Should the JAK inhibitor tofacitinib be continued in pregnancy for patients with alopecia areata?
Current Evidence Supports Stopping JAK Inhibitors in Women with Alopecia Areata Who Immediately Plan to Become Pregnant
I’ve selected this question below for this week’s question of the week. It allows us to review some concepts related to the use of tofacitinib (Xeljanz) in pregnancy.
Question
I had alopecia areata and I took Xeljanz 5mg twice a day for 8 years now. My hair grew back and everything is fine. My question is does Xeljanz affects fertility? Does it cause birth defects? Because I am trying to get pregnant and I'm worried that Xeljanz might be the reason why I haven't conceived yet. I am in my early 30s.
I also want to know if I stopped Xeljanz, my hair will fall again?
Thank you
Answer
Thanks for the great question. The “short answer” to these questions is 1) I generally do NOT recommend that tofacitinib be used during pregnancy and 2) yes, hair could fall out again if Xeljanz is stopped but it may or may not fall out as much as it did before starting.
Let’s look at all these issues in more detail.
Tofacitinib and other JAK inhibitors like baricitinib and ruxolitinib and ritlecitinib and upadacitinib and abrocitinib are now commonly used to treating more advanced forms of alopecia areata. Baricitinib and ritlecitinib are of course FDA approved but other JAK inhibitors are used off label.
Because tofacitinib is such a small molecule, it is thought that it can easily cross the placental barrier. In other words, a mother using tofacitinib is likely to transfer the tofacitinib to the developing fetus. However, information on the effects of tofacitinib on pregnancy outcomes in humans is somewhat limited.
In some autoimmune diseases, the decision to withdraw immunosuppression during pregnancy is not taken lightly. In fact, in some diseases, many immunosuppressives are in fact continued. For example, patients with ulcerative colitis (UC) have a significantly higher risk of adverse birth outcomes compared with controls, including low birth weight, preterm delivery, and neonatal death. Many immunosuppressants (but not all of them) are continued during pregnancy for women with ulcerative colitis.
Is tofacitinib harmful during pregnancy in animal studies?
Tofacitinib - when used at high doses - was shown to be teratogenic at high doses in animal models. For example, in preclinical animal studies, tofacitinib was both feticidal and teratogenic in rats when used at doses 146 times above the typical human dose and in rabbits when doses were 13 times greater than the typical human dose.
Is tofacitinib harmful in humans during pregnancy?
The Pfizer drug monograph for tofacitinib is clear that tofacitinib is contraindicated in pregnancy. The drug monograph for tofacitinib reminds us that there is a registry of tofacitinib use in pregnancy. In other words, the company is keeping track of patients who become pregnant while on tofacitinib to follow outcomes of babies and mothers. Pfizer invites patients to call the toll free number 1-877-311-8972 if they wish further information. The company is doing the same with their JAK inhibitor ritlecitinib LITFULO.
For now, the official stance of the company is that available data is insufficient to say whether or not tofacitinib “is associated with a risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.”
The company reminds us that in the general U.S. population, about 2-4 % of pregnancies are associated with babies being born with some type of major birth defect and at least 15-20 % of clinically recognized pregnancies lead to miscarriages. This is the statistics for women who do not use tofacitinib. Whether these numbers are truly different for tofacitinib users is not known. in addition, it is not know if these numbers are different for tofacitinib users with ulcerative colitis who use tofacitinib or rheumatoid arthritis who use tofacitinib or alopecia areata who use tofacitinib.
In clinical trials of tofacitinib, women of child bearing potential were required to use contraception and were required to stop tofacitinib if pregnancy did occur. Therefore, we have very limited data on tofacitinib in pregnancy.
Are other JAK Inhibitors okay to use in pregnancy?
The product monographs for baricitinib and upadacitinib are very clear that these drugs should not be used in pregnancy. The product monograph for abrocitinib advises against using the drug in pregnancy as does ruxolitinib.
The ritlecitinib (LITFULO) product monograph is perhaps the most confusing, in my opinion, with no clear and bold statement against pregnancy but rather information that risks are unknown who do contact if pregnancy does occur. In my opinion, I would not advise my patients with alopecia areata to consider pregnancy while using ritlecitinib until we have more data.
Do women with alopecia areata and active autoimmune diseases have worse pregnancy outcomes?
For some autoimmune diseases, like rheumatoid arthritis, lupus, and ulcerative colitis, the data is pretty clear that women with more active disease have a higher chance of negative outcome in pregnancy. This includes outcomes such as preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age (SGA) at birth.
