for them so they can get back to living their lives freed from the pain of arthritis” said Helen.

If you want to see Helen’s group in action, check out their video: