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The recent 2015 Autumn Meeting of the Irish Association of Dermatologists, which took place in the La Mon Hotel, Belfast, at the end of September, focused on a number of topics, ranging from chronic urticaria to skin cancer.
In the Novartis Satellite Symposium, which began proceedings, Prof Maurice Van Steensel, Professor of Genetic Dermatology in the College of Life Sciences at the University of Dundee, UK, spoke about the genetics of psoriasis treatment. Prof Van Steensel said research suggests that the final common pathway in psoriasis is regulated by IL-17, a protein with a key role in inflammatory responses.
“It looks like ‘the only game in town’ in terms of how to go with drugs and it is telling us something really, really intriguing about psoriasis,” according to Prof Van Steensel.
Keratinocytes are the major constituent of the epidermis and form the epidermal barrier, and play a major role in skin inflammation.
“Based on the information that we now have, it looks like keratinocytes are responsible for most of what goes on in psoriasis and they signal to various other cell types and mast cells, which are emerging now as a major player,” he said.
Prof Van Steensel dismissed the idea that psoriasis is an autoimmune disease: “It is an autoinflammatory disease caused by hyperactive anti-immune responses to our microbiome.”
He pointed out that IL-17 and IL-23 are involved in fungal immunity, adding that people who are born without IL 23, for instance, are known to get severe fungal infections. Therefore, what could be happening with psoriasis is really an “exaggerated anti-fungal response,” Prof Van Steensel explained.
‘What you want to have is something that is going to offer you very high sensitivity and specificity and prevent that unnecessary biopsy’
“For one reason or another, due to the genetic make-up that people have, the antifungal response gets out of hand and that might be related to the fact that the majority of the genes in psoriasis are involved in things like bacterial pattern recognition and the like,” he said.
“So what might be happening is because of those defects. One of them, for example, is a gain-of-function mutation IN A protein called CARD14. CARD (caspase-associated recruitment domain) proteins are in the business of bacterial pattern recognition. You have a gain-of-function mutation in this protein. Your skin starts to wipe out certain species of bacteria that are normally beneficial and keep others in check and keep the fungi in check. What happens is that those now unfettered will start to grow and your skin recognises that, and now there is this crazy antifungal response, which is psoriasis.”
Prof Van Steensel predicted that the new frontier of treatment for psoriasis is going to involve microbiota.
“That it might actually be the fungi. And if you correct the host response using for example IL-17 inhibition, IL-12/23 or whatever inhibition you like to use, you then go and do something about the microbiota. Once you correct that, you might be able to restore the balance between host and microbiome, because that is what this is all about.”
Chronic spontaneous urticaria
The next presentation in the symposium focused on chronic spontaneous urticaria and was delivered by Dr Niall Conlon, Consultant Immunologist, St James’s Hospital, Dublin.
It is a complex multifactorial disorder, where there is mast cell degranulation, with or without angioedema, and the absence of a defined allergic trigger.
He said that data on the incidence of the condition, which is thought to have a prevalence of approximately 0.5 per cent in the US, is not strong. However, Dr Conlon said that patients with chronic spontaneous urticaria are responsible for a large and increasing number of presentations in his clinic.
“The proportion of chronic urticaria that I can identify from the referral letters has gone up,” he told delegates.
“Hospitals are also an increasing source of referrals. I think one of the reasons for referral rates is that this is a frequently misunderstood condition.”
Dr Conlon said that chronic urticaria is frequently misdiagnosed as an allergic reaction. Stress is believed to be an important contributor to disease severity. Hormonal changes may also be involved, with a striking preponderance in females during middle age.
‘When we are talking about sunlight as a trigger, we also need to look at the detail of that in terms of what sort of sunlight’
Although there is also an autoimmune component, Dr Conlon conceded that it is probably not cost-effective to be testing for this in the clinic.
“My thinking has changed on this; stress is probably a bigger component,” he said.
“Autoimmunity based on a few studies that we have been involved in may be a little bit less important.”
