Systemic and Topical Treatments For Atopic Dermatitis

 In this feature interview with The Dermatologist, Dr Derek Chu discusses systemic treatments for atopic dermatitis (AD) and also how physicians can consider the benefits and harms of prescription topical treatments following his 2 large studies, “Systemic treatments for atopic dermatitis (eczema): systematic review and network meta-analysis of randomized trials”¹ and “Topical Treatments for Atopic Dermatitis (Eczema): Systematic Review and Network Meta-Analysis of Randomized Trials.”²

Derek Chu, MD, PhD, FRCPC, is an assistant professor in the division of clinical immunology & allergy at McMaster University in Hamilton, ON, Canada. He is also the director of the Evidence in Allergy Research Group.. He co-chairs the upcoming atopic dermatitis guidelines by the American Academy of Allergy, Asthma and Immunology (AAAAI) and American College of Allergy, Asthma and Immunology (ACAAI).

What are the benefits and harms of prescription topical treatments for AD?

In our most recent publication², there is a complete systematic summary of all available topical treatments. There are 68 different ones that are compared against each other using network meta-analysis, including topical corticosteroids (TCSs), topical calcineurin inhibitors, and topical Janus kinase (JAK) inhibitors such as ruxolitinib and delgocitinib, as well as PDE-4 inhibitors such as crisaborole. Each has benefits and harms.

There are also other treatments such as topical antibiotics, as well as topical prescription moisturizer devices. Each has their own advantages and disadvantages. Some of those have to do with health benefits and harms, which are summarized in the publication as a single summary table that will walk physicians through the efficacy and safety of each treatment and can even be used at the point of care, if they would like, as a handout or poster. It has all the advantages and disadvantages for improving signs and symptoms of eczema, including validated indices, such as the Eczema Area and Severity Index or Scoring Atopic Dermatitis, itch score, sleep disturbance, and overall negative effects.

However, some of the advantages and disadvantages of each treatment might be more subtle. Clinicians really must think about their individual patients. For example, if you are comparing a routine topical moisturizer, such as one that you would get over the counter, versus a prescription moisturizer device, they may both have little to no negative health side effects. While there might be some small and uncertain benefits to using a prescription moisturizer in terms of improving signs of eczema, from a practicality standpoint, prescription moisturizer devices tend to come in small sizes and tend to be much more costly compared to over-the-counter moisturizers, and they may be harder to access depending on the circumstance. Now that can vary a little bit between patients and how these prescription moisturizers are purchased, but the key point is that clinicians should talk to their patients directly to understand what their values and preferences are, and what makes treatment makes the most sense for them.

For the topical corticosteroids, after looking at all the different types of steroids available, there were 4 main categories that emerged: (1) little to no difference from placebo or moisturizer alone, (2) intermediate-low category, (3) intermediate-high category, and (4) the highest potency category. The certainty of the evidence for each treatment to improve each outcome varies. In general, those that are moderate potency in the US group system (group 3-5) tend to be our usual therapy that we use, and they tend to be among the best for at least getting the majority of patients with mild to moderate disease under control. Of course, the highest potency steroids, US Group I, are the most effective in improving signs of disease, but will not be very practical or potentially safe to use as a chronic long-term therapy to maintain disease control.

If physicians are going to gain control of mild-moderate disease, they may often want to use a moderate potency steroid, and in some circumstances by considering things such as location, a different potency steroid. Whereas to maintain disease control they may want to use a moderate potency steroid. We also found that pimecrolimus, as well as low-dose tacrolimus (0.03%), were just slightly better than TCS Group 6/7 for gaining eczema control. In a separate study, we found that topical pimecrolimus and topical tacrolimus across the entire age spectrum were generally safe to use.³ Tacrolimus 0.1% came out as an intermediate-high potency type treatment for both gaining control and maintaining control of atopic dermatitis. In contrast, it had minor harms, such as stinging and burning, but clinicians have well-known strategies to address those. Other interventions such as crisaborole tended to be classified among the intermediate inferior category and similar to TCS group 6/7, but were associated with local adverse effects such as stinging and burning.

