Considering a Role for Oral JAK Inhibitors in AD Care

Oral JAK inhibitors upadacitinib (Rinvoq, AbbVie) and abrocitinib (Cibinqo, Pfizer) have raised the bar in terms of the efficacy we expect from atopic dermatitis treatments. Across various measures—skin clearance, improvement in pruritus, or speed of response—results have been quite impressive, and these treatments are revolutionizing our approach to patient care.

Most impressive is that we have a statistically significant number of patients who are able to achieve an EASI-75, which is a 75 percent improvement from baseline, as early as week two. We have patients who are able to achieve a four-point or greater reduction in itch—what’s considered a meaningful reduction in itch—as early as day two. This is not just in trials but in the clinic. For the first time ever, with a medicine like upadacitinib (the JAK inhibitor with which I have the most experience), we can talk about endpoints we couldn’t talk about before, like EASI-90, EASI-100, and complete clearance of itch.

Dupixent (dupilumab, Sanofi and Regeneron) was a great addition to our atopic dermatitis portfolio and a life-changing drug for many patients. Prior to its approval, we were limited in terms of treatment options, so it was great to finally have a targeted treatment for atopic dermatitis. However, even with Dupixent, there were still patients whose treatment goals were not being met and who did not achieve high levels of efficacy in terms of skin clearance or itch reduction that they were seeking. There remained an unmet need for drugs to fill this gap. Now that oral JAK inhibitors have come to market, they have changed patient expectations. We are changing the bar in terms of the efficacy eczema treatments should offer. Being 50 percent better or 75 percent better isn’t good enough anymore. Our patients want to be 100 percent better.

Shared Decision Making

Shared decision making is a key part of my practice. In conversations with my patients, I have noticed that patients want to be more clear, have more itch reduction, and have reduction or even eradication of their flares. Thankfully, we have medicines that can help meet patients’ ever-changing expectations.

Notably, these are expectations of patients in the office. An ongoing obstacle in eczema care is to inform atopic dermatitis patients about the new treatment options and motivate them to seek care and commence therapy. The difference between patients with eczema and those with psoriasis, for example, is that many patients develop psoriasis in adulthood. That motivates them to seek out treatment. Atopic patients, for the most part, have the disease their whole life. They have been dismissed. They have been told they will grow out of it. And they have learned to live with the disease and all its challenges. Therefore, they may be less likely to seek treatment.

Some patients with moderate to severe AD with whom I’ve talked about these newer agents are unwilling to consider a therapeutic change because they think their skin is “just good enough.” But when I talk to them about their daily activities and their life, they acknowledge the impact of their skin disease. They have problems with relationships. They have problems interacting with their peers. They avoid trips to the park because they might have an atopic flare. I point out that this may not seem like a lot, but eczema is really impacting their day-to-day life and quality of life. Of course, having the patient agree to a new treatment is just the start. Selecting the right treatment is a crucial step. Discussions must focus on the potential benefits and risks of treatment. However, I tell patients, “The biggest adverse event you should be worried about is living with the sequalae of atopic dermatitis for the rest of your life.”

Risks in Context

The first thing that many people will think about in association with the JAK class is the boxed warning that cites risk for heart-related issues, cancer, and death. Boxed warnings are not new to dermatology, nor do they preclude the use of labeled drugs. We prescribe methotrexate, cyclosporine, adalimumab (Humira, AbbVie)—one of the number one biologics in the country; all of these have boxed warnings. Much of the safety data for JAK inhibitors comes from data within the rheumatoid arthritis population, patients who are not only on a JAK inhibitor but often on other immunosuppressant medications concomitantly. In addition, rheumatoid arthritis patients are sicker with more significant comorbidities at baseline in comparison to the atopic dermatitis population, which can impact the risk for many of the issues noted in the boxed warning.

I try to normalize this for the patient who is an appropriate candidate for JAK inhibitors. I advise them, “When you get the box in the mail, you’re going to see some scary words on the label. It’s going to say things like mortality, cardiovascular disease, blood clots. I want you to know that those warnings are not specific to Rinvoq. They have to do with another medication that is used to treat a completely different condition, but because it has a similar mechanism to Rinvoq, the FDA , in order to be cautious, had to include these warnings on Rinvoq’s label, which is why we are having this conversation. In my professional opinion, and after reviewing your medical history, I do not think these are significant risks for you. However, if anything feels ‘off’ after you start the medication, I want you to call me.”

