PracticalDermatology

Practical Dermatology^® worked with Dr. Andrew C. Krakowski, a pediatric dermatologist, to convene an expert roundtable of pediatric dermatologists to share updates, practice pearls, insights, and more. Topics included in the wide-ranging discussion include new and current, therapies, tips for treatment, discussions of current and ongoing research, and much more. This is the first installment of the Roundtable. The second installment will be published in the May 2024 issue of Practical Dermatology^®. 

Biologics Timelines: When Can Treatment be Declared a Failure?

Dr. Andrew C. Krakowski:  It is truly amazing that we can practice pediatric dermatology in an era when so many new and effective medications have come out of the research pipeline and are now at our clinical disposal. As positively life changing as many of these new therapies are, the patients and their families inevitably want to know how long to wait to see if a new medication works. What timeline do you generally give a systemic/biologic before considering it a treatment failure?

Dr. Lisa M. Arkin: This really depends on the diagnosis and the data specific to the drug. For example, trials in atopic dermatitis (AD) are typically done over four-month periods, with expected responses by that time. The dupilumab trials were done over four months in all populations, but the evidence shows responses continue to improve until around 12 months of age. I rarely declare failure for dupilumab prior to 4 months of age in the absence of significant adverse events, but we can add on to that with light, with topical therapy, with targeted topical therapies like topical ruxolitinib, with the roadblock being insurance approval. That said, if the patient can’t tolerate the medication due to injection pain, fear, or significant adverse events, that would move up the timeline.

In contrast, the studies for alopecia areata (AA) and vitiligo require much longer time periods to evaluate efficacy – these were done with 24-to-36-week placebo-controlled time points, with cross over after that time point, and evaluation of endpoints at 36 to 48 weeks. This is because the immunologic signal is targeted by the medication, but hair/melanin repopulation takes much longer. You need to be clear about how the trials were executed and why prior to starting patients on therapy, so families know what to expect. If you are expecting vitiligo to have improved by four months, you are declaring failure way too early. That said, as in AD, adding on therapies to augment responses is something we regularly pursue (light in vitiligo and low-dose oral minoxidil in AA are examples). Walking through the expectations for patients is important. A year can seem like a lifetime when you have no hair, or your face is entirely discolored.

Dr. Craig Burkhart: In general, I try to give a certain amount of time before considering a particular treatment a failure: I give psoriasis three months, AD two months, AA six months, and Hidradenitis suppurativa (HS) three months.

Dr. Robert Sidbury: For kids with AD and taking dupilumab, for example, I generally say we will plan for one year of treatment and then consider, if possible, decreasing the dose/frequency of injection or stopping the medication. I will tell them that we will together read the tea leaves of inevitable missed or delayed doses. If a child has a missed or delayed dose yet has no uptick in symptoms during this period, he or she may be ready to down-titrate or stop the medication. Conversely, if the child has increased symptoms in the days leading up to his or her scheduled dose, he or she is likely not ready to consider such a move absent any adverse effects or intolerance. I will generally keep a child on dupilumab for at least six months before declaring it a failure, again assuming at least some improvement and no adverse effects. With oral JAK inhibitors, I have a similar approach in terms of timing. However, I expect a) a more rapid response, b) a need to monitor labs (so have more frequent interval checks), and c) I have the option of potentially doubling the dose after three months or so if the response is suboptimal and the drug is well-tolerated.

Dr. John Browning: Generally, I can tell if a biologic is going to work within 12 weeks of therapy. However, it is my preference to wait 16 to 24 weeks when possible before stopping it. This is because a few patients can be late responders or there may be an issue with adherence to therapy that makes a biologic seem like a failure. With AD, I often see faster results with dupilumab than with the biologics for psoriasis. This is because one of the greatest signs of effectiveness is reduction in itch, which can occur after two to four weeks. Peak results occur at 12 weeks, but it is gratifying to see improvement early on. For HS, results are less robust even when a biologic is effective. I like to wait at least 12 weeks and preferably 24 weeks before deciding if a biologic is a failure for HS. I judge success by a decrease in the number of abscesses and draining fistulas, as well as improved quality of life by the patient. With the oral JAK inhibitors, reduction in itch occurs quickly with AD, but peak results are the same at 12 weeks as with dupilumab, except at the higher doses, which outperform dupilumab. I’ve also seen success with oral JAK inhibitors after dupilumab failure. I think some cases of AD with concurrent allergic contact dermatitis do better with the oral JAK inhibitors than with dupilumab. For AA, response is slow to oral JAK inhibitors, and I council patients not to expect significant results until at least six months of therapy, and to wait at least a full year for peak results.

