Drs. George Martin and Ted Rosen talk candidly about why JAK inhibitors are important in the treatment of atopic dermatitis (AD), when dermatologists should consider using them, and how to safely mitigate risks and side effects while effectively treating AD patients with these powerful, “revolutionary” medications.
0:50 – The role of JAKs in AD
4:50 – JAK nuances
9:13 – The ORAL study and expanded black box warning
15:07 – Newer JAKS and black box inheritance
17:00 – The new molecules
18:00 – How to present biologics vs JAKs to patients (age + delivery)
21:10 – Women of childbearing years
27:00 – Legacy black box on mace events, PEs, and DVTs – who’s at risk?
30:44 – Cancer and risk
32:10 – Patients at risk for serious infections
35:27 – JAKs and vaccinations
38:47 – Dosing adjustments
46:20 – Final thoughts on biologics and JAKs
George Martin, MD, is Founder of Maui Derm dermatology meetings and The Dermatology Digest’s Executive Director
Ted Rosen, MD, FAAD, is Professor of Dermatology at Baylor College of Medicine in Houston and Editor-in-chief of The Dermatology Digest
“Why do we need JAK inhibitors to treat atopic dermatitis? Like so many things, we’ve had treatments before. This isn’t a disease that has no treatments at all, but I think we can always do better. That’s the goal, one way or another, with something that’s more efficacious, safer, or better,” said Dr. Rosen.
AD treatments are experiencing a revolution and the addition of JAK inhibitors is part of that, according to Dr. Rosen.
“Think about what we did for atopic dermatitis that required systemic therapy in the past. Cyclosporin was my favorite rescue drug. But you know there is a time limit on it, there is the potential for hypertension, renal toxicity. Then we have things like azathioprine. About one in three patients that get started on that drug stop it because of side effects. It’s a great drug but with serious problems. Methotrexate [has] a bunch of Black Box warnings. It can be a difficult drug to give, and tolerance is not so great. We could use mycophenolate. I love mycophenolate mofetil, but it’s slow. It takes forever to work. And because it’s slow and may be a little safer, it’s not as efficacious.”
There’s always phototherapy, but then there are the issues of convenience, travel time and expense and more, according to Dr. Rosen.
“Yes, all those therapies work, but all of them have significant downsides and all of them sometimes didn’t work. Between side effects, downsides, and inconvenience, we needed other drugs.”
That ushered a revolution in treatment, namely dupilumab (Dupixent, Sanofi and Regeneron Pharmaceuticals), according to Dr. Martin.
“The introduction of dupilumab for atopic dermatitis clearly was a total gamechanger and enabled us to treat atopic dermatitis. Now in the space of two months, December to January, we had the introduction of an IL-13 specific monoclonal antibody in tralokinumab (Adbry, LEO Pharma). And in January we got two Janus Kinas (JAK) 1 inhibitors, abrocitinib (Cibinqo, Pfizer) and upadacitinib (Rinvoq, Abbvie) that are absolutely amazing. Much to my surprise, based on comparative data, the two JAK 1 inhibitors are as good or better than dupilumab, which has heretofore been our gold standard.”
Dupilumab is a good drug. It has been relatively well accepted by dermatologists, it is a pretty safe drug and doesn’t really require lab testing, according to Dr. Rosen.
“I think its downside, if you want to call it that, is its efficacy. … we could do better and in fact have done just that.”
Nuances of JAK Inhibitors
There are four JAK inhibitors: JAK 1, 2 and 3 and TYK 2. [For more on those see parts 1 and 2 of this series in the April and May issues of The Dermatology Digest at https://thedermdigest.com/.] Different JAK inhibitors block different JAKS and affect different cytokines. Interestingly, the Janus kinas/signal transducer and activator of transcription (JAK/STAT) pathway controls over 50 inflammatory and immunomodulating signals in dermatology, according to Dr. Martin.
“As we think specifically about AD and look at the different JAKs that we can block, blocking JAK 1 makes total sense because JAK 1 is the signal transduction molecule for important cytokines like IL-13, and IL-4. We know dupilumab targets IL-4 and IL-13 and tralokinumab targets IL-13. Additionally, blocking JAK 1 inhibits thymic stromal lymphopoietin (TSLP) which is released by keratinocytes and recruits inflammatory T cells, IL-31 which is really important in itch and other cytokines that really are very important in atopic dermatitis.”