For topical ruxolitinib and delgocitinib, they led to improvements for most eczema signs and itch. However, these outcomes fell into intermediate-inferior categories. Additionally, many are aware now, the US Food and Drug Administration, as well as many jurisdictions around the world, have placed a box warning label applied to topical JAKs. Due to the ORAL Surveillance study, there are concerns about systemic exposure to JAK inhibitors and adverse outcomes such as cancer, particularly in at-risk populations. Even though there is very reassuring data so far, topical JAK inhibitors can have systemic absorption and definitive evidence of no serious harm has not yet emerged. Those are the main highlights, but please see the entire manuscript and especially the summary table that goes through all the different interventions. I have only touched upon the major classes.

In your study, your team, “classified TCSs using 7 classes—group 1 being most potent.” How exactly did your team go about classifying TCSs for each group?

There are many ways to classify TCSs. The most common way, especially in North America, is the US class system. It is a 7-class system roughly associated with clinical outcomes but, until our analysis, has never been rigorously tested in an evidenced-based or data-driven way. It has primarily been informed by vasoconstrictor assays. What we did is use that system, at least as a base, to inform how we would categorize individual drugs. By doing that, we did find consistency among each category on the clinical outcomes. Then we compared among all the individual categories to find how they came out in terms of clinical effects. For example, did, say, the highest potency in Class I lead to the greatest changes in signs and symptoms of eczema? Using network meta-analysis, we did find the 7-class system very helpful for categorizing the different drugs into the gradations of potency.

However, there was variation in terms of which TCS class proved among the most effective for each outcome, and which ones can be used long-term due to concerns about adverse effects. By using other approaches to categorizing corticosteroids and other topical treatment potency, found that other classification systems, such as the World Health Organization Anatomical Therapeutic Chemical system, as well as a UK-based system, have significant limitations in how you use those systems on a research basis.

What we describe in the discussion is that we probably need this 7-class system at minimum to maximize how systematic reviews and meta-analyses combine all the data statistically. In practical terms, if you use a data-driven approach, there are 4 main categories that I’ve described above.

Your team noted, “The efficacy and safety of azathioprine, oral corticosteroids, cyclosporine, methotrexate, mycophenolate, phototherapy, and many novel agents are less certain.” How can future studies address the safety and efficacy behind these treatments?

We just talked about the topical treatment systematic review and network meta-analysis, which as far as we know is the first of its kind that has been done on over 200 randomized trials with over 40,000 patients analyzed and compared against each other for comparative efficacy and safety. Now we are talking about systemic treatments, including phototherapy (UV light therapy), primarily for patients with more moderate to severe disease. This is just over 140 randomized trials, and over 28,000 patients, so still a very large network meta-analysis that combines all advanced treatments for those with more severe disease.

We did look at several typical treatments that we would think about nowadays like oral JAK inhibitors, such as upadacitinib, abrocitinib, and baricitinib, as well as monoclonal antibodies such as dupilumab, tralokinumab, lebrikizumab, and other biologics. Then the conventional treatments that we think about, such as the conventional disease-modifying antirheumatic drugs or immunomodulatory treatments like azathioprine, methotrexate, and mycophenolate, as well as phototherapy. Even though conventional immunosuppressants are often less costly, the evidence for them is not as certain. For example, the network meta-analysis shows that cyclosporine may be very efficacious at either low or high doses to improve clinical signs, but because of the nature of some of the randomized trials in the past, they did not capture all relevant outcomes such as patient-reported symptoms, itch, sleep disturbance, quality of life, or flares of disease. So, we really need better trials and new trials to address these gaps, especially in those patients who maybe cannot access expensive drugs, such as dupilumab or oral JAK inhibitors. There are some exciting trials out there that may help address the issue. One is the National Institute for Health and Care Research in the UK, which is addressing this in a platform trial called BEACON. We talk about it in the discussion of the manuscript as that is going to be testing some of these drugs as active comparators of say dupilumab vs cyclosporine or methotrexate vs cyclosporine. Those are definitely necessary.

Another one is the US Atopic Dermatitis Research Network. We really do need a stimulus from this network meta-analysis to support new trials to be launched. Lastly, in Canada, we have established a national network called the Skin Investigation Network that is going to be planning some of these kinds of trials, which are going to be generating and addressing these big gaps in evidence, especially for those patients who need it the most.