Use of Live Vaccines When Using Dupilumab

Dr. Krakowski:  This is probably preaching to the choir, but I have gone on record that dupilumab is the second miracle I have witnessed as a pediatric dermatologist in terms of its overall efficacy and what we believe to be its very safe side-effect profile. One aspect of management that has posed a clinical conundrum for me and maybe others has been the issue of how we deal with live vaccines in the setting of this medication’s use and continued administration. I would love your individual perspectives on how you approach this issue with your patients and their families.

Dr. Browning: In an article published by Martinez-Cabriales and colleagues in 2021, a group met to establish consensus and made the following recommendations¹:  

• Based on available data, dupilumab does not appear to affect the development of protective antibody titers to inactivated vaccines. 
• Dupilumab treatment does not need to be interrupted for administration of inactivated vaccines. 
• For patients on dupilumab treatment, seasonal inactivated influenza vaccination should continue as recommended. 
• Based on available data, live attenuated vaccines should be avoided while on dupilumab. However, such vaccines can be considered on a case-to-case basis weighing the risk of infection versus the risks of vaccination. 
• When live attenuated vaccines are required, they should be given at least four weeks prior to initiation of dupilumab treatment, if possible. However, such vaccines can be considered on a case-by-case basis weighing the risk of infection versus the risks of vaccination. 
• While on dupilumab, measurement of specific antibody levels can be considered to ensure serologic protection after vaccination. 
• There is no evidence to suggest that immunization while on dupilumab causes an exacerbation of AD. 

This is great information to share with patients, and in keeping with my own recommendations since dupilumab was first approved. I believe that over time we will also be able to show the safety of dupilumab with live vaccines.

Dr. Sidbury: This has become a more pressing issue with the recent labeling change down to 6 months of age.  Children this age have busy vaccine schedules including some live vaccines (e.g., MMR) which are contraindicated with dupilumab use.  Though stating the obvious, if vaccines can be brought current prior to dupilumab initiation that is an optimal first step.  Non-live vaccines can then be administered as needed, generally at the midpoint of the monthly dosing schedule (kids aged 6 months to 6 years receive dupilumab every 30 days rather than every 14 days like older kids and adults). If live vaccines are needed there is not great evidence to support how best to administer them.  To stay “on label” a child would need to stop dupilumab for one to two months (imperfect evidence here), or skip one to two shots, then vaccinate, and dose one to two months later. That is a long-time off medication for what many experts feel is a very low risk proposition (i.e., live vaccine while on dupilumab). Accordingly, many pediatric dermatologists will — after thorough counsel and shared decision making, which includes the primary care provider — consider live vaccines as well.  

Dr. Sheila Friedlander:There is not good data to direct us currently, so this is my approach.  First, I try to get as many vaccines done as possible before initiating dupilumab.  If the patient is already on dupilumab (e.g., 200 mg every four weeks) and needs to receive a live vaccine, I hold one dose, give the live vaccine when that dose was due, and then resume the next month.  

Dr. Burkhart: Ideally, I like to stop 12 weeks before giving any live vaccines and then restart four weeks after (based on what they did in the clinical trials for dupilumab). If the patient’s eczema is especially fragile, then I stop six weeks before giving live vaccines and restart dupilumab four weeks later.

Dr. Arkin: Dupilumab is not immunosuppressive and even studies of methotrexate have been reassuring from a vaccine immunogenicity perspective. That said, there is minimal guidance regarding the dosing of live vaccines with dupilumab because it hasn’t been studied rigorously. I think we can safely say that non-live vaccines can be given on schedule without any concern. From a live vaccine perspective, however, it’s really MMR and Varicella we worry about in childhood. This is a balance of risks/benefits because flaring AD is a known risk factor for cutaneous dissemination of virus, and this has been reported with live vaccines.  Based on the number of cases in the literature, it might represent the most significant risk to administer a live vaccine to a child with severe flaring AD. 

