New hope, new treatments for eczema
This is an article from our magazine, Exchange, which was based on a talk given by Professor Andrew Wright (Consultant Dermatologist at St Luke’s Hospital, Bradford, and Honorary Visiting Professor at Bradford University) at our Eczema Information Day in September 2018.
The development of new treatments for eczema has lagged behind that for similar conditions. For example, a number of new treatments, taken by injection, have proven very effective for psoriasis in recent years. Many people with severe psoriasis who, in the past, would have been in and out of hospital, now only come to outpatients every three months to check that their skin is still clear. Unfortunately, there hasn’t been the same improvement in the management of eczema … but there is a profusion of exciting new treatments on the horizon!
Eczema is a multifactorial condition: it’s caused by many contributing factors – genetic and environmental – rather than a single factor. This multifactorial aspect of eczema is significant because it has led to a relatively slow improvement in the management of the condition, even though we now have a greater scientific understanding of it.
Understanding inflammatory pathways
In recent years, our understanding of the mechanisms of inflammation has improved tremendously. We now understand more about how cells interact with each other to produce different chemicals, which then ‘switch on’ other cells producing more chemicals and causing inflammation or itching.
Each cell in the skin uses chemical messengers (for example, interleukins) to communicate with other cells to tell them what to do. When you get the wrong type of inflammation, it’s because a cell has told another cell the wrong thing, or it has been reprogrammed or incorrectly programmed.
When I was 19 and doing a degree in immunology, we knew about interleukin 1 and interleukin 2, and thought these were the main messengers in inflammatory pathways. We have now identified interleukin 36 or 37! In fact, there are hundreds of chemical messengers telling the skin what to do, and part of what goes wrong with people with inflammatory conditions is that these messengers are either under or overworking.
Inflammation is a cascade process, almost like an avalanche. One cell tells two cells to do something, those two cells tell four cells to do something, and those four cells tell eight cells to do something. Suddenly there is a huge mass of cells doing the same sort of thing. ‘Upstream’ is right at the beginning of the process and the further down you go is ‘downstream’. When you switch off the mechanisms for inflammation by using steroids and immunosuppressant drugs, you are often working upstream; it’s a non-specific calming down of all the things that are communicating with each other. The problem with cutting something off upstream is that you don’t necessarily learn about the benefits of the downstream mechanisms; you are blocking things off at an early stage. Hopefully, the newer treatments for eczema will be downstream treatments – the further downstream you go with a treatment, the fewer side effects you should have.
The fact that eczema is multifactorial has hindered the development of new treatments for it. For psoriasis, if we inhibit one of the interleukins that play a big part in the condition, 17 or 23, we can effectively ‘switch it off’. The problem with eczema is that there isn’t one interleukin that controls it. The discovery of dupilumab – a monoclonal antibody that switches off two different messengers – helped us understand that such antibodies, which interact with messengers and switch them off, could be effective for eczema.
Dupilumab and other blocking agents
Dupilumab was recently launched in the UK. It’s a relatively expensive treatment and the NICE guidelines indicate that it is for people whose eczema has failed to respond to a variety of other recognised treatments, including at least one immunosuppressant drug. But it does represent the dawning of a new era. Dupilumab isn’t without side effects. Some patients get quite severe conjunctivitis when using it, although this is relatively rare. So far it has proved to be an extremely safe treatment for those it has helped.
What is promising and gives great hope is that there are many other similar blocking agents in the research pipeline. These include:
Dupilumab is a costly treatment relative to existing drugs to treat eczema. This gives pharmaceutical companies an incentive to develop more treatments, for which they can charge a similar amount. In psoriasis, it’s been a number of years since the first biologic treatments were introduced. Since then many companies have introduced so-called ‘biosimilars’, which is leading to a significant reduction in the cost of these treatments, thus making them more widely available. Eczema drugs will go through the same cycle, with the drugs initially being very expensive.
Nemolizumab is an eczema drug that is currently at phase 2 stage. Patients on this drug experienced a 40% improvement in their Eczema Area and Severity Index (EASI) score.
