Sample 3 of 3 from Under The Skin: My Fight To Save The NHS
My research was gathering momentum. I had chanced upon the mechanism for severe drug toxicity with azathioprine, a drug that had been prescribed for decades; this resonated throughout dermatology. To have a science-based explanation for this toxicity made clinicians sit up and take notice. There was an important patient safety issue at stake with a simple laboratory test which could detect patients who were vulnerable to this severe side effect. Without the test, the danger was severe suppression of the bone marrow leading to a life-threatening fall in the white cell count (white cells are important in fighting infection; low white cell count renders patients vulnerable to severe bacterial infections and sepsis). My publications on this niche topic of azathioprine toxicity started to accumulate.
In due course I was asked by my professional association to lead a small team in writing a clinical guideline on the use of azathioprine in dermatology. This was the first clinical guideline from the British Association of Dermatologists relating to a drug. It was also the first drug for which our professional association published an on-line patient information leaflet. Clinical guidelines emerged in the 1990’s as an instrument for raising standards in healthcare, based on a review of the literature and expert opinion, and became an important work stream for our professional body. It was exciting to see my academic efforts noted by others, and humbling to realise that our recommendations would be heeded by clinicians throughout the world. We carefully considered the issue of pre-testing patients for susceptibility to massive bone marrow suppression with azathioprine. There was not yet sufficient evidence to support mass screening of patients prior to prescribing azathioprine; furthermore, the blood test was not yet widely available in the NHS. But we raised this issue and provided details of UK laboratories that could offer this test.
The final authorship meeting was at Willan House, the headquarters for the British Association of Dermatologists in London’s Fitzroy Square. We were now leading the way on this topic, and I was lucky to have two highly respected colleagues as co-authors. We agreed on the final draft of the publication, and went our separate ways. Knowing that in a few months’ time this clinical guideline would be published in the British Journal of Dermatology, and dermatologists throughout the world would be taking on our recommendations, was the result of years of research and great team work.
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Dermatology in Cardiff was an opportunity to take stock. Here the department felt like a family, safe and supportive for trainees who were guided by experienced dermatologists. Importantly, this department had critical mass. It was stimulating to be in such a large and dynamic team, with a wide range of research activities. I soaked it up, learning about research and how best to do it. I soon discovered that research required clarity of purpose and a professional team approach. Research also required funding, but grants were hard to obtain, tending to go to those with a record of success. I spent the next few years completing my clinical training, and observing how research was done. I did small research projects, and kept publishing.
Perhaps the most important lesson I was to learn from my time as a junior dermatologist in Cardiff was the concept of running research and education as commercial enterprises. The Professorial head of department was an academic entrepreneur. He was successful at attracting money to pay for his departmental research. I observed how to be professional in setting up and running clinical trials. Participation in these clinical trials generated money for our department which was needed to pay the salaries of academic staff, and to keep the academic department afloat. This was my first experience at participating in randomised controlled trials, the highest level of evidence to assess the effectiveness of treatment. These studies were set up and funded by pharmaceutical companies. They were typically multi-centre, which meant that our unit in Cardiff was just one of many units in the UK and in Europe doing exactly the same trial.
This was also an important time for my family. Sarah and I moved to Cardiff with our baby Rebecca. It was a period of consolidation and learning, building up a large network of close colleagues and friends. Additionally, we had another baby on the way. I had achieved more than I was expecting, but had not yet gained a research degree (a research degree is one where a significant element of the degree involves research that was novel and original). Without this, there was no chance of becoming a clinical academic (a doctor who does both research and clinical medicine). In the absence of a research degree the window of opportunity for this career path was closing fast.
