Expectations for JAK Inhibitor Treatment of Alopecia Areata

Oral JAK inhibitors should be considered for patients with more than 20% scalp hair loss or lesser involvement accompanied by rapid progression, eyebrow or eyelash loss, or significant psychosocial impact, given limited response to conventional therapies. Brett King MD, PHD, shares how clinicians should set expectations that regrowth often requires 6 to 12 months and avoid switching therapy before 6 to 9 months unless intolerance occurs. Dose tapering should be gradual due to delayed flare risk, and failure of one JAK inhibitor does not preclude response to another.

Dr King is the professor of Dermatology and Pediatric Dermatology at Yale University School of Medicine, CT.

Transcript

How do you determine when to initiate JAK inhibitor therapy in alopecia areata, and which clinical or disease features most strongly influence that decision?

So, there are two patients who merit treatment with oral JAK inhibitors. The first is the patient who we all think about, and that is the patient with severe alopecia areata. Now, clinical trials defined severe as 50% to 100% scalp hair loss, but I would argue that we should be using a more holistic scale to take account of disease severity. And the one that I would put forth is the alopecia areata scale. This scale says that anybody with 50 to 100% scalpair loss is severe, but that patients with 21 to 49% scalp hair loss who also have eyebrow or eyelash involvement, who are refractory to treatment or who have rapidly progressive disease or who have negative psychosocial impact related to their alopeciata, that those patients who might otherwise be categorized as moderate alopecia areata by amount of scalp hair loss are actually severe. So in summary of that population, it's the patient with more than 20% scalp hair loss really merits treatment with an oral JAK inhibitor.

I would go so far as to say that patients even with less scalp hair loss, let's say 10 to 20% scalp hair loss, but who also have eyebrow or eyelash involvement or facial hair involvement or who are rapidly progressing. I would also say that those patients merit treatment with an oral JAK inhibitor. Really, there is not high quality data to say that other therapeutics are particularly effective. We even have a randomized double-blind placebo controlled trial of methotrexate for six months followed by methotrexate plus prednisone for six months that shows that even that combination of therapy only reaches reasonable efficacy in combination and over a period of treatment of one year. And given that there's no off-ramp for prednisone, I would say that that clinical trial that was published in JAMA dermatology really highlights that conventional therapies like methotrexate and prednisone are ineffective and that we should leave them behind and sort of move on to this kind of future which is here, and that is the oral JAK inhibitors.

Based on available trial data and real-world experience, how should clinicians counsel patients on the expected timeline for hair regrowth after starting a JAK inhibitor?

This is a really important question. Treating patients with alopecia areata is very different than treating patients with atopic dermatitis or psoriasis. In atopic dermatitis or psoriasis, we see improvement in weeks for sure over two or three or four months. In alopecia areata, we sometimes see dramatic improvement over three or four months, but more often we see those changes that we think are telling us that somebody is going to achieve complete or near complete scalpel regrowth over a period of six, seven, eight, or nine months of treatment. And so the question becomes, what are the changes at earlier time points that help us predict near complete or complete scalpel regrowth at later time points? And we now have really great data from clinical trials in particular of baricitinib that show that we're looking for a 30% improvement from baseline to mark or help us identify patients who are likely at a later time point to achieve near complete or complete scalp hair regrowth.

And so again, this idea is the patient who at day zero has 100% scalp hair loss, if they come back at month three, four, five, or six with 70% scalp hair loss, then we need to keep going because that 30% improvement over that period of time, clinical trials tells us that that patient is very likely by one year to have their hair, the patient with 50% scalp hair loss at baseline. Again, they come back at month three, four, five, or six with about 35% scalp hair loss. We're going to keep going because again, the clinical trial data says that by one year they are more than likely to achieve near complete or complete scalpel regrowth. So it's just really important. We don't want to abandon or switch between JAK inhibitors never before month six, unless of course there's an adverse event or an intolerability to a medicine.

But if all we're judging is amount of scalpel regrowth, we must not ever abandon or switch therapy before month six and ideally month nine. Lastly there, it's really important that we optimize therapy, I would say, out of the gate. So it's a rare patient in my care who does not leave my initial consultation, not on a JAK inhibitor and oral minoxidil. And so please, please, please consider optimizing treatment out of the gate. But for sure, again, if the patient comes back at month three and you're relatively underwhelmed by their treatment response, don't change JAK inhibitors, but add oral minoxidil. Or if the patient is on baricitinib two milligrams, then progress the patient to baricitinib four milligrams. The other JAK inhibitors, ritucitinib and durexolitinib only have a single dose, and so the issue doesn't come into play there.