I have absolutely had patients get live vaccines while on dupilumab and have yet to witness a single adverse event. That said, because there is limited guidance on live vaccines and the absence of rigorous evaluations, I typically tell families to schedule the vaccines around the timing for scheduled dupilumab dosing. Most of these kids are on monthly dosing because of the timing of administration of MMR and varicella. I have told them to hold the scheduled dose, with reinitiation of the drug one month later. This has meant that kids were off for a month, not long enough to develop a severe AD flare. 

But your question — and the likelihood of varied responses from other physicians — underscores the need for more guidance, which should be rooted in evidence. Even a large retrospective study of patients on dupilumab who take live vaccines and the proportion who develop adverse events that are deemed related to the vaccine would help here. The Pediatric Dermatology Research Alliance (PeDRA) may have something in the works to address this need.

Tralokinumab and Dupilumab in Pediatric AD Populations: Which to Use?

Dr. Krakowski:What is your overall experience using tralokinumab versus dupilumab in the pediatric AD population?  No hidden agenda here.  I will be the first to admit that I almost exclusively use dupilumab, but I am open to expanding my clinical armamentarium.  I would love to hear if there is a particular clinical setting that you feel tralokinumab could work better or as an alternative to dupilumab.

Dr. Caroline Piggott:I have used both dupilumab and tralokinumab in adults (less so in children since tralokinumab only recently received FDA approval for 12 years of age and older). I have found cases where patients respond better to one drug versus the other.  Usually, I start with dupilumab because, at least in older patients, dupilumab maintenance is only one injection every two weeks instead of two.  Interestingly, in adults I have had a few cases where patients had eye or joint side effects on dupilumab, which then resolved on tralokinumab.

Dr. Browning: My greatest experience in using tralokinumab was as an investigator in the trial. I found tralokinumab to be very similar to dupilumab in effectiveness. However, access was difficult at first, and it is hard for me to recommend twice the number of injections compared with dupilumab. I might recommend tralokinumab to patients who had a bad experience with dupilumab, for whatever reason, and were hesitant to go back on it. Tralokinumab would offer an alternative and might be effective for them. I would also recommend tralokinumab when insurance denies dupilumab.

Dr. Sidbury: The American Academy of Dermatology (AAD) recommends both. My own personal approach is to use dupilumab first because it has been around longer, it is approved to a younger age group (6 months vs. 12 years), and although there were not head-to-head trials so it’s not an evidence-based conclusion, the absolute efficacy metrics (e.g., percent clear or almost clear on IGA, or percent reaching EASI-75) was better in dupilumab monotherapy trials than tralokinumab trials, while adverse effect profiles were negligibly different. The one clinical scenario I would certainly reach for tralokinumab would be if concerns for dupilumab initiated or exacerbated lymphoid reaction or cutaneous T-cell lymphoma (CTCL) exacerbation/initiation. Though unproven, there is some suggestion this event, albeit extremely rare, is IL-4 (not IL-13)-driven.

Different Strategies for JAK Inhibitors

Dr. Krakowski:  Given the reported rapid efficacy of Jak-inhibitors, I have considered trying one as a type of “bridge” to long-term dupilumab therapy, but because of the age of our patients I have been afraid to pull the trigger.  Has anyone from this esteemed panel tried an approach like that?  Along those lines, how do you use Jak-inhibitors and other medications concurrently with dupilumab administration?

Dr. Sidbury: I have not. Dupilumab works fast enough in most that I don’t feel the need to start with a JAK simply to get them better faster.  I am more comfortable with dupilumab’s safety profile given it has been around longer for AD and is approved by the FDA down to a much younger age.  The lack of a boxed warning is reassuring to parents though I am also perfectly comfortable using JAKs when indicated (e.g., dupilumab failure, child’s inability to try or tolerate injections, unacceptable dupilumab adverse effects like conjunctivitis) and properly contextualizing the boxed warning for patients and parents. I should add that this is my personal approach.  In my role as co-chair of the AAD AD Guidelines committee I will say that, at least for adults (the pediatric manuscript is in preparation), we did not rank the newer systemic agents as first line or second line. Rather, we noted that both dupilumab and tralokinumab, and both FDA- approved JAKs [upadacitinib and abrocitinib as well as a third, baricitinib, approved by the European Medicines Agency (EMA)] were strongly recommended for moderate-to-severe AD with moderate certainty of evidence.