Dr Conlon cited a review of patients in the Immunology Department in the Royal Victoria Hospital, Belfast, which found that the average duration of symptoms in the cohort was about five years, with many waiting a long time to get a referral. Of the patient group, 10 per cent responded to standard-dose antihistamines and 70 per cent responded to high-dose antihistamines, with Dr Conlon suggesting that many of this group could be treated in primary care.
Before the arrival of recent new treatments, he said that 20 per cent of the group, however, provided a “significant management challenge”. The approval of omalizumab as an add-on therapy for the treatment of patients with the condition has been a revelation, according to Dr Conlon. Omalizumab is a recombinant humanised monoclonal antibody that reduces the levels of free IgE and the high-affinity receptor for the Fc region of IgE (FcεRI), both of which are essential in mast cell and basophil activation. Dr Conlon acknowledged that the drug is expensive, which will be an issue for the future treatment of patients.
Continuing, he reported that the establishment of a new referral pathway in his clinic has had a positive impact on waiting times.
“It has made our waiting times much better than they were,” Dr Conlon commented. “We have established protocol-driven treatment, which allows us to identify these treatment-resistant cases, which we want to be focused on in a tertiary referral centre.”
However, one problem that he has noticed is that patients are often reluctant to be discharged. “Sometimes they have waited five years to see us and they don’t want to be let go,” he told the conference.
“They don’t want to go back to the GP, as they say the GP doesn’t understand the condition… certainly, a notion in the Republic is if somebody is referred from a GP practice to an immunologist, they have an immunological process that is perceived as being too complex for primary care. ‘It is too hard; it is an immunology problem.’ Trying to change that approach and to build bridges with primary care, so that the more common conditions immunologists look after can be managed in effective partnership, is certainly a key challenge.”
Imaging in skin cancer
At the beginning of the afternoon session, Dr Emma Craythorne, Consultant Dermatologist and Dermatological Surgeon at St John’s Institute of Dermatology, London, UK, gave a presentation on ‘Imaging techniques in the management of skin cancer’.
Dr Craythorne argued that the ultimate aim of skin imaging techniques is to be able to provide a virtual biopsy.
“What you want to have is something that is going to offer you very high sensitivity and specificity and prevent that unnecessary biopsy,” she told the conference.
“You also want to have something with an instant diagnosis, so if you see a patient you can reassure them or perform the correct treatment straight away rather than have to wait the five days or the 14 days to get what the histological diagnosis is. Another advantage of skin imaging techniques is, when it comes to cutting them out, we can mark out exactly where these end, so for lentigo maligna or basal cell carcinomas, we can mark out where the boundaries of these are so they can be removed to prevent unnecessarily large removal, or even worse, leaving a bit behind.
‘The main hallmark is establishing the correct diagnosis, removing any trigger such as culprit drugs, suppressing existing disease activity, and of course, preventing further flares’
“Also we can use this technology to assess response to treatment, so for somebody who doesn’t want to have any surgery, they can use the topical agents or they can use radiotherapy and the imaging techniques can be used to check if things are clear.”
Dr Craythorne presented a list of the most advanced new technologies, such as: Optical coherence tomography (OCT); reflectance confocal microscopy (RCM); multiphoton microscopy (MPM); fluorescence lifetime imaging microscopy; and multimodal spectral imaging. RCM is “probably the most exciting” out of all the new technologies and along with OCT, is the one which has amassed the most evidence, she commented.
It uses infrared light and interferometric (Michelson) methods to generate real-time vertical images. Confocal microscopy can achieve a depth of 250um, which is greater than OCT, and unlike OCT, it can achieve cellular resolution.
In Dr Craythorne’s unit, RCM, for research purposes currently, is used as an adjunct to surgery and also as a method of assessing treatment response. It can be used as a virtual biopsy and also some of the multiple lesions that are seen in some melanoma patients.
Various algorithms have been developed to help decide which lesions need to be cut out. RCM can also be utilised for “margin mapping” lesions that are difficult to see clinically. It is useful to scan patients with lentigo maligna and decide whether it is appropriate to use the topical treatment imiquimod, she said.
