VITILIGO
Dr. Neal Bhatia: What are your current preferred treatments for vitiligo?
Dr. Adam Friedman: The one FDA-approved topical for vitiligo is topical ruxolitinib. That FDA approval gives us both insight and confidence that a certain percentage of patients will get a response, even if it is slow. Additionally, any drug that is FDA-approved for a condition that has never had an FDA approval is an opportunity to inspire patients because people are paying attention to their condition.
For anything more than limited body surface area involvement, I typically utilize a combination of narrow-band ultraviolet-B therapy (NB-UVB)—ideally three times per week—and ruxolitinib cream 1.5% or tacrolimus ointment. Ruxolitinib cream 1.5% is my preference, but many insurance providers consider vitiligo cosmetic, even though it is an autoimmune disease. Tacrolimus ointment has its own benefits, according to the literature; in addition to being anti-inflammatory, there is evidence that it can induce melanogenesis. My experience with tacrolimus ointment, however, has been that it tends to only work on thinner-skinned areas such as the genitals, or hair-bearing areas such as the extremities—if it works at all. Sometimes, I alternate 1 week at a time between tacrolimus and a Class I steroid. If I can get ruxolitinib cream 1.5% covered, however, the patient will be on it continuously, plus-minus light.
One therapy for rapidly evolving or unstable vitiligo is pulse dosing of systemic steroids. It does not repigment per se, but it stops the progression. Off-label use of oral JAK inhibitors is supported by some literature; I have not used them yet for that, but I think that could be an opportunity to have a better option than immunosuppressants for very severe disease.
Dr. Bhatia: Have any conventional therapies exhausted their place in the market?
Dr. Friedman: Phototherapy has been utilized effectively for decades, but it poses logistical challenges. I am not a huge fan of at-home units. If someone has focal vitiligo, we still need to put them in a light box. We have an excimer laser, but it is only approved for psoriasis, so getting that treatment covered is also a struggle.
ALOPECIA AREATA
Dr. Bhatia: What are your preferred treatments for alopecia areata?
Dr. Natasha Atanaskova Mesinkovska: That depends on the severity. For anything that affects more than 10% to 20% of the scalp, or anything that is bothersome to the patient, I use a systemic JAK inhibitor as my first line. The two approved by the FDA are baricitinib and ritlecitinib. Baricitinib comes in doses of 2 mg and 4 mg; I usually use the higher dose regardless of severity. Ritlecitinib has one standard dose, which is 50 mg. I go directly to one of those two options, and I sometimes combine them with minoxidil, either topical or oral.
Dr. Friedman: Those two oral JAK inhibitors have different targets, and I do not know if one is better than the other, but I am just happy we have two options. Ritlecitinib is approved now for ages 12 and older. There are plenty of 12- to 18-year-olds who are suffering, for whom I have been using off-label baricitinib or tofacitinib.
Before we talk about systemic therapies, however, the first-line therapy for the more classic disease, which is more limited or isolated, is intralesional Kenalog. Evidence indicates that high dosing is not necessary, so I usually start low—2.5 mg/cc or 3.33 mg/cc—to avoid atrophy and the consequences of atrophy, because if you thin the skin and you get rid of that supporting fat tissue, there is nothing for the hair to come back from. If that does not generate a response, then I increase the dosage. I do that every 3 weeks to 4 weeks until I see the hair fill in, and I utilize topicals in between those visits. One study showed betamethasone lotion with steroid injections is better than steroid injections alone. I typically use Class I steroids.
Ideally, topical ruxolitinib would be a great option, but the problem is delivery, because it is not designed to penetrate the follicular ostia into the hair follicle. If you were to design a carrier system that could get the topical JAK inhibitor where it needs to be, that could be effective, and that is something I am working on right now by using nanoparticle drug delivery, so stay tuned.
Topical calcineurin inhibitors, such as tacrolimus and pimecrolimus, certainly, are options as well. I also find that minoxidil works in conjunction with anti-inflammatory activities. I prefer oral minoxidil to topical because topical is very difficult to adhere to, whereas low-dose oral minoxidil ranging from 0.625 mg to 2.5 mg per day is very safe and very effective.
Antihistamines are another option. Studies indicate that while they will not treat existing lesions, they may stop new ones. I have many of my patients on double the daily dose of fexofenadine.
There is some evidence that vitamin D is important for not only hair growth but also immunomodulation, so I want patients on a daily dose of vitamin D. Several of my patients have used hydroxychloroquine and have not been very happy with the results.