Dr. Piggott: I have not tried getting patients under rapid control with an oral JAK prior to dupilumab.  There are still some concerns about the risk of infection and cancer with oral JAK inhibitors. For that reason, in children, I prefer to initiate treatment with dupilumab, first, due to its reassuring safety profile.

Dr. Browning: I have never used a JAK inhibitor for rapid control before transitioning to dupilumab, but it certainly could be done. You could consider using a JAK inhibitor for a short period of time, such as a month or six weeks, like you might prescribe a short course of prednisone. There would be fewer side effects with the JAK inhibitor than with prednisone and this might calm the dermatitis before transitioning to dupilumab. However, I suspect most patients would prefer to stay on the JAK inhibitor once they try it since the results are robust and they would be hesitant to stop it, especially if they have already had lab clearance to stay on it.  Much more often, I transition patients to an oral JAK inhibitor after failure with dupilumab and usually see good results with this regimen, although sometimes I do have to use the higher dose of the oral JAK in order for patients to have relief of symptoms. I am now starting to offer either injectable systemic therapy or oral systemic therapy to my patients right at the beginning of treatment, rather than reserving JAK inhibitors for use after dupilumab failure. This all allows for greater collaboration with the patient and families to find out the best therapy for the individual.

Dr. Arkin: The data for abrocitinib vs dupilumab in AD (and head-to-head) looks extremely similar (36% IGA for low-dose abrocitinib (100 mg) vs 36% for dupilumab at four months.² We have more safety data for dupilumab, and so I also reach for that first. That said, there is no drug more effective for AD to date than upadacitinib, which is FDA approved over age 12, and the HEADS-UP trial showed significant efficacy relative to dupilumab (72% EASI-75 vs 61% at four months).³ There are no head-to-head studies of upadacitinib vs abrocitinib. So, if a patient is failing dupilumab and if they meet the age criteria, I reach for Upadacitinib first, even though the JAK inhibitor data so far has been reassuring in the AD population.

Dr. Burkhart: Insurance step therapy in my area requires failure of dupilumab before they will cover JAK-inhibitors. So, I usually try dupilumab first before initiating a JAK-inhibitor.

Topical Therapies and Phototherapy

Dr. Krakowski:  Do you still have your patients use topical therapies while on dupilumab and JAK inhibitors? How do you feel about utilizing concurrent phototherapy?

Dr. Burkhart: Yes. I continue topical steroids and topical calcineurin inhibitors while on dupilumab and JAKs. I will usually add phototherapy if dupilumab or JAKs have not worked on their own.

Dr. Browning: I love phototherapy and have a phototherapy booth at each of my clinic locations. I often recommend it as monotherapy for patients who are phobic of topical steroids and want to avoid systemic therapies. In some cases, however, I do use it concurrently with dupilumab as it is helpful and adjunctive in care. I think it is especially effective when you are trying to treat or correct the post inflammatory hypopigmentation that often occurs in atopic dermatitis. I also think phototherapy is very helpful in patients with vitiligo who are receiving a topical JAK inhibitor, such as topical ruxolitinib cream, or compounded tofacitinib, and those vitiligo patients who are on an oral JAK inhibitor.

Dr. Sidbury: Yes, absolutely to topical therapy.  In fact, if I see a patient who has improved on dupilumab or a JAK start to see attenuation of benefit, I often wonder if they have become less consistent with their topical therapy. These kids have been using topicals — to their chagrin — all their lives so are thrilled to finally not have such dependence.  Alas, their skin barrier is still their imperfect skin barrier so emollients at least, and potentially PRN topical anti-inflammatory (e.g., TCS, TCI, PDE4i), remain an important part of their care.  I do not use phototherapy simultaneously with these other medications on the front end generally but consider it as a bridge to help get kids off systemics when we need or want to do so and simply stopping or tapering proves untenable.