What do we know about the effectiveness of JAK inhibitors for eyebrow and eyelash regrowth, and how should clinicians set expectations when these areas are a primary concern?

Again, another really important question, we know that alopecia areata can affect all hair bearing sites, right? So scalp, eyebrows, eyelashes, facial hair, and then body hair, eyebrows and eyelashes are a critical part of human appearance and human expression. And so when patients have involvement of these sites, we want to provide appropriate expectations of treatment when we begin a JAK inhibitor. And it's important to understand that regrowth ... So if you take the curves for scalp hair regrowth, the curves for eyebrow regrowth, for this curves for eye lashes regrowth, they really look very similar. That is, we achieve normal near complete or complete scalp hair regrowth on a similar time scale as we achieve normal or near normal eyebrows or normal or near normal eyelashes. And so again, going back to the previous question about treatment expectations regarding time of scalp hair regrowth, we want to inform patients out of the gate, we are looking for regrowth over these important hair bearing sites over a period of six to nine to 12 months.

I think one of the things that gets tricky here, in particular, when we consider somebody who has scalp hair loss, eyebrows loss, eyelashes loss, is that a patient doesn't always regrow all three of those hair bearing sites. And so they may achieve scalp regrowth and eyebrows, but imperfect or maybe even absent eyelashes regrowth. They may achieve eyebrows and/or eyelashes regrowth and incomplete scalp hair regrowth. And so we have to, again, ahead of treatment, say in this patient who's sitting before us, who's missing their scalp hair eyebrows and eyelashes, say, "I'm hopeful that we are going to grow all of your hair back, but we won't know for sure until month nine or 12 or longer exactly where we are going to land in you in particular." And again, the data informs us that many patients will get it all back, but some will not. And so we just want to set those expectations early because otherwise, right, a patient leaves our office, we gave them a pill to regrow their hair.

They're looking in the mirror at month one, at month two, and they're saying, "Well, gosh, this is happening, but this isn't happening. This must not work the way it's supposed to. " Or, "This is growing, but this is not growing," or, "This is growing in patchy. That's not right." No, it's the importance of this conversation that we're having right now. We have to set treatment expectations appropriately, otherwise patients leave, you've given them a prescription to regrow their hair, and they're saying, "But wait a second, this isn't all happening exactly the same and in exactly the way that I'm thinking it should happen, and on the timescale that I think it should happen, therefore something must be wrong." And we want our patients to come back to that next visit and the visit after, again, with their expectations having been set early so that we can continue to have productive conversations with them in the future.

What happens when JAK inhibitor doses are reduced or treatment is stopped, and how do you approach long-term maintenance versus tapering in responders?

Yeah. So this is really important because the cost, if you will, the personal cost to the patient of hair loss is so dramatic and hair regrowth takes so much time that we must not undertake treatment withdrawal or dose reduction without very careful consideration and discussion with the patient. So the clinical trials of baricitinib to date have most carefully answered this question about, or these questions about dose reduction and drug withdrawal. Remember again, baricitinib is the only approved JAK inhibitor that has two doses, and so again, those clinical trials addressed this question or these questions. So let's take the first one, tapering. So in the clinical trials of baricitinib, patients who had achieved complete or near complete scalpel regrowth at one year underwent dose down titration from four milligrams to two milligrams, and that happened at a moment in time, literally at week 52, the dose was reduced from four milligrams to two milligrams.

Watching those patients over the next six to 12 months or longer, about almost, not quite, but almost half of those patients who had achieved complete or near complete scalpel regrowth at 52 weeks with four milligrams, they started to flare sometimes severely, meaning a lot of hair loss over a very short period of time, over the next four to 24 weeks after dose reduction. Please pay attention here. Dose reduction does not lead to disease flare in one or two or three weeks. That would be rare. It can happen out at eight weeks or 12 weeks or 16 weeks or even 24 weeks. And so it's really important. Don't assume that because a patient dose reduced and four weeks later they're doing fine, that they are going to do fine. That would often be true in atopic dermatitis or in psoriasis, that a dose reduction today, you would understand the effect of it in four weeks.