I had decided to specialise in photodermatology (skin conditions characterised by sensitivity to sunlight), a sub-speciality of dermatology which was completely absent from this part of the UK. It appealed to me because it was possible to objectively measure and assess the disease using sophisticated optical phototesting equipment. I knew it to be a field of dermatology characterised by great suffering a disability for affected patients. This was a field of medicine where my efforts could make a difference to patient care. I was also attracted to photodermatology by the potential for clinical research. The best clinical research, I had discovered, involved looking at the condition from different but complimentary perspectives: the patient (in other words, how the disease impacts on the patient and their quality of life); the dermatologist (in other words, the clinical features observed and recorded in the skin by the clinician); objective laboratory-based investigation. If all three were done to a high standard, it was possible to generate high quality research which was able to advance our understanding of these diseases. With improved understanding came the potential for developing new treatments, which in turn could move things forward to improve patient care.
In 1994, Professor Ronnie Marks helped me to set up a new clinic at the University Hospital of Wales in Cardiff. I took referrals from consultant dermatologists across South Wales, the Midlands, Bristol and the South West of England, a huge catchment population for this new clinic dedicated to patients with sensitivity to sunlight. In one of my first clinics, a boy aged six attended with his parents. The room for the clinic was cramped: three medical staff, Howard and his parents. Howard had profound learning difficulties and was also physically disabled. He was tiny for his age, sitting in a giant pushchair, being unable to walk. Although unable to talk, Howard smiled a lot and made affectionate babyish sounds by way of communication. His parents were both loving and attentive, completely relaxed with his care, attending to his needs. It was apparent that they had limited funds, and were coping as best they could with the challenges of caring for their son. They knew all about the health consequences of this metabolic condition.
‘When did you first become aware that Howard was sensitive to sunlight?’ I began with.
‘As soon as we took him outside as a baby. It was March, the first sniff of spring. Howard was nearly six months old. I took him outside in my arms, wrapped up because it was still a bit chilly. Only his face and hands were showing.’
‘And what happened?’
Howard started crying. He was such a contented and placid baby; this was unusual. I sniffed his bum, thinking he might have pooed himself, but all was well. I took him back inside to try to calm him down. When I took off his clothes, I noticed his face and hands were bright red, like sunburn.’
Howard had a brother and two sisters, none of whom were affected by photosensitivity. They showed me photographs (this was pre-mobile phones), which included a family shot on the beach. In the middle of the group picture was someone small, wearing a home-made one-piece suit, covering all of the skin, including the face, with small holes for the eyes and mouth: it was Howard enjoying a day on the beach with his family.
After this consultation I did some background reading. I also spoke to other colleagues around the UK who specialised in photodermatology. No one knew anything about this condition, and there was nothing about it in the dermatology literature. It was apparent that this was a new, previously unrecognised photosensitivity condition. I then heard about a trainee geneticist in Newcastle, Anna, who was doing research into this metabolic condition. Two thirds of the twenty-five children she had seen in the UK with this condition shared this story of sun sensitivity. It turned out that these kids also had multiple health issues: feeding difficulties; digestive difficulties; failure to grow; profound physical problems; behavioural problems; speech and language difficulties. According to Anna, sensitivity to sunlight came very low on the hierarchy of problems that the parents were faced with. Furthermore, covering the skin with clothing or sunscreen seemed to solve the problem for most of these kids. Howard was the exception, as his parents were determined that he should join his siblings for trips to the beach. In other words, it was the context of the sun sensitivity that was making Howard’s parents seek help, which led to her attending my new skin photosensitivity clinic in Cardiff.
We arranged for Howard to attend for special phototesting, to determine the nature of the photosensitivity. We also observed the skin reaction first hand, observing what happened to a small area of exposed skin following a few minutes of sun exposure. We carried out some blood tests to exclude other forms of photosensitivity, and wrote up the case for publication as a case report in the British Journal of Dermatology. We included photos of the skin reactions to sun light, and reported the specialised photosensitivity tests carried out. This would be a first report of a new photosensitivity disorder. Howard’s parents had consented to their son’s case being published in a medical journal.