How can physicians consider whether upadacitinib is the best treatment for their patients, or whether they should stick to the intermediate effectiveness and favorable safety of dupilumab, lebrikizumab, and tralokinumab?

These network meta-analyses offer a rapid and structured summary table that can be used at point of care to inform shared decision-making with patients. Physicians can use the tables by printing them as posters or using them as discussion points to have with their patients. They can have them even in the waiting area printed out for patients to read and consider. In addition, there are going to be 2 aspects, and we will elaborate this in detail in upcoming new guidelines from the AAAAI and ACAAI, which are going to be coming out very shortly. They will go into detail about what might make key conditions to consider for shared decision-making. The 3 key elements to guide patients to optimal decisions are (1) what are the benefits and harms of each treatment, (2) what are the values and preferences of the patient, and lastly, (3) what are the other relevant contextual factors, such as accessibility, feasibility, and equity. The network meta-analysis addressed a major point, which is what are the health upsides and downsides of each treatment.

Not only can this information be used to inform individual patient discussions but it can also be used to inform future randomized trials and research. Then, when it comes to discussing, say, oral JAK inhibitors, such as upadacitinib, abrocitinib, or baricitinib, physicians might need to not only discuss the benefits, but whether the patient is going to be harmed by the medication and how the patient views such harms. Are they going to be worried about the potential harms even if they are uncertain or unlikely? Some of those potential harms may include venous thromboembolism, the potential for cancer, and the potential for arterial clots, as well as infections. While things like cancer and arterial blood clots may not be a major risk factor in most individuals at a young age, when they get older then it may become a major consideration.

Additionally, outcomes like venous thromboembolism can be promoted by other factors, including lifestyle. Maybe they are frequent travelers, maybe they frequently get immobilization for some reason due to sports injuries, or maybe they are on oral contraceptive as well as nonsteroidal anti-inflammatory drugs. These are risk factors promote venous thromboembolism and need to be considered. Lastly, physicians need to ask patients about practical issues, "Do you want to take a pill once a day every day and have all blood monitoring before and after starting the drug, or would you want something different, maybe an injection medication once a month, once a week, or every 2 weeks, or something else?" It is this kind of discussion that includes understanding the evidence and understanding what the patient perspective is, bringing them into the decision-making process, and then lastly, understanding those contextual factors. What is realistic and practical for this patient is what is really going to make a difference in finding the best treatment for them. So, use these 2 network meta-analyses. The summary tables are easy to use, and the new AAAAI/ACAAI guidelines will be coming out to really help bolster those discussion points.

Are there any tips or insights you would like to share with your dermatologist colleagues regarding systemic treatments for AD?

Everything I just summarized here, which is using these instruments, summary table tools, and these 2 publications, are detailed in the open-access (free to access) publications. You can download them, post, or print them to be use at the point of care. The upcoming guidelines are really going to bolster the discussion points and make it easy to do shared decision-making. They will list out key points to consider when discussing whether to use a specific treatment, and where they fit compared to all the other treatment options. They will also be accompanied by 1-page, double-sided handouts that can be used as discussion points addressing practical issues either for physicians themselves or to give as a handout to patients.

References
1. Chu DK, Chu AWL, Rayner DG, et al. Topical treatments for atopic dermatitis (eczema): systematic review and network meta-analysis of randomized trials. J Allergy Clin Immunol. Published online September 5, 2023. doi:10.1016/j.jaci.2023.08.030

2. Chu AWL, Wong MM, Rayner DG, et al. Systemic treatments for atopic dermatitis (eczema): systematic review and network meta-analysis of randomized trials. J Allergy Clin Immunol. Published online September 5, 2023. doi:10.1016/j.jaci.2023.08.029

3. Devasenapathy N, Chu A, Wong M, et al. Cancer risk with topical calcineurin inhibitors, pimecrolimus and tacrolimus, for atopic dermatitis: a systematic review and meta-analysis. Lancet Child Adolesc Health. 2023;7(1):13-25. doi:10.1016/S2352-4642(22)00283-8

This article originally appeared on The Dermatologist.