The Tofacitinib Legacy and Black Box Warning
Today’s Black Box warning on all JAK inhibitors is based on a year-long study called the ORAL Surveillance study,1 which involved only tofacitinib (Xeljanz, Pfizer), according to Dr. Rosen.
“You have to understand that tofacitinib at therapeutic doses is sort of a pan JAK inhibitor. It’s primarily JAK 1 and 3 but it can block all. Its side effects are not necessarily generalizable to other JAK inhibitors that are more selective in which JAKs they block.”
And subjects in the ORAL Surveillance study are not representative of most AD patients. Most subjects in that study were older than 50 years, had rheumatoid arthritis (a T helper 1 (Th1) cytokine driven disease versus AD which is driven by Th2), and at least one pre-existing cardiovascular risk factor, according to Dr. Rosen.
“That is a study that is destined to give you results that are somewhat negative and a lot of that is then translated into an expanded Black Box warning. This does not necessarily apply to giving a non-tofacitinib JAK inhibitor to a 28-year-old with atopic dermatitis.”
Among the things that ended up in the Black Box warning in large part because of that study included increased all-cause mortality; increased major adverse cardiovascular events (MACE), like myocardial infarction (MI), stroke; increased risk of cancer; increased risk of infection; and increased risks of deep venous thrombosis (DVT), pulmonary embolism (PE), even arterial thrombosis, according to Dr. Rosen.
“Think about that. Some of my patients actually read that package insert and they see these horrible Black Box warnings right at the start, based upon this study that wasn’t necessarily applicable to the JAK inhibitor that they just picked up at the drug store, and it really sounds scary.”
Putting Things in Perspective
The Black Box warning on JAK inhibitors does not necessarily apply to AD patients. And it is the dermatologist’s job to put things in proper context for patients, according to Dr. Rosen.
Rheumatologists, according to Dr. Martin, use tofacitinib and other JAK inhibitors it to treat rheumatoid arthritis (RA), psoriatic arthritis, ulcerative colitis, and ankylosing spondylitis. Most of the safety data has come from the use of tofacitinib for over a decade in the RA population, a disease state inherently prone to strokes, DVTs, lymphoma and MACE events, he said.
The reality for dermatologists is that JAK inhibitors have the potential to revolutionize what dermatologists do, according to Dr. Rosen.
“We need to approach these drugs very thoughtfully.”
That’s where the data in dermatology comes in, according to Dr. Martin. In Phase 3 comparator trials with dupilumab,2 upadacitinib outperformed dupilumab for every measure, including Eczema Area and Severity Index (EASI) 75, 90 and 100, as well as itch reduction.
“And abrocitinib, even though not powered, the 200 mg dose taken once daily was as effective or more effective than dupilumab.”
Abrocitinib is approved for 18 years and older and upadacitinib for 12 years and older. Dupilumab is approved for patients 6 years and older, while tralokinumab is approved for AD patients age 18 and older, according to Dr. Martin.
Mitigating Risk
According to Dr. Martin, when it comes to safely prescribing JAK inhibitors to AD patients, there are several important considerations: patient age and drug delivery; sex of the patient, with childbearing considerations; as well as risks of cardiovascular/MACE/mortality, cancer, DVT/PE, and serious infections, and renal/hepatic impairment.
Age is an important consideration when deciding whether to recommend one of the JAK inhibitors or one of the two available biologic therapies, according to Dr. Rosen.
“We need to stay in the guidelines for age. You probably wouldn’t get insurance to pay for it anyhow.”
Then there is the issue of drug delivery. The biologic therapies are injected versus the JAK inhibitors are pills, said Dr. Rosen.
“I used to think when the biologics came out for psoriasis the injections would be very difficult. Now with self-injectors it’s easy as pie. I think ultimately anybody can be taught to give themselves injections. But there are some people who are incredibly needle phobic.”
The potential for pregnancy is a concern, according to Dr. Martin.
“We know from the data that half of pregnancies are unplanned, and most women do not know they are pregnant until 4 to 6 weeks into it. We also know that JAK inhibitors cross the placenta and that biologics take about until week 13, at which point they become transported across the placenta. So, we have a little leeway until about week 13 with the biologics.”
The message there is to have a frank discussion with patients that they must not be pregnant when they start JAK inhibitors and have to be on a reliable form of birth control while taking JAK inhibitors, according to Dr. Martin.
