When Does Regrowth from Baricitinib Occur?

Not all Patients have Regrowth. But 30 % Start Growing in 3 Months

In case you didn’t know it already, I’d like to point out that no two humans are exactly the same.  It comes as no surprise then that no two humans respond exactly the same way when using the same medications.

This concept certainly seems to be true with use of JAK inhibitors used to treat alopecia areata. Some patients respond with evidence of new regrowth within a month or two,  and some patients take many months before growing. Some patients may take even longer. Some patients don’t grow at all when using JAK inhibitors – these patients seem as though they weren’t even taking a pill.

What proportion of patients respond quickly and start growing hair within weeks? What proportion of patients are sluggish in their responses? Are there any factors that make it more likely someone will starting regrowing quickly or be more delayed in their regrowth ? For example, are their factors that might suggest that a given patient might take 6 months or 8 months to respond rather than 6 or 8 weeks ?

Well, these were some of the key questions addressed in a new study by King and colleagues. Authors of the BRAVE AA studies set out to re-examine their data on the JAK inhibitor baricitinib to determine when exactly patients start showing some significant changes in their hair regrowth and if there were factors associated with these patterns of regrowth.

Background to the BRAVE AA trials

We have reviewed the BRAVE-AA1 and BRAVE-AA2 trials in the past. The BRAVE AA trials were two double-blind, randomized, placebo-controlled trials conducted at 169 centres in 10 countries. The trials enrolled patients aged 18–60 years (men) and 18–70 (women), with a SALT score ≥ 50 (severe AA) and a current alopecia areata episode lasting 6 months to 8 years without evidence of a spontaneous improvement. Patients were randomized 3 : 2 : 2 to receive once-daily baricitinib 4 mg, baricitinib 2 mg or placebo for 52 weeks, with placebo non-responder patients switched over to baricitinib at week 36. All patients who completed the 36-week placebo-controlled period entered an extension phase for up to 68 weeks of additional treatment.

The authors’ study here addressed patients who were randomized at baseline to receive baricitinib 2 mg or 4 mg and who maintained the same dose through to week 52.

King et al 2023

There were 515 patients assigned to 4 mg baricitinib and 340 patients assigned to 2 mg baricitinib.

In the baricitinib 4-mg and baricitinib 2-mg groups, respectively, mean patient age was 37.1 and 38.4 years, 60% and 62% were female, 52% and 54% were White, 35% and 37% were Asian and 9% and 6% were Black or African American. Also, the duration of current episode of hair loss at baseline was 3.68 and 4.10 years, with 36% and 32% having a duration of ≥ 4 years, respectively. Mean baseline SALT score was 85.1 and 86.3, respectively, with 52% and 57% of patients, respectively, reported as having a very severe AA (SALT score 95–100) at baseline.

Patients who achieved a 30 % improvement in their SALT score (or what’s called a SALT30) were said to be treatment ‘responders’. 51 % of those given 2 mg achieved a 30 % improvement in their SALT score at least once over the first 52 weeks of treatment.  Of those patients who received 4 mg of baricitinib in the trials, 69% achieved a SALT30 score at least once.

Three Groups of Patients: Early Responders, Gradual Responders and Late Responders

When the authors examined exactly when patients start regrowing hair after baricitinib treatments, the authors found there were 3 subgroups of patients.

There was a group of “early responders” (those achieving SALT30 by week 12), “gradual responders” (those achieving a SALT30 between week 12–week 36) and “late responders” (those achieving a SALT30 after week 36–week 52).

For those patients receiving 4 mg of baricitinib,  33 % were found to be early responders, 28 % were gradual responders and 8% were late responders. There were 31% of patients that were non responders.

Patients with a disease duration less than 4 years were more likely to be responders than patients with a disease duration more than 4 years.  However, what was interesting was that patients with a disease duration less than 4 years were not necessarily more likely to be “early responders.” Disease duration did not affect whether someone was early or late responder – just if they responded to treatment or not.

The authors showed that it was the extent of hair loss that had key influence the timing of regrowth.

“Early responders” were more likely to be patients with less severe forms of AA (such as a SALT 55 instead of SALT 100).  About 70 % of late responders had very severe AA. In contrast only 15-20 % of those who were considered “early responders” had very severe AA (SALT 95-100).

Early Responders Have Better Chances of Good Growth by Week 52 than Late Responders

A Closer Look at the “Early Responders”

When examining trajectories of response, >80% of “early responders” treated with baricitinib 4 mg achieved a SALT50 response by week 16 and >70% achieved a SALT score ≤20 as early as week 24, with up to 62% achieving a SALT score≤10 by week 52.

A Closer Look at the GRADUAL Responders

Among the baricitinib 4-mg gradual responders, 79% of gradual responders achieved SALT50, 51% achieved a SALT score ≤20 and 34% achieved a SALT score≤ 10 by week 52.

