WCD2023: botox complications and the non-visible burden of AD

After 2 days of attending lectures focused on autoimmune diseases of the skin, it was time for something completely different on the morning of day 3: medical aesthetics (botox, to be precise). For those of you not interested in the fascinating world of minimally invasive aesthetics procedures, you can skip straight ahead to the next header. For those who have a professional or personal interest in botox, read on...

Botulinum toxin A: why are not all patients happy?

Botulinum toxin A (BTXA) is the most common non-surgical medical aesthetics intervention in both men and women. It is therefore no surprise that not all patients are universally happy with their outcome. Dr Marina Landau delved deeper into this topic by presenting a number of "facts about BTXA you didn't know" (and - in my case at least - she was right, as I'm far from an expert on the topic). Compared to dermal fillers, BTXA has a delayed onset and a shorter duration of effect. Furthermore, its application may sometimes result in an unnatural look, in adverse events, or in a lack of the intended effect.

Why does BTXA sometimes not work as intended? Of all the potential reasons, antibodies / resistance is probably the least important one, or so the data indicates. On the other hand, potential issues include logistics / storage (must be kept at cold temperatures), underdosing (e.g. men have more muscular faces and may need higher doses), air in the syringe during administration, and inter-batch reproducibility. The latter point was somewhat surprising to me: apparently, a BTXA batch that has a stated vial size of 100 units can contain anywhere between 80 and 125 units per vial and still be within legal limits. Dr Landau even brought up the example of there being rumours during the COVID pandemic that BTXA was being affected by the virus, as results appeared to lack efficacy. In her opinion, this was most likely due to a large batch containing lower than usual doses; as manufacturers don't reveal their batch sizes, this could hypothetically result in quite widespread underdosing. Quite a controversial statement, in my opinion, and while I'm by no means in a position to question the opinion of a renowned expert, I'd like to clarify that I have no idea whether the above hypothesis is true.

Dr Fotini Bageorgou next took us through potential complications of BTXA, and how to avoid them. She started her talk by highlighting that BTXA products are very safe and rigorously tested, and that any complications that arise are due to the injector, not the product. This could be due to poor training, inadequate lightning, poor technique, bad equipment etc. The next key point was that individual patient characteristics require different approaches.

She then showcased a variety of complications (and solutions), including eyelid ptosis (heaviness), mephisto brow, the formation of new wrinkles, lower eyelid oedema, diplopia (double vision), xerophthalma (dry eyes), xerostoma (dry mouth), dysphagia (problems chewing), floppy neck syndrome, headache and photophobia, botulism, infections, granulomatous reaction, and pseudomorphea. That's a pretty long list, but the main conclusion was that all of these can be avoided as long as the following key success factors are taken into account: thorough clinical assessment prior to the procedure, including touching and palpating the muscles, using dynamic anatomy, and injecting slowly and with small volumes. All of this, Dr Bageorgou stated, is why it is important to get BTXA treatment from board-certified dermatologists.

Lastly, before diving back into the world of atopic dermatitis (AD), I'd like to share one discussion that arose from a question from the audience. This question was about how to best apply BTXA to the trapezius (the large triangular muscles that extend over the back of the neck and shoulders). Before going into some practical tips, the panel declared this to be "another social media trend" that can allegedly give the illusion of a long neck. The power of social media in shaping attitudes towards beauty truly is something. In fact, I was involved with an Ipsos study about 18 months ago that looked at perceptions of beauty among young women in China, and how they were shaped by photo editing apps on social media. It was quite revealing just how widespread the usage of such apps is, how normalised it really is, and how there was seemingly little disconnect in young women's minds about the use of such apps to guide discussions with aestheticians/dermatologists and the fact that beauty was strongly linked to looking natural and healthy. But I digress...

Evolving paradigms in AD: addressing the non-visible disease burden through new targets, and in the long term

It was time for another industry-sponsored session, and feeling like a right WCD-veteran by this point, I actually managed to join the queue early enough to not only get in, but also get a free bento lunch box before they ran out. Score.

The session's topic was Thinking differently about AD: is it time to evolve our paradigms?, and the first presentation - by Dr Melinda Gooderham - was entitled Beyond the visible: Alleviating the Disease Burden for Patients with AD. AD is by nature a highly visible disease, but it also carries a non-visible disease burden with an important impact on quality of life (QoL). Of these non-visible symptoms, itch consistently tops the list of most burdensome symptoms for patients; in fact, in one large survey, 2 out of 3 patients said they experienced itch on parts of the skin with no visible lesions.

You will have to forgive my handwriting (I swear, I am not a doctor!), but I thought the below graphic was quite interesting:

When patients are subdivided into 4 quadrants based on (a) the severity of their lesions and (b) the severity of their itch, it is not surprising that those in the two quadrants marked by severe lesions (making up ~15% of patients) are considered to be severe by HCPs. However, patients also consider those with severe itch in the absence of severe lesions to have severe AD, resulting in an important disconnect between patients and dermatologists, which as the graphic illustrates (if you can read it), affects around 25% of patients.