Dupilumab may be a slightly different story, although the data is not yet clear, said Dr. Martin.
“The data with the biologics, particularly the longest standing biologic dupilumab, does not offer tremendous guidance but at the same time … data with pregnant monkeys on dupilumab showed no impact on pregnancy, and the pregnancy registry data so far looks pretty favorable as far as dupilumab.”
“With regard to JAK inhibitors, our longest standing registry data comes from tofacitinib. And when I really began to do a deep dive on it, I was perplexed because I was getting mixed messages. When you look at the data on tofacitinib, what you find is that half the births or more do just fine and there are about a quarter that elect to terminate the pregnancies. But when you look at the background, the baseline incidence of severe birth deformities doesn’t appear to be that much different at about 2 to 3% and miscarriages at about 15% to 20%.”
The 2020 American College of Rheumatology guidelines “Reproductive Health in Rheumatic and Musculoskeletal Disease,” does not provide guidelines on whether to administer JAK inhibitors during pregnancy because of a lack of evidence regarding the use and safety of tofacitinib during pregnancy, according to Dr. Martin.
“I tell my patients: ‘Don’t get pregnant while on this medication. We don’t have long-term pregnancy data.’”
Dr. Rosen said that since even reliable forms of contraception have been known to fail, it is important that dermatologists document those conversations and consider having patients sign a patient consent form that they understand the risks.
As for the potential risks of MACE, Dr. Rosen said dermatologists should think about who is at risk at baseline, which includes patients who are obese, have hyperlipidemia, have had past MACE events, or have a stent.
“Whether you believe that the ORAL study applies to other JAK inhibitors or not, people who are at already high cardiovascular risk (unless your back is against the wall) should not receive JAK inhibitors,” said Dr. Rosen.
Patients at baseline risk for thrombotic events include those who are very sedentary, people on estrogen dominant hormones, smokers (who also are at increased risk for MACE and cancer), and those who have had thrombotic events, according to Dr. Rosen.
“Those would be the patients I would seriously consider not giving a JAK inhibitor to, or I would have them sign an informed consent if I do.”
Determining a patient’s cancer risk involves common sense, according to Dr. Rosen.
“I do the same with the biologic drugs, even though the data over the years has not shown a terrible increased risk of cancer, but someone who has had breast, prostate or lung cancer two years ago, I might consider not using JAK inhibitors. Someone who had lymphoma two years ago, I might consider not using a JAK inhibitor. A strong genetic predisposition for cancer … I might think twice about using these drugs, and if I did, I would certainly get my informed consent.”
Patients at serious risk for infection are another group that may not be candidates for JAK inhibitors, according to Dr. Rosen.
“Again, common sense. If someone has an infection, that’s not the time to start a JAK inhibitor.”
The infections to worry most about are things like hepatitis B, hepatitis C, and tuberculosis, said Dr. Rosen.
“From the outset, we rule out these kinds of chronic, smoldering, possibly asymptomatic infections that may be latent infections, but they’re not gone. You’re going to have to get lab work anyhow, so looking for those chronic infections I think is reasonable.”
Early studies on tofacitinib described a zoster signal, which brings up the issue of vaccinations for people who are going to take JAK inhibitors, according to Dr. Martin.
To address zoster and other vaccines, including for influenza, pneumococcal, and COVID-19, Dr. Rosen said dermatologists should recommend patients get the live vaccines before starting JAK inhibitors.
“Maybe talk to their primary care provider to make sure their vaccinations are up to date. We do not give live vaccinations to anybody who is on a JAK inhibitor. It’s not dangerous. it’s just that the vaccine won’t work because the patient doesn’t get an immune response to the vaccine.”
Dr. Martin studied cytokines upregulated in the SARS-CoV-2 vaccine platforms and found that indeed the vaccines upregulated tumor necrosis factor (TNF), IL-6 and interferon gamma.
“It turns out IL-4 and IL-13 were not upregulated so there is not an issue with IL-13 and IL-4aR monoclonal antibodies in COVID vaccinations. With JAK 1 and 2 inhibition, you may suppress vaccine uptake and antibody formation particularly in older individuals and withholding JAK therapy for a week after immunization is currently recommended,” said Dr. Martin.3
It’s also important that dermatologists prescribe JAK inhibitors to patients who have working kidneys and livers, according to Dr. Rosen.