A Closer Look at the LATE Responders

Among the late responders, 51% achieved SALT50, 20% achieved a SALT score ≤ 20 and 10% achieved a SALT score≤10 by week 52.

Conclusions and Comments

This is a helpful paper ! The findings of this paper guide us with regard to the counseling we need to give to patients in different scenarios.

This study is a helpful reminder that if a patient is going to respond to the drug, most will respond by week 36 (8 months). About 33% of patients are early responders and 28% are mid range “gradual” responders. There are a very small proportion of late responders (under 10%) who start showing some growth after week 36.

It’s a small proportion of late responders but nevertheless an important message. If a patient is willing to keep going, it’s worth trying even beyond month 8 or 9. Some patients can still respond although the chances get lower and lower as time goes by. If a patient has not responded to baricitinib by week 36, it’s more likely than won’t grow hair than they will grow hair. So it’s not simply that many people are delayed it’s more that a small proportion are delayed.

Our patients with more severe forms of AA are more likely to be delayed in their response. It’s helpful to know this up front so that we can counsel patients not to be all that discouraged if they don’t’ see growth happening in the first 3-5 months.

But this study also helps with realistic expectations. Realistically, most of the  “late responders” are not going to achieve as good of result as early responders!!!!!!!!!!! Only 20 % of late responders achieve a SALT <20 at week 52. 80 % will not.

Of course, some of the late responders will probably keep improving beyond the end of week 52 so the number 20% is not the proportion that will ever achieve a SALT 20.

But still the point is this – late responders probably have a lower chance of achieving great results compared to early responders (even if you do take into account the growth that may still occur in year 2)

I think this is really important. I view it differently than simply “some take a while to respond to baricitinib.”

I basically take the number of months it takes to start showing some good growth (SALT 30 improvement). Then multiply this by 10. Subtract this from 100. Now you have  the proportion of patients that will achieve a SALT <10 result by week 52.

Put another way:  

If you are seeing some evidence of growth by week 12 (month 3),  then there’s a pretty good chance (70%) that you’ll achieve some pretty significant growth (i.e. SALT <20) by week 52 and a 62% chance of amazing (SALT <10) results.

If you are not seeing some evidence of growth by month 3, but you see some take place between week 12  and week 36 then there’s a 50-50 chance that you’ll achieve some pretty significant growth (i.e. SALT <20) by week 52 and just a 34 % chance of amazing (SALT<10) results by week 52.

If you are not seeing some evidence of growth by month 3, and you are not seeing some growth take place between month 3 and 8 then there’s a low chance (20%) that you’ll achieve significant growth (i.e. SALT <20) by week 52 and less than a 10 % chance you’ll have amazing SALT <10 results. There’s probably a 15-20% chance you’ll eventually get some really nice result if you wait long enough.

All in all the authors propose that the time point at which a SALT30 response is achieved could have some helpful prognostication.

I like this concept and my formula seem to work ok: I basically take the number of months it takes to start showing some good growth (SALT 30 improvement). Then multiply this by 10. Subtract this from 100. Now you have  the proportion of patients that will achieve a SALT <10 result by week 52.

It would have been nice for the authors to include their 2 year data. What we don’t know in this paper is what proportion of late responders do eventually have good results by year 2. That’s a missing piece of the puzzle here in this paper.

The question I’m often asked is: Should we start adding some other combination therapy if you are not seeing growth with baricitinib?

That’s a bit of a tricky question and answers will depend on the expert you ask.

Some doctors say “Oh, I always like to add oral minoxidil to baricitinib”

Some say, oh, I like to give a pulse of dexamethasone if I’m not seeing results”

Some say “Oh, I like to give a tiny dose of cyclosporine”

Now, personally I’m not a great fan of adding multiple therapies too early on in the course of treatment. Even if there’s not much of a response at 6 months, 50 % of patients will still achieve at least some good growth (SALT <20) by week 52. If you go adding too many therapies you lose the ability to figure out just how much each is contributing. I think this is too often forgotten. This is so important for treatments that are probably going to be lifelong for many.

Now, there are those who feel this paper by King et al tells us all to just keep giving medications even up to week 36 as patients can have delayed responses.

In my opinion, that’s true but this study has a more important message to me.

MESSAGE 1: THE FIRST THREE MONTHS IS SO IMPORTANT!

What this study reinforces to me is just how important growth in the first three months is. Yes, I really really hope that my patient respond in the first three months if possible. That’s not to be missed here!!!!! Whether or not there is early growth in the first 3 months is so so important. Very important in my opinion.

This study by King et al would tend in some ways to suggest that early and gradual responders are fairly balanced. After all 33 % were early responders and 28% are gradual responders. This is a bit inaccurate in how the data is portrayed.

The reality is that 33 % of patients were early responders, and probably some 15 % or so responded between month 3 and month 5 and another 15 % probably responded between month 6 and week 36. So the three month time period with the most responders was the first three months. 