I had also decided to carry out a UK-wide study as I was convinced that it was more than coincidence and actually represented a new and hitherto unreported form of photosensitivity. Howard’s case had led to the identification of an important feature of this new photosensitivity condition: it was mediated by ultraviolet A radiation (UVA). UVA is biologically much less potent than Ultraviolet B radiation, which is primarily responsible for sun-burn reactions in the skin. This was relevant to Howard, as conventional sunscreens at that time were mainly formulated to protect against UVB. He required a sunscreen which protected against UVA as well as UVB, to prevent sunburn when on the beach at Southern Down, Ogmore-on-Sea or Barry Island with his siblings. I was now able to explain this to Howard’s parents, and prescribe a suitable sunscreen. I also recommended that the family car to be fitted with special clear window film to block UVA, to make it safer for Howard. It was great to know that these small practical measures would help to prevent future painful sunburn reactions.
This discovery enabled me to carry out a systematic study on this new inherited photosensitivity syndrome; it would be ideal for a medical doctorate. Fortunately, the NHS was supportive. The medical director of my Trust granted me one day per week for my medical doctorate studies. I found myself a research supervisor, at Kings College, London and wrote a study proposal. I then registered for a medical doctorate degree with London University. Within two years I had completed the project, written it up and submitted my thesis. I also gained a number of publications along the way, which helped to establish me within the UK academic community of photodermatology. I successfully defended my thesis and the medical doctorate was awarded by London University.
With the medical doctorate secured, I now needed to develop my own strategy for research. This time I was able to take over unused offices at St Woolos Hospital in Newport and set up a small academic dermatology unit. This was the base from which to coordinate courses and commercial clinical trials to generate an income stream to support our research; before long we had an active unit run by a small team of administration staff.
I focused on one post-graduate research student at a time; over the next 15 years I supervised five junior dermatologists in medical doctorate projects. Two of these five MDs were on porphyrias, the disorder I went to South Africa to study in 2005. One particularly interesting condition called erythropoietic protoporphyria, or EPP for short, is a hard condition to diagnose as there is often nothing to see. Patients develop intense pain in their skin within a few minutes of being in bright sunshine. Most patients had onset of these symptoms in early childhood, often before they could properly articulate what they were experiencing. As there was nothing to see, their parents tended not to be taken too seriously when they sought advice from their GP a few days after an episode of skin pain. The pain was so severe, that these children rapidly sought the shade or went indoors again. If they were quick enough, the pain subsided within minutes, and all was well. However, these symptoms impacted significantly on the child’s quality of life, preventing participation in outdoor pursuits.
Jess came from Yorkshire. She enjoyed telling the story of her mother taking her as a young girl to see the local GP in a village not far from Leeds.
‘She took me t’ see the GP after I had suffered a really painful episode of sun-induced skin pain on’t previous weekend. I was ‘bout eight-years-old. The GP said that all was well, and there was nothing to worry about, and in future mi mam should apply more sunscreen, and no I didn’t need to see a specialist at Jimmies (St James’ Hospital in Leeds). Mi mam hit the roof. She started shouting at the GP and told him he didn’t know nothin, and could she see a better GP, and he must think she was soft-tween ears for thinking her kids were unwell when there was nowt wrong with’m. Corse she knew when there was something wrong! How dare he doubt a mother’s word about her bearns!’
The GP changed his tune. Both Jess and her brother (who had similar, but milder symptoms) were referred to the local dermatology service, where the diagnosis of EPP was eventually established in both boys by characteristic changes in a blood test.
The University Hospital of Wales in Cardiff was already long-established as a preeminent centre for porphyria diagnosis and research on account the professor of Biochemistry, who also happened to be our next-door-neighbour. When he retired, he was replaced by Mike, a young biochemistry consultant. Mike and I set up a cutaneous porphyria clinic and forged a research partnership: Mike had access to the labs and had biochemical expertise; I had access to the patients and clinical expertise. Our first big project was a UK-wide study on EPP, set up as an MD project for Dr Alex Holme, a Scottish Dermatologist who was training in Cardiff.