If someone is not happy with other treatments and not past the 50% SALT score needed for an oral JAK inhibitor, intramuscular kenalog 3 months in a row is a very safe way of delivering systemic steroids without some of the negative consequences of oral steroids because it defuses out of the fat of the buttock very slowly. That can be a temporary fix.
Overall, a giant gap exists between the patient who has a few spots you can treat with intralesional topicals and the patient with alopecia totalis or universalis and a SALT score greater than 50%. A large percentage of my patients are in between, and we need something better for them.
Dr. Bhatia: Which conventional therapies for alopecia areata have exhausted their place in the market, and why?
Dr. Mesinkovska: Many of the topical sensitizers, such as diphenylcyclopropenone (DPCP), and a lot of the stronger systemic therapies—especially oral prednisone—really do not have much of a role anymore. Classic options such as methotrexate and cyclosporine are losing their place simply because both the efficacy and the safety of the JAK inhibitors are proving to be superior at this time.
Dr. Jason E. Hawkes: More selective or targeted treatments, such as dupilumab, just do not appear to be able to adequately block the pathogenic immune response in and around the affected hair in the majority of alopecia areata patients.
Dr. Andrew Weinstein: When I worked at a pediatric dermatology practice, one of the saddest things to see was the ophiasis pattern of alopecia areata in children. Injecting children serially with steroids was disquieting because it was painful, potentially damaging, and not particularly effective. The idea of putting them on unguided immune suppressants was harrowing. Having JAK inhibitors has been a game-changer.
Dr. Bhatia: In my JAK inhibitor talks, I poke holes in all of the black boxes and scary warnings.
Dr. Weinstein: What was scary was putting someone on cyclosporine and having them get renal insufficiency; putting a child on cyclosporine and running out of data after a year; and knowing proof-positive that there is an increased risk for malignancy. Cyclosporine was my go-to because it really was the best of all evils that I treated many children with, and some adults as well. Having patients on steroids forever or getting avascular necrosis is scary. These are real things. These were not infrequent side effects of the drugs we used to utilize.
Dr. Bhatia: What are the obstacles general dermatologists face when attempting to prescribe systemic therapies for alopecia areata?
Dr. Mesinkovska: No. 1 is we do not tend to recognize the effect this condition has on patients, so we may tend to overlook it or avoid treatment. Many patients, especially those who have had the condition for a while, may be stoic about it.
Second, JAK inhibitors are unfamiliar to many patients. We need to emphasize that they are pills, not injections, so they have short half-lives and you can always stop taking them. They are so easy to prescribe, and we just need to become more comfortable with them because they are a great family of medication for all sorts of inflammatory disorders, not just for alopecia areata.
The third challenge is access. For someone without a PPO plan, especially if they have state or government plans, JAK inhibitors can be expensive. There are options for those patients to access medication for free in clinical trials. For the latest available, visit clinicaltrials.gov.
Dr. Friedman: Even for on-label uses, but especially for off-label, it comes down to documentation. Get ahead of the ridiculous, nonsensical but purposeful questions to prevent approval that these companies will put before you. Document the severity of the disease in the language they understand, which involves validated research tools. Document past failures. For off-label uses, whether it be dose escalation or a product that is not approved, supporting documentation is critical to show it works.
HIDRADENITIS SUPPURATIVA
Dr. Bhatia: Why have conventional therapies for hidradenitis suppurativa needed to be replaced?
Dr. Hawkes: The treatment of chronic hidradenitis suppurativa has been problematic for many reasons, including inadequate disease classification measures, conflicting clinical trial data, and variable or unrecognized disease phenotypes. There is a huge unmet need for hidradenitis suppurativa-specific treatments, so the renewed commitment and recent research activity in this disease state is very welcome. Historically, we have largely relied upon anti-tumor necrosis factor agents, such as adalimumab, with or without adjunctive surgical interventions. This has worked well for many of my HS patients who are on 40-mg weekly dosing, versus the alternative 80 mg every other week. That said, I am very excited about the potential benefit of broader-acting IL-17 inhibitors such as bimekizumab, especially for use in the early stages to potentially halt or prevent irreversible disfigurement.
Dr. Friedman: Adalimumab was the first FDA-approved agent for hidradenitis suppurativa that had studies with more than double-digit numbers of patient. Adalimumab is good but not great. We recently saw the label extension for secukinumab, with perhaps slightly better data in terms of efficacy.