Beyond itch, pain also contributes heavily to the non-visible burden, with around 50% of patients reporting pain at least 2-3 times per month. Sleep disturbance and fatigue are significant, which can be caused by the symptoms of the disease (including stress), the altered cytokine expression of the disease itself, or systemic treatment in some cases. Very important to highlight is the mental health burden, in particular anxiety and depression. Then there is cognitive dysfunction, which may be secondary to the sleep disturbance, itch and pain mentioned earlier.

Where things got really interesting was when Dr Gooderham highlighted a case study from one of her patients, who was given a biologic after presenting with uncontrolled AD. The patient's EASI score improved markedly and her skin looked great. And yet.. the patient was unhappy. Why? Because the itch and skin pain persisted. Therefore, Dr Gooderham pointed out, skin clearance cannot be the sole marker of success, when itch and pain relief are among the top patient-reported goals of treatment. In fact, patients often feel HCPs underestimate this non-visible burden and its emotional impact. To complicate things further, language barriers and cultural factors (which may make it hard or even inappropriate to talk about some of the non-visible impacts) can further the disconnect. Lastly, the speaker highlighted it is key to take into account the psycho-social needs of young patients with AD.

Dr Martin Steinhoff next delved deeper into the science of those non-visible symptoms, by tackling the topic of IL-31, which is regarded as the mastermind of itch, through stimulating neurons and activating neuronal growth. Things got fairly technical pretty quickly, which is no surprise: the itching process is very complex. Involving levels 1 through to 4, itch can be produced directly through itch receptors, or by downstream signalling (involving cytokines and the JAK receptors), through the spinal cord, or other parts of the central nervous system. The key point was that there are many different mediators of itch; in AD, it appears that IL-4, IL-13 and IL-31 are the most important factors. IL-31, in particular, doesn't just affect itch, but also skin inflammation and skin barrier function.

Next up was an overview of IL (and JAK) signalling inhibition strategies, as presented by Dr Diamant Thaçi. The speaker showcased the "2nd wave" of investigational therapies, including nemolizumab (the session sponsor's compound) targeting the IL-31 receptor, eblasakimab targeting the IL-13 receptor, various pipeline products targeting OX-40 and its ligand, another set of products targeting IL-4, gusacitinib targeting JAK and SYK, and lebrikizumab and cendakimab targeting IL-13. Various other targets have been repeatedly investigated, but so far without much success. And yet, Dr Thaçi assured us that it's only a matter of time before the 3rd wave arrives.

Dr Kenji Kabashima then explored the full potential of IL-31 inhibition in the long term. Due to the chronic nature of AD, patients unfortunately tend to experience a lifelong impact, so the question of whether to keep patients on treatment long-term is an appropriate one. Data that was presented indicates that 79% of patients continue on biologics for 1 year or more; for JAK inhibitors, not much long term data is available yet, but low discontinuation rates are shown to date. RWE studies like the Ipsos AD Monitor are an example of using RWD in the clinic to track actual persistence rates, as well as reasons for discontinuation.

In the panel discussion at the end of the sponsored session, a question was asked on what to do with patients who fail to show response to any treatment. The panel advised that the first thing to do is to make sure that it is actually AD, by doing a rebiopsy. An example was given of a patient for which no options (JAKi, cyclosporin A, biologics,...) seemed to work; upon performing a re-biopsy of the skin lesions, it turned out that the patient was in the beginning stages of developing CTCL (a type of skin cancer). However, if the re-biopsy does confirm that the AD diagnosis, it is important to remember that the disease is phenotypically very heterogeneous (a point repeated in every talk on AD at the conference), and there is unfortunately no one-size-fits-all solution, re-iterating the point that additional targets (and associated biomarkers) are needed.

Posing with our poster

Before we wrapped up day 3, Hamizah and I headed over to the poster hall, to do something that was long overdue: take a picture in front of our poster. More details to follow shortly (we will share the actual poster here on LinkedIn), but I can reveal that it covered a very important topic: to what extent physicians are actually discussing advanced therapies with their eligible AD patients. But more on this later...

For now, a quick wrap-up of the learnings from day 3:

1. BTXA, while widely used, can sometimes result in unhappy patients, either through a lack of desired effect, or complications. Appropriate training of the injector, combined with proper assessment and technique are crucial to avoid those
2. AD has both a visible and a non-visible burden. The latter is sometimes underestimated by physicians, even though it can be extremely debilitating for patients. A wave of novel therapies to address this disease burden by targeting mediators of itch and other symptoms is (potentially) about to hit the market, though questions remain over long term use of advanced systemic therapies
3. If you want to grab (free) lunch at a conference, make sure you join the queues early (took me three days to figure that one out)

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References

All findings taken from presentations as delivered on Thursday 6th July 2023 at the World Congress of Dermatology 2023, in Singapore:

1. Facts about BTXA you didn't know Marina Landau (Israel)
2. BTXA induced complications: How to avoid and treat Fotini Bageorgou (Greece)
3. Beyond the Visible: Alleviating the Disease Burden for Patients with Atopic Dermatitis Melinda Gooderham (Canada)
4. IL-31 - A Mastermind of Itch, Inflammation and Skin Barrier Dysfunction Martin Steinhoff (Qatar)
5. IL-31 Signalling Inhibition - a Global Clinical Perspective Diamant Thaçi (Germany)
6. Exploring the Full Potential of IL-31 Inhibition in the Long Term Kenji Kabashima (Japan)