Evidence for using imiquimod in these cases is getting stronger, according to Dr Craythorne. A study is currently taking place entitled RADICAL (Radiotherapy or Imiquimod in Complex Lentigo Maligna), which has been designed to investigate the effectiveness of using imiquimod either to treat the lentigo maligna, when surgery is not possible, is refused, or fails.
Within the margin assessment category, another use for RCM is to reduce the length of time required in the preparation stages for Mohs surgery of large tumours in radial growth phases. The process is much quicker than haematoxylin and eosin staining protocol (three minutes compared with 45 minutes) and research is currently taking place to assess its effectiveness compared with the traditional method, she explained.
The final main presentation of the conference was delivered by Dr Sally Ibbotson, Clinical Senior Lecturer in Phobiology and Honorary Consultant Dermatologist, Ninewells Hospital and Medical School, Dundee, UK, on the diagnosis and management of photosensitivity.
Dr Ibbotson said that while an acute erythemal response to sunlight exposure may be entirely normal, abnormal photosensitivity is defined as an abnormal reaction quantitatively and/or qualitatively to ultraviolet and/or visible light. She stressed that it is a diverse group of diseases, and the first step is to consider it as a possible diagnosis.
Different immunological types of photosensitivity include: Polymorphic light eruption (PLE); chronic actinic dermatitis; solar urticaria; actinic prurigo; juvenile spring eruption; and hydroa vacciniforme.
“When we are talking about sunlight as a trigger, we also need to look at the detail of that in terms of what sort of sunlight — is it a seasonal or perennial problem and in addition to direct sunlight, is it also triggered by light through window glass, clothing or by artificial light or sunbeds?” stated Dr Ibbotson.
“And patients can often be caught out with perennial photosensitivity and not realise that sunlight has a role to play. A patient with PLE will only have problems in spring/summer, while a patient with solar urticaria could easily have this provoked in January, when out on a bright day.”
One of the most common forms of photosensitivity is PLE.
“It is extremely common and actually we do not investigate straightforward PLE; the patients who are referred to us for investigation are usually those where there is diagnostic doubt, or there are other things going on, such as photocontact allergy to sunscreens as well,” Dr Ibbotson reported.
“PLE is considered to be a type IV immune-mediated photosensitivity, with resistant Langerhans cells that don’t migrate following UV radiation as easily as in normal skin. It can present in quite a variety of morphological ways.”
Dr Ibbotson said there is still a lot of work to be done in understanding the pathogenesis of these immunological or idiopathic photodermatoses. She also pointed out that photosensitivity can often occur due to a variety of other causes, including rare genetic diseases, photoaggravated diseases and drug photosensitivity. The latter can result from drug interactions with light (phototoxicity), such as with quinine, for example. Dr Ibbotson said that drug photosensitivity, which may be characterised by immediate prickling, erythema and urticaria, is usually reversible.
Speaking about photodermatoses in general, Dr Ibbotson said: “The main hallmark is establishing the correct diagnosis, removing any trigger such as culprit drugs, suppressing existing disease activity, and of course, preventing further flares. Photoprotection is of course paramount for all these diseases.
“If the patient isn’t too photosensitive, it may be possible to use phototherapeutic approaches. Treatment such as using antihistamines to treat solar urticaria may be beneficial, and systemic immune suppression may also be required.
“The emphasis for photoprotection should be on behaviour, clothing and judicious use of sunscreens.
“For the photosensitive patient, understanding the nature of their photosensitivity is really critical because different approaches to photoprotection may be needed, as one sunscreen may not necessarily suit all. Desensitisation may or may not be possible, and it is important not to forget the impact psychologically of photosensitivity, and of course vitamin D supplements for patients who are strictly sun-avoiding.”
Concluding, she said there are “lots of clues to photosensitivity in clinical assessment, which are very important to pick up on, as you need to have a good idea of likely diagnosis on clinical grounds before investigating. It is important to have a low threshold for referring for phototesting investigations, as photosensitivity may otherwise be missed, such as, for example, when trying to distinguish between photoaggravated eczema and the photosensitive condition, chronic actinic dermatitis”.