Now the inflammatory pathways that we think play a part in causing or exacerbating itching have been discovered, pharmaceutical companies are looking at drugs and molecules that will inhibit some of the messengers that control these pathways.
Some new developments are outlined here:
- Phosphodiesterase is one of the targets. Crisaborole cream (brand name Eucrisa), a phosphodiesterase-4 inhibitor, was recently launched in North America and has been shown to have a very significant impact on itching. It should soon be available in the UK. It’s not going to change the world but it will lead to more research into phosphodiesterase inhibitors. Other drugs in this group have reached phase 2 and 3 levels in trials. It’s likely that these will be effective non-steroid treatments – particularly for itching – and will probably be as effective as topical calcineurin inhibitors (tacrolimus and pimecrolimus). The first Janus kinase (JAK) inhibitors were introduced to treat very severe rheumatoid arthritis. It was found that they helped a number of other conditions, including alopecia, lichen planus, psoriasis and eczema. The biggest problem with JAK inhibitors is that when given by mouth or injection, they can have significant side effects. However, since they are very small molecules and can be absorbed through the skin, a number of companies are developing topical JAK inhibitors, which is an exciting development.
Other developments in the pipeline are:
- Transient receptor potential subfamily V member 1 (TRPV1) is part of another inflammatory pathway that seems to have a significant role to play in eczema. It appears to be at least partly involved in barrier repair mechanisms and the prevention of water loss from the skin. This may produce a topical treatment in the future.
- Regarding drugs that inhibit specific cells, we divide lymphocytes into t-cells and b-cells. T-cells play an important role in eczema, and the inhibition of t-cell activity could lead to the development of exciting new treatments. Tezepelumab is currently in phase 2 studies and similar drugs are in trials at the moment.
- Another pathway is the prostaglandin/leukotriene pathway. There is a lot of interesting work in this area, giving rise to relatively straightforward, simple drugs that can be given orally – there are many currently in the early stages of trials, which could well be used in maintenance therapy, just as montelukast is currently used in asthma.
- There are a lot of other targets we can look at. There has long been a theory that infection on the skin aggravates the immune system, which is why simply treating infection in someone with eczema can often improve their condition. Work is currently being carried out looking at drugs that could antagonize the chemicals produced by bacteria, and there is a topical anti-bacterial gel under trial for this at the moment. This could be extremely effective for people with eczema.
- Bleach baths have been around for a long time; there is some evidence that dilute bleach and similar chemicals can have anti-inflammatory properties on the skin. It’s an area that needs more work – one of those areas that’s included in old textbooks but which hasn’t been properly assessed.
- Regarding antihistamines – research has focussed on H1 and H2 antihistamines and seems to have missed out H3, and there is now work on H4 – a whole new group of antihistamines. I normally teach that antihistamines don’t help much for eczema, but there is some evidence to suggest that there are histamine receptors that are not H1 or H2, and that H4 antihistamines might help with eczema itch.
- One exciting thing developed by a team in Bradford is a non-invasive way of measuring what inflammatory markers there are in inflamed skin. We use a fairly sticky sellotape, putting it on the skin before taking it off again and using a special staining technique. This enables us to see what type of inflammation there is in the skin. If we use it regularly in patients who are using treatments, we can see what pathways have been switched on and off by the treatments we are using, and therefore what other drugs we can use to treat the pathways that are still active in those patients.
The future is looking bright for eczema treatments. There is a plethora of new treatments in the pipeline, several of which should be available within a few years. This has been driven in part by the success in treating psoriasis. The fact that eczema is a multifactorial condition is likely to mean that many of these new treatments will be moderately effective for some people. When these new drugs are launched, we’ll need to go back and look at the pathways they are acting on – and I strongly suspect that we may be using at least two if not three of these new treatments as downstream blockers of the inflammatory pathway. This will mean we don’t get the side effects we see with the upstream blocker treatments, but we will still reap the benefits. It’s likely to take some time for us to work out which combination of new treatments will be most beneficial for most people.