I use a lot of off-label therapies because I see a lot of severe cases. One of my favorite options is infliximab, with high dosages—7.5 mg/kg to 10 mg/kg every 4 to 6 weeks. You need to go strong, or don’t even waste that patient’s time. If I can get sarecycline covered, I like that because I feel more confident using it longer than the indicated 3 months of oral tetracyclines; sarecycline is a narrow-spectrum antibiotic, so I am not as concerned about antimicrobial resistance. Clindamycin and rifampicin in combination work better than doxycycline alone, but there are more side effects—such as accelerating the metabolism of oral contraception—and the adherence is not great. I have had some success with metronidazole, 500 mg twice a day, especially with patients with smelly discharge because it kills anaerobes. I also use topical metronidazole.
Intralesional kenalog has been a big part of our treatment of focal disease; I give patients Class I steroids for at-home use because if they put it on immediately when the condition starts boiling up, they may not need an injection. Even in the most delicate areas, a couple days of a class I steroid will not cause harm. We need to get away from this mindset of never using an ultrapotent steroid on the face or the genitals. We can do that safely. We can, for example, use halobetasol in the groin for a couple days to shut down an evolving lesion.
I have also used a combination of 1,000 mg of vitamin C twice a day and 50 mg per day of zinc copper composite for anti-inflammatory wound healing properties if the patient is willing. I have been starting to use more oral roflumilast, which is a phosphodiesterase-4 inhibitor approved for treating COPD; it is much more potent and has a greater binding affinity to phosphodiesterase-4 than apremilast has, and I have had success with it in several patients as an add-on to biologics.
I am really excited about the label extension of bimekizumab. I am also interested in spesolimab, an IL-36 receptor antagonist approved for GPP. Also, several studies are evaluating both novel and established JAK inhibitors, and I have a couple patients on upadacitinib with some improvement when other options were failing. I think JAKs will be game-changing for hidradenitis suppurativa. I anticipate a psoriasis-like situation where we have almost too many options, which is so sorely needed.
CHRONIC SPONTANEOUS URTICARIA
Dr. Bhatia: What are your preferred treatments for chronic spontaneous urticaria?
Dr. Hawkes: Currently, the best scientific evidence supports the use of omalizumab as a preferred treatment for chronic urticaria patients who are recalcitrant to high-dose (four-fold) antihistamines. Omalizumab is a reliable workhorse with a complete response rate of more than 75% based on meta-analysis data. That level of complete response is remarkable and exceeds even the very best biologic treatment for atopic dermatitis and plaque psoriasis. Unfortunately, too few dermatology providers use this biologic medication, out fear of anaphylaxis and/or not assuming care of chronic urticaria patients, which is detrimental to patients suffering with this condition. We may see that change in our specialty as newer treatment options become available, including promising therapies such as oral remibrutinib and subcutaneous dupilumab.
Dr. Friedman: Our ability to use omalizumab has gotten easier, though many do not realize that. Previously, we needed to stir it for approximately 30 minutes before injecting, and then we needed to keep the patient in the office for 2 hours in case of anaphylaxis. Now, there is a pre-filled syringe, and while the black box warning for anaphylaxis still exists, patients only need to stay three times, and if they do not have adverse reactions, we can start having them self-inject from home. Also, the dosing is not based on pretreatment immunoglobin E (IgE) or weight levels. So, the label has changed to make it easier to use, and it works well. It really is a good drug.
Of course, omalizumab is a second-line option, for use after a patient fails the up-dosing of antihistamines. Prior to that, second-generation H1 antihistamines can be used up to four-fold the recommended dose; the standard dosing for allergies will not work. There has been some indecision about whether H2 inhibitors are worthwhile or whether leukotriene antagonists are, and the guidelines keep shifting. I used to combine all three: H1, H2, and leukotriene antagonists. Now, it seems as if H2 is out of favor, but leukotriene antagonists are back in favor. Several studies show that high-dose vitamin D can be a booster for antihistamines, and patients need that anyway. Also, vitamin D deficiency can be a marker of disease activity.
Everything else is off-label, from dupilumab—which is in the pipeline for FDA approval—to cyclosporine, which works fast but can only be used for approximately 6 months. I used to use a lot of mycophenolate mofetil, and there is some data to support that, but the current guidelines out of Europe do not recommend it. Dapsone, hydroxychloroquine, and colchicine have been effective. There is some evidence that narrow-band UVB is useful, and I have used that a few times.