Two years later we published a large cross-sectional study of EPP in the UK with over 200 patients recruited. This was a key paper for patients with EPP and was followed by many similar papers from around the globe. The combination of carefully recorded clinical features, high quality biochemistry and genetics studies, and the use of a validated quality of life questionnaire in all patients created three different perspectives of the same disorder. It was a potent combination; one we were to repeat in our next big porphyria research study. Alex Holme was first author on a number of studies that were generated by this MD project. He passed his MD with style. An unexpected outcome of this research was the identification of a small group of patients with features that were slightly at odds with the other patients. It transpired that we had inadvertently identified a new and hitherto unrecognised form of porphyria. We collaborated with colleagues in South Africa and France, as they too had small numbers of similar cases. Together we had enough cases to prove the point. The science was strong, and the paper was published in a top American genetics journal.
The second porphyria medical doctorate project we set up was for Dr Ru Katugampola. Ru had confirmed herself to be a hard-working, bright doctor, and was keen to do a research degree before she completed her training in dermatology and became a consultant. There was growing research interest in the most severe and mutilating form of porphyria, Congenital Erythropoietic Porphyria, or ‘CEP’ for short. As a result of the structure of the NHS and the collaborative nature of the biochemical labs, it was possible to set up a UK study on this very rare condition. We identified 17 cases across the UK, but really needed a few more. We again collaborated with Porphyria experts (and friends) based in France and in Switzerland. With the additional cases, we had 26 patients. All patients were visited by Ru, who systematically gathered together the data, photographs and testing that we were seeking. It was the largest and most detailed study of this rare condition that had ever been performed. Again, we used the tried and tested technique of studying the condition from three complimentary perspectives: the patient’s own, by quality-of-life studies; the dermatologist’s, through carefully standardised photography of skin lesions and identification of the features; the laboratory studies, with high quality biochemistry and genetics studies. The overall aim of the study was to come up with a way to help parents of children affected by CEP when faced with the question of a potentially curative bone marrow transplant. The issue being that such a procedure was potentially life-threatening and was not always a success.
Ru Katugampola passed her MD with great aplomb, impressing the examiners in the process. Another successful MD, a string of important research findings which were published in top journals, and important research advances in this challenging condition. By this stage my research interests were broadening. I had become aware of mathematical modelling as a research tool and wanted to learn more about this, to add it to my research repertoire.
A SIX_YEAR_OLD CHILD WITH SENSITIVITY TO VISIBLE LIGHT
Riinu is just six years old. Her skin is still almost blemish-free, just a few small scabs and scars on the back of her hands, and partial separation of the end of a finger nail. Mum and dad are intelligent and attentive; both have well-paid jobs. They are also first cousins; they carried the same dodgy gene, harmless in isolation, but harmful if joined in their offspring by the same dodgy gene from the other parent. This is what had happened in Riinu. They were in the porphyria clinic to better understand the treatment options for Riinu. Riinu is suffering from congenital porphyria, a metabolic disorder with the potential to cause severe scarring and mutilation of sun-exposed skin. Riinu is exquisitely sensitive to visible light. For her skin to remain undamaged, when outside, she would need to cover up with clothing, gloves and a mask to block out all light, for the rest of her life. “We can’t do that to her” they tell me. “Kids need to go outside and play”. “Of course they do”, I agree. We go over it carefully, not rushing the discussion. The only way that Riinu can have a normal life is to have a bone marrow transplant. But this is risky, with failure of the procedure and even death as possible outcomes. How to decide? It is an agonising and impossible choice. We are there to aid with the decision-making process, to help them to think it through, not to make the decision for them. “There is also the prospect of future gene therapy”, we tell them; not as fanciful as it sounded. We knew the French porphyria group were close to achieving this.
Alex Anstey 