Remember: these warnings are here because the JAK inhibitors are a new drug class, and the FDA wants prescribers to be cautious, and avoid exposing patients to undue risk. As clinicians, we have the ability and duty to decide on a patient-by-patient basis who will be a good candidate for any given treatment. We assess medical history, medication use, and risk factors in order to avoid prescribing JAK inhibitors to patients who are not appropriate candidates for this treatment. It is important as prescribers to understand the risks of these new medications in context. Over time, we will certainly learn more about the true incidence of these adverse events within the atopic population, and I anticipate seeing evidence that these agents are quite safe when used properly to manage AD.

A patient with severe hepatic impairment is not a candidate for systemic JAK therapy. Additionally, any patient over age 50 with more than one cardiovascular risk factor may not be an ideal candidate. However, this is not a true contraindication. With education and a thoughtful discussion, the patient and the dermatologist may determine that an oral JAK inhibitor is appropriate for such a patient. As clinicians, it is our duty to inform patients of all the available options, discuss the risks/benefits and include their treatment goals in the decision making processs. All patients require laboratory blood monitoring, with which dermatologists are very familiar.

JAKs in Practice

There is strong evidence for the oral JAK inhibitors used as stand-alone treatments. In AD Up, the third pivotal Phase 3 study of Rinvoq in AD, the adjunctive use of topical corticosteroids did not significantly increase the efficacy of oral therapy. This indicates that a medication like Rinvoq does not rely on topical therapy for full efficacy. However, in practice, atopic patients are used to having a topical agent for flares. If a patient is already on a topical agent, I usually continue them on this agent, advising them that they can back off the topical accordingly when they feel their eczema is sufficiently under control. Similarly, they can add the topical back in, as needed. Interestingly, the majority of my patients on JAK-inhibitors state they seldom need their topical agent once the medication has fully kicked in. In my experience, every atopic patient is going to have random breakthrough flares, and having a topical on board can help them manage these flares.

At this point, the majority of prescriptions I’ve written for upadacitinib have been for individuals previously treated with dupilumab, who either had had an allergic reaction or what I consider a treatment failure due to insufficient response or tolerability issues. When switching, I have patients stop dupilumab, and I initiate upadacitinib shortly thereafter. I see no need to “wash out” dupilumab prior to initiating Rinvoq. Given the mechanism by which the two drugs work, it is unlikely that slight overlap in systemic drug levels would cause any significant safety concern.

There are patients in which I choose Rinvoq first line over Dupixent. In patients in which the speed of efficacy is important, they need fast itch and skin relief, or in patients who have involvement of sensitive areas like the face or eczema covering the majority of the their skin and I need to cool the disease down quickly, I reach for Rinvoq. These patients are so uncomfortable that I just can’t wait for Dupixent to kick in. Historically, I would’ve started these patients on cyclosporine; now, I have, in my opinion, a safer cyclosporine.

Because JAKs can be used continuously or intermittently, they also present a viable option for patients who are generally well controlled with topicals but prone to seasonal flares. Think of the patient who flares each winter. They can use an oral JAK for just two to three months to get them beyond that flare. The mechanism of the drug allows one to start and stop it easily without needing to wean someone off the drug. It’s worth noting that, based on the label, the oral JAK inhibitors are positioned after a patient has had an inadequate response to a topical or a systemic agent. But remember, that systemic agent may be a biologic, prednisone, or another oral agent used for AD. A patient does not have to fail dupilumab to be a candidate for a JAK inhibitor.

Providing Relief

The consequences of living with uncontrolled eczema can be significant. There are emotional and psychosocial impacts of the disease. There are children and adolescents diagnosed as having ADHD or behavioral issues who, in reality, are simply so distracted by itch that they don’t function effectively in the classroom. I believe that if we intervene early and treat atopic dermatitis at a young age, we can change the trajectory of a patient’s life. We need to ask about, assess, and take seriously the important disease effects beyond just the skin and actually treat the patient who walks through the door. Patients come to their doctor seeking meaningful relief, and we now have tools along with the medical expertise to provide that.