I am certainly excited about the new Bruton tyrosine kinase (BTK) inhibitor remibrutinib, which should be available shortly: great safety profile, intracellular target, small molecule inhibitor, and better absorption. Some other biologics coming down the pipeline as well. Dupilumab may finally get approval; it is slow, but it works, it has a great safety profile, and we all are comfortable using it. This is a disease that goes from 0 to 60 in about 10 nanoseconds, though, so something that works immediately is preferable, and I think small molecule inhibitors will work faster.
Dr. Weinstein: Remibrutinib is interesting because BTK inhibitors can dramatically increase bleeding risk. You just need to be very careful when your patients are on BTK inhibitors and they are having elective surgery. Mechanistically, we now understand things that were not known even 20 years ago. The ability to target diseases at their root and provide targeted therapy has never been higher. However, we must remain aware of potential adverse events associated with these therapies.
Dr. Bhatia: The example I use is turning off the faucet; we can stop these processes in their tracks. You are not expressing any cell lines or blowing up any dendritic cell surveillance. You are literally just stopping that particular process.
Dr. Weinstein: There are many types of urticaria, and certainly, the first step in treatment is stopping the end effect of histamine. Of course, the second step is inhibiting IgE, but that does not work all the time.
Dr. Bhatia: We used to rely on antihistamines, treating the end products. When omalizumab came out to block IgEs, that was the first template for how to stop the process.
Dr. Weinstein: The arrival of omalizumab reminded me of when infliximab was introduced—probably a little bit better than when etanercept came out. Finally, we had drugs that were really revolutionary. We never thought we would need another drug for psoriasis. We thought we had found the secret. But, as with the early biologics used to treat psoriasis, we have omalizumab failures. We have patients who cannot be controlled even on high-dose antihistamines. We have patients who cannot take higher-than-normal doses. We have patients who, for a variety of reasons, cannot take any antihistamines at all. Having more tools available is ideal.
Dr. Bhatia: Part of the problem is everything has to come from some indication, but there is always chronic spontaneous urticaria. However, once a drug hits the market for one indication, you can use it for others as well.
Dr. Friedman: Do not be afraid to embrace off-label uses. Take CME courses to become comfortable with different therapeutic options. Utilize resources from the American Academy of Dermatology and various societies to challenge insurance companies.
It is in our DNA to resist change and get comfortable, but dipping your toe into the water will create a tremendous ripple effect not only on the lives of your patients but also on you in terms of expanding your repertoire and keeping your job exciting.
Neal Bhatia, MD, FAAD, is a dermatologist in private practice in San Diego, California, and Chief Medical Editor of Practical Dermatology.
Adam Friedman, MD, FAAD, is Professor and Chair of Dermatology, Residency Program Director, Director of Translational Research, and Director of the Supportive Oncodermatology Program at The George Washington University School of Medicine & Health Sciences.
Jason E. Hawkes, MD, MS, FAAD, is a board-certified medical dermatologist in the greater Sacramento area with a specialization in the treatment of inflammatory skin diseases.
Natasha Atanaskova Mesinkovska, MD, PhD, FAAD, is Vice Chair of Clinical Research at the University of California, Irvine – College of Medicine.
Andrew Weinstein, MD, FAAD, is a dermatologist in private practice in Boynton Beach, Florida, and Chair of the Advisory Board for the American Academy of Dermatology.
Dr. Bhatia reports the following relationships: Consultant for InCyte, Novartis, and Pfizer.
Dr. Friedman reports the following relationships: Speaker for Incyte, Regeneron/Sanofi. Consultant for Lilly, Galderma, Pfizer, Regeneron/Sanofi, and Incyte. Grants from Pfizer, Lilly, and AbbVie.
Dr. Hawkes reports the following relationships: Advisor/Consultant for Apogee, Arcutis, BI, Blueprint Medicines, BMS, Boxer Capital LLC, Galderma, Institute for Systems Biology, Janssen, LEO, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, Takeda, and UCB. Speaker for BMS, BI, Galderma, Regeneron, Sanofi, and UCB. Medical Board Member and Scientific Advisory Committee Member for the National Psoriasis Foundation. Councilor for the International Psoriasis Foundation.
Dr. Mesinkovska was not able to report relevant disclosures in time for publication.
Dr. Weinstein reports the following relationships: Speaker for Leo and Regeneron.