In alopecia areata, that is not the case. It is going to take many weeks to know whether or not that dose reduction was too much. Therefore, my personal feeling or my personal approach to dose reduction is that you go very slow, small dose reductions over long periods of time. So for instance, with baricitinib, you would have a patient on four milligrams, go from four milligrams daily to four milligrams every other day, alternating with two milligrams every other day. So effectively, a three milligram dose, and you would do that for a period of at least four months before you would consider another small dose reduction. Again, why four months, preferably six months on every dose before you consider another dose reduction? Because the clinical trial data says that some patients will not flare for 24 weeks after dose reduction.

Okay, so that's answering the question of dose reduction. What about drug withdrawal or treatment withdrawal? So again, the baricitinib clinical trials address this question. Patients who had achieved complete or near complete scalpel regrowth at week 52 underwent continued dosing at two milligrams or four milligrams, and half of them underwent treatment withdrawal. And what we see is that four or eight or 12 or 16 or 24 weeks after treatment withdrawal, 80 to 90% of patients will flare and often experience rapid and significant hair loss. Again, not one week after stopping, not two weeks after stopping, not three weeks after stopping, usually not even four weeks after stopping, but eight, 12, 16, or 24 weeks after stopping, they will flare and experience, again, sometimes rapid and significant hair loss.

What I think is interesting about that data is that it's not 100%, it's 80 to 90%. So it tells you that some patients may get by without treatment in the long term. When you look at the patients who did not flare those 10 or 20% of patients, they were patients who had a short duration of current episode of severe disease, which is why, coming back to an earlier question, I really believe that patients with 10 or 20% scalp hair loss who are rapidly losing their hair should be treated with an oral JAK inhibitor because I think that we might be able to not only rescue those patients, but we might be able to change their disease course forever. We might be able to durably remit their disease. This is, of course, a question, but I think we may be able to durably remit their disease by treating them early with a JAK inhibitor.

So again, I would argue that unless, say, again, there's drug intolerance or a woman wants to become pregnant, well, those are two cases where, okay, we're going to stop treatment. But if that is one of those scenarios is not the scenario that you are considering, then rather than just stop medicine, you instead do this very slow taper. And again, this is a taper over one and a half or two years to see if the patient can get to a very, very low dose of JAK inhibitor or ultimately come off without flaring their disease.

In patients with partial response, loss of response, or intolerance, is switching between JAK inhibitors supported by evidence or clinical experience, and when might this strategy be appropriate?

This is a really important question because JAK inhibitors are relatively new to us in dermatology for the treatment of skin disease, for the treatment of atopic dermatitis and now alopecia areata and in the future vitiligo and for certain other conditions. Because of our relative unfamiliarity with them, you might conclude, well, one JAK inhibitor is like another, that if I have a patient who at month six or month nine did not achieve reasonable regrowth, again, kind of 30% or more scalp hair regrowth, that they're unlikely to regrow their hair at all with another JAK inhibitor because they're all JAK inhibitors. It's just not true. We have data in alopecia areata that failure to regrow hair with one can be followed by successful treatment with another JAK inhibitor. Indeed, my wife, Britt Craiglow and I recently published a series of 13 patients showing that failure of one JAK inhibitor to regrow hair can be followed by successful treatment with a second JAK inhibitor.

Similarly, we showed in that series that some patients who failed the first one and also failed to regrow with the second one regrew with a third JAK inhibitor. And we even show in that series that some patients who failed treatment with one, two, or three different JAK inhibitors regrew with a fourth JAK inhibitor. And what's sort of astonishing when you think about that is these are all patients who are undergoing six to 12 months of treatment with each one before we are considering another one. So this process can take time, but again, that series really beautifully illustrates how, again, failure of one does not predict failure of another or rather successful treatment can be achieved after failure of one or two or even three other JAK inhibitors. And so here again, be really careful in your conversations with patients. Don't say, "Gosh, I'm sorry, you're here at month nine. We really gave this a good shot. You didn't grow your hair. Good luck. Let's look to the future to some other class of medicines."

No, no, no. Let's say, "Gosh, this first one didn't work, but we have presently today we have baricitinib, ritucitinib, and do ruxolitinib." So we have three different medicines that we can try. We're going to have other ones in the future. And so again, failure to regrow with one, let's reach for another one. But again, getting back to earlier parts of this conversation, let's always be sure that we're never declaring that a treatment was a failure before month six or ideally month nine, because again, hair regrowth takes a long time.