MESSAGE 2: PATIENTS WITH EARLY REGROWTH HAVE A HIGHER CHANCE OF AMAZING RESULTS AND PROBABLY DON’T NEED OTHER THERAPIES RIGHT AWAY

If the patient does show evidence of early regrowth, there is a high chance (more than 70%) of nice results by week 52 (SALT <20) and a 60% chance of a SALT less than 10 (in other words “amazing” results). If there is growth in the first three months, I don’t want to add anything else to the treatment plan. I don’t want to add oral minoxidil or topical steroids or anything!! GROWTH in the first three months is hugely important and tells me that a single drug might be able to do this on its own.  Growth in the first three months is basically all the hair follicles shouting out “we can do this with baricitinib”.

The patient might only need baricitinib!

If there is not good signs of  growth by 3 months, you are reducing your chances day by day that you’ll achieve good results by week 52 – and probably similarly a reduced change you’ll get good result even if one waits longer.  There is only about a 30 % chance you’ll achieve amazing (SALT <10) results by week 52.

This is important for me because I personally feel that if I’m not seeing some evidence of growth by 6 months it tells me that more likely than not we are not doing to get great results. It’s still possible to get great results, but it’s becoming less and less likely. So should be continue baricitinib or should we abandon therapy?

Well this study tells us that there is still a chance of getting growth – even if no good growth by month 6. So if I see no growth at six months, I will continue baricitinib without adding any other therapies. For me, I need to figure out if am I going to need to have the patient stop the baricitinib in the near future or will I continue. Is it an effective treatment for this patient or not?

I’m personally not a fan of now adding low dose cyclosporine or oral minoxidil to see what happens in this situation.

I feel I owe it to the patient to figure out if this works or not. So if I’m not seeing ANY growth by month 6, I’m NOT going to add other treatments quite yet.

If there is some growth happening at 6 months but not a lot of growth, that’s the tough part. That’s where professional judgement comes in. It’s more likely than not that the scalp will need some help. It’s more likely than not that baricitinib is not going to be able to do this all on its own.

Not impossible - but increasingly unlikely.

50% of “gradual responders” will achieve a nice results but that includes all patients in the 12 week (3 month) to 36 week period (8 month) window. It’s clearly going to be a bit less of a chance for a patient showing growth at 6 months compared to 3 months and a bit less for someone with alopecia totalis or universalis than other forms.

If there is only a bit of growth at 6 months or 8 months and the patient has AT  or AU, I still might wait to see what might happen if we wait longer. That is my preference. However, the options I am thinking about are adding oral minoxidil, adding steroid injections to “one side” of the scalp at a low dose like 2.5 mg per mL. The bigger decision is whether to add oral immunosuppressants like methotrexate or a pulse of steroids. I’m not a great fan of these steps. I generally would rather wait a bit longer but it's increasingly becoming a reality that maybe just maybe baricitinib is not going to be able to do this on its own.

We need to be open to understanding these odds. As time marches forward, and there is no growth or poor growth, the odds are diminishing that good growth will occur. 

All in all, I think we have to be careful about concluding that this study simply teaches us that some patients respond late to baricitinib. That’s true but the reality is that less than 20 % of patients respond well if it’s been more than 8 months before growth starts taking place. Even with more time, it’s unlikely that more than 25% -30% of late responders will achieve a SALT <20 and unlikely that more than 10-15 % of late responders achieve a SALT<10. Most are not going to respond well.

The title of this paper is “When to expect scalp hair regrowth during treatment of severe alopecia areata with baricitinib”

I think it’s one thing to conclude “ oh, be patient - you can expect some to respond late!”

I think the correct conclusion is “some do respond late. The longer and longer you go after 6 months-8 months the less and less likely you are to get amazingly good growth.

We need to not only be patient for those who are going to grow but we need to be patient to be ready to hit the big red button that says this drug does not work for you!

1 of 3 patients in this study with advanced alopecia areata are not responders to baricitinib!!!!!!!

So the title of the paper “When to expect scalp hair regrowth during treatment of severe alopecia areata with baricitinib” is probably better written “When to expect scalp hair regrowth during treatment of severe alopecia areata with baricitinib if the patient is going to respond at all”

There is no right or wrong answer as to when to start “combination” therapy. Lots and lots of papers are coming out about combination therapy and personally I differ in my views. That’s okay – you figure out you own views!!!

I feel that we owe it to patients to help them answer the question. Is this particular JAK inhibitor even doing anything ? Patients probably are  going to need to use it forever so this is important.  So if there is anything we can do to help answer that question, then it’s important to do.

This study does not take away from the key message: good growth in the first three months is just a wonderful sign. Absence of good growth does not mean the treatment won’t work but the chances are reducing.

REFERENCE

King B et al. When to expect scalp hair regrowth during treatment of severe alopecia areata with baricitinib: insights from trajectories analyses of patients enrolled in two phase III trials. Br J Dermatol.. 2023 Sep 14:ljad253.