He does that by ordering laboratory blood draws, which the doctors said they check at regular intervals when patients are on JAK inhibitors.
“Dermatologists don’t like drawing blood, but look we’ve had enough training with methotrexate, cyclosporin and Isotretinoin,” said Dr. Rosen.
“I don’t want to start a JAK inhibitor in somebody who is already anemic, has thrombocytopenia or leukopenia. I want to know that they have a decent CBC. A comprehensive metabolic panel is reasonable because you want to make sure they have good renal and hepatic function and that there isn’t some hidden thing. I also want to know they are not pregnant to start with.”
Checking Labs
Dr. Martin agrees that JAK inhibitor patients should have baseline comprehensive testing for peace of mind. At 3 to 4 months out, he rechecks the CBC and comprehensive metabolic profile (CMP).
“If everything is still good and I have a fairly healthy individual, I’m probably good for a year unless the patient complains that something has changed. We follow patients [in the office] on these drugs usually every 6 months—first seeing them at 3 months to see how they’re doing.”
To limit his test taking and documenting, Dr. Rosen asks patients when they are seeing their primary care doctor.
“If they’re seeing their primary care doctor six months after I do the draw, that’s good. I’ll ask to see those results. That’s one less thing you have to do and keep track of.”
Built-in Dose Adjustments
With upadacitinib, dermatologists can start with 15 mg QD and go up to 30 mg QD. With abrocitinib, they can go from 100 mg QD to 200 mg QD, according to Dr. Rosen.
“So, you can change those doses and there is increased efficacy with the higher doses. We have dose adjustment built in, but then we also have to think about the increased risk and have that discussion with the patient about how we haven’t quite gotten to where we want even though this is a great drug, let’s go up on the dose.”
Bottom Line
Dr. Martin calls the two biologics and two JAK inhibitors for AD “an embarrassment of riches.”
But a confusing, complex one at that.
“We’re not talking about methotrexate, cyclosporin, azathioprine, and mycophenolate mofetil anymore, and we’re not talking about dragging people in for phototherapy. These are more convenient and are as or more efficacious than we had before,” said Dr. Rosen.
Dermatologists should offer AD patients who are candidates for systemic therapy an objective presentation, allowing patients to them guide them, according to Dr. Rosen.
“Give these new drugs their due. Remember they’re good. They are potent, powerful and outdo the biologic drugs. It’s a little more complicated for everybody but do not go into this thinking: ‘Oh, we’ve got new drugs but they’re oh so scary.’ That’s really the message I hope you take away from this discussion.”
References
- Ytterberg SR, Bhatt DL, Mikuls TR, et al. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis. N Engl J Med. 2022;386(4):316-326. doi:10.1056/NEJMoa2109927.
- Blauvelt A, Teixeira HD, Simpson EL, et al. Efficacy and Safety of Upadacitinib vs Dupilumab in Adults With Moderate-to-Severe Atopic Dermatitis: A Randomized Clinical Trial [published correction appears in JAMA Dermatol. 2022 Feb 1;158(2):219] [published correction appears in JAMA Dermatol. 2022 Feb 1;158(2):219]. JAMA Dermatol. 2021;157(9):1047-1055. doi:10.1001/jamadermatol.2021.3023
- Curtis JR, Johnson SR, Anthony DD, et al. American College of Rheumatology Guidance for COVID-19 Vaccination in Patients with Rheumatic and Musculoskeletal Diseases – Version 3. Arthritis Rheumatol 2021. https://onlinelibrary.wiley.com/doi/10.1002/art.41928
Disclosures:
Dr. Martin is on the Scientific Advisory Board of: Bristol Meyers Squibb (BMS), DUSA/SUN, AbbVie, Ortho/Bausch Health, Galderma, Pfizer, LEO, Janssen, Horizon, UCB, Trevi, Almirall, Dermavent, Incyte, Lilly, EVELO, and Sanofi/Regeneron. He is a consultant for: Bristol Meyers Squibb, DUSA/SUN, AbbVie, Ortho/Bausch Health, Galderma, Pfizer, LEO, UCB, Trevi, Almirall, Lilly, Arcutis, Dermavent, and EVELO. And is a speaker for: UCB, Almirall, LEO, Incyte, Dermavent, BMS, and Sanofi/Regeneron.
Dr. Rosen reports no relevant disclosures.