Dr. Piggott: Yes, I have had cases of patients who needed both dupilumab and topicals or nbUVB.  However, since a theoretical risk of immunosuppression exists for JAK inhibitors, especially the oral ones, I have not yet utilized dual therapy with both narrowband ultraviolet B (nbUVB) and oral JAK inhibitors.

Dr. Arkin: Yes absolutely. When I can get topical ruxolitinib approved in patients on dupilumab (if not denied by insurance), it has been helpful. Phototherapy is also extremely helpful, and often we can get patients a home light unit.

Discontinuation of Oral Propranolol in Hemangioma

Dr. Krakowski: Shifting gears a bit, I find there is no clear guideline for discontinuing oral propranolol in a hemangioma patient. I do not have a hard and fast rule that I follow except that I tend to taper rather than stop cold turkey. I would love to hear this group’s approach.  Is there an absolute age when you start to think about discontinuing oral propranolol? Do you stop cold-turkey, or do you taper down? If you taper, is it a physiologic taper (i.e., the patient continues to, naturally, put on weight, but the dose is purposefully not increased to match the weight gain) or are you actively, directly lowering the dose at a given cadence?

Dr. Friedlander: Unfortunately, not all hemangiomas in infants have read the textbook on classic behavior.  I have found that the hemangiomas themselves will tell you when to start tapering down on the dose by starting to involute while on treatment. Most experts believe that hemangiomas requiring systemic therapy also require prolonged therapy in the order of 10-12 months. Also, some types, such as parotid hemangiomas, often take longer to involute and often require even longer courses.  I usually do not taper therapy in the first six months of life.  

There are multiple options in terms of tapering. Some physicians will use the “physiologic taper” where the child grows out of the dose. Others will taper more rapidly. One must keep in mind the risk of deformation of certain hemangiomas, such as those in the central facial area — especially the nose and lips — and those involving the central breast tissue or anogenital area.  I generally try not to stop cold turkey.

Dr. Browning: When starting propranolol, I tell the parents of hemangioma patients to expect to be on it for nine to 12 months at a minimum. In some cases, I have stopped it closer to six months when there has been rapid response or intolerance of the propranolol due to reflux or sleep problems. Sometimes parents want to stop it early because they do not like giving their children oral medication. When I stop propranolol closer to six months of age, I usually transition to a topical beta blocker that can be continued until a year of age. I do find that stopping the oral propranolol closer to 9 to 12 months of age reduces the risk of rebound growth. I do prefer to continue adjusting the medication by weight until they are 9 to 12 months of age and then will stop it cold turkey, although sometimes I will tell them to cut their dose in half and continue it until they finish the medication in the current bottle. This can be a helpful approach when parents are reluctant to stop it due to fears over rebound growth. If parents want to continue past a year of age, I do like to let the children outgrow their dose. In some cases, a longer course of therapy may be necessary, and this is usually when there are large segmental hemangiomas as you might find with PHACE syndrome, or when there is involvement of the nasal tip or another area where growth of the hemangioma is causing some sort of functional or cosmetic problem.

Dr. Burkhart: My preference is to do a trial of stopping propranolol at 9 months of age. I stop cold turkey and if the hemangioma rebounds, then I continue for another two months before doing the next trial of stopping propranolol.

Dr. Arkin: There isn’t a ton of guidance on this, and for me it depends. On the face, I often treat closer to 12-14 months to optimize their result and reduce the risk for any rebound when you take them off. Segmental hemangiomas have a longer proliferative growth phase, and often these patients are on for even longer. I tend to hold weight adjustment in the month or two before we taper, to test to see if they are still proliferating.  I generally taper over a few days to a week, again just to evaluate the response. We have them stop cold turkey in the setting of viral infections or poor feeding, and I don’t think there is any contraindication to that if you aren’t worried about the hemangioma rebounding.

Dr. Sidbury: Tapering propranolol is highly patient-specific. The biggest question I ask myself, assuming that efficacy (i.e., the hemangioma is well-treated and may not need propranolol any longer) and not safety is the driver, is “what are the consequences if we taper too soon?” Generally, they are few as one can easily restart the drug if the need becomes apparent. That said, I am more conservative when a.) there is a function-threatening lesion such as an upper eyelid or periocular hemangioma; b.) there is a hemangioma in a location notorious for prolonged growth phase (e.g., “parotid lesion”; c.) a troublesome hemangioma such as one that has ulcerated, and propranolol has helped this problem. It is important to note that paradoxical initiation or exacerbation of ulceration has been described in response to propranolol.  In all the aforementioned scenarios I will a.) wait until the expected growth phase has passed (e.g., six-12 months depending;) b.) vet this expected stability due to age with parental reports; c.) then engage in a weight-based taper (i.e., not increase the dose to match weight gain) for one to three months up to 1 year of age at which time a more intentional taper will be attempted. An intentional taper for me is halving the dose for a week under careful parental observation, followed by another halving of the dose for another week if no untoward changes, followed by cessation if the lesion remains stable. I generally don’t stop cold turkey in the absence of unacceptable side effects. n

Andrew C. Krakowski, MD, is dermatologist and is the Network Chair of Dermatology and Program Director of the Residency in Dermatology at St. Luke’s University Health Network in Pennsylvania.  

Lisa M. Arkin, MD, is an Associate Professor and Director of Pediatric Dermatology at the University of Wisconsin-Madison School of Medicine and Public Health.

John Browning, MD, is a dermatologist and Adjunct Associate Professor at UT Health San Antonio, an Assistant Professor at the Baylor College of Medicine, and clinical faculty at the UIW School of Medicine.

Craig Burkhart, MD, is a dermatologist in private practice in North Carolina specializing in pediatric and adolescent dermatology.

Sheila Friedlander, MD, is a dermatologist specializing in pediatric dermatology at Scripps Clinic Carmel Valley in San Diego.

Caroline D. Piggott, MD, is a dermatologist specializing in pediatric dermatology at Scripps Clinic Rancho Bernardo in San Diego.

Robert Sidbury, MD, is a Professor in the Department of Pediatrics at the University of Washington School of Medicine, and Chief of the Dermatology Division at Seattle Children’s Hospital. 

Dr. Arkin reports the following relationships: Consultant for Merck, NoblePharma, and Sanofi/Regeneron. Principle Investigator for Amgen. Received grant funding from Dermatology Foundation, ICTR, PeDRA, SWF, UW.

Dr. Browning reports the following relationships: Speaker for Regeneron, Pfizer, and Krystal. Advisory Board Participant for Dermavant. Investigator for AbbVie, Arcutis , Aceleryin, Aslan, Concerta, Dermavant, Eli Lilly, GSK, Galderma, Incyte, Janssen, Johnson & Johnson, Pfizer, Regeneron, Sanofi, and UCB.

Dr. Burkhart reports no relevant financial relationships. 

Dr. Friedlander reports no relevant financial relationships. 

Dr. Krakowski reports no relevant financial relationships. 

Dr. Piggottt reports no relevant financial relationships.

Dr. Sidbury reports the following relationships: Investigator for Galderma, Pfizer, Regeneron, UCB, and Castle. Speaker for Beiersdorf. Advisory Board Participant for Avene,  Arcutis, Dermavant, Leo, and Lilly.

References

1. Sylvia Aide Martínez-Cabriales, Kirchhof MG, Constantinescu C, Murguia-Favela L, Ramien M. Recommendations for Vaccination in Children with Atopic Dermatitis Treated with Dupilumab: A Consensus Meeting, 2020. Current Opinion. 2021;22(4):443-455. doi:https://doi.org/10.1007/s40257-021-00607-6

2. Bieber T, Simpson EL, Silverberg JI, et al. Abrocitinib versus Placebo or Dupilumab for Atopic Dermatitis. New England Journal of Medicine. 2021;384(12):1101-1112. doi:https://doi.org/10.1056/NEJMoa2019380

3. Simpson EL, Paller AS, Siegfried EC, et al. Efficacy and Safety of Dupilumab in Adolescents With Uncontrolled Moderate to Severe Atopic Dermatitis. JAMA Dermatology. Published online November 6, 2019.