A few years ago, I reviewed an important paper from South Korea. Authors used the Korean National Health Insurance claims database to investigate the association between AA and obstetric complications. They identified 4,552 patients with alopecia areata and compared data to 508,345 individuals without alopecia areata (control population). After the authors used statistical analyses to adjust data for age, comorbidities, and obstetric and gynecological diseases, they found that the total live birth rate was significantly lower in patients with alopecia areata compared to controls (73.31 % vs 76.35%), the rate of miscarriage was significantly higher in patients with alopecia areata compared to controls (17.55 % vs 16.33%), the rate of ectopic pregnancy was significantly higher in patients with alopecia areata compared to controls (5.69% vs 4.48%). There were no differences in rates of cesarean deliveries, stillbirths or infertility. All in all, it’s clear that alopecia areata can impact pregnancy outcomes.
There were two key limitations of this Cho et al 2021 paper that are relevant to the question today. First, we don’t know if patients with more severe AA have worse outcomes than patients with less severe AA. Second, we don’t know if treatment has any impact either. For example, would it at all be possible that treatment with an immunosuppressive drug would improve outcomes rather than make it worse. These are answered questions.
IMPORTANT STUDIES OF TOFACITINIB USE IN PREGNANCY
STUDY 1: Clowse and colleagues, 2016
A 2016 report by Clowse and colleagues reported outcomes of women who became pregnant while receiving tofacitinib. These were pregnancy cases identified from a variety of sources including tofacitinib randomized controlled trials (of Rheumatoid arthritis and psoriasis), other RA studies, and spontaneous adverse-event reporting.
Authors reported 47 women who became pregnant on tofacitinib. This included 33 women who received tofacitinib monotherapy and 13 who received combination therapy with methotrexate, and one patient whose therapy was still blinded. There were no fetal deaths. There was one congenital pulmonary valve stenosis (monotherapy patient), seven miscarriages (4 from monotherapy group and 3 from combination therapy group.
All in all, there were 25 reported healthy newborns among the remaining cases. 6 patients were lost to follow up.
STUDY 2: Mahadevan and colleagues, 2018
A 2018 study reported eleven cases of maternal exposure and 14 cases of paternal exposure to tofacitinib (doses of 5 mg or 10 mg twice daily) before/at the time of conception or during pregnancy. Outcomes included 15 healthy newborns, no fetal deaths, no neonatal deaths, no congenital malformations and 2 miscarriages. The tofacitinib was used for treating ulcerative colitis in this study.
SUMMARY
All in all, we don’t really know if tofacitinib is completely safe in pregnancy. That’s the reality. There is ongoing research about the safety of tofacitinib in pregnancy. At the present time, most practitioners and most physician-based organizations and societies and most product monographs for the drugs do not generally support the use of tofacitinib in pregnancy. We can’t exclude the possibility that it has some safety issues.
Some publications and writings are stronger in their opinion than others. In 2016, EULAR (Götestam Skorpen C et al, 2016) formally stated that tofacitinib be stopped during pregnancy until more information and data can be obtained. The gastrointestinal community has a similar but ever so slightly less negative stance that tofacitinib should be used with ‘extreme caution’ if it ever were to be used in pregnancy by patients with inflammatory bowel disease (Laube et al 2021). The same authors note that tofacitinib is teratogenic in animal studies and for the most part should be ‘generally avoided.”
A Mother to Baby Ask the Experts Fact Sheet highlights to readers that so very little is known about tofacitinib in pregnancy.
In my professional opinion, JAK inhibitors should not be used in pregnancy in patients with alopecia areata until we have more data. Across the board, there is so little to support the use of tofacitinib in pregnancy by patients with alopecia areata.
Before I leave the subject, I would like to mention a few things. First, you should speak with your physicians as soon as possible. That means right away if possible. If you are trying to conceive and using tofacitinib, you need to have some serious discussions right away. I can’t give you advice one way or another (because you are not my patient) but you and your doctors should review carefully all the information about what is known and what is unknown about the safety of tofacitinib in pregnancy. You should speak with your physicians as soon as possible.
Second, it’s important to speak with a gynecologist as well regarding fertility. Just like we don’t know for sure if tofacitinib increases the chance of birth defects and other issues, we don’t know for sure if tofacitinib affects the chances of becoming pregnant if a person were to use the drug. But in general, if you have decided to try to become pregnant while on tofacitinib and you’ve been trying with regular frequency for more than 1 year, you really need to see an expert for a full assessment regarding all fertility issues. All women under 35 who can not become pregnant after 1 year of trying need full evaluation by a gynecologist. Your gynecologist can evaluate if this could be due to tofacitinib or due to other factors. But this too needs evaluation.
All in all, most of my own patients with alopecia areata are recommended not to use JAK inhibitors during pregnancy until we know more information about their safety. Several professional societies have this viewpoint too. I can’t say what you should or should not do as you are not my patient but I would urge you to speak to your doctors immediately so that you can review all this information and understand what plan is best for you and your specific situation.
You had asked in your second question whether you will lose hair if you stop tofacitinib (Xeljanz). That answer is maybe but most patients who had advanced alopecia areata and regrew back their hair with a JAK inhibitor will lose some or all of the hair again if they stop. What we can’t predict is whether it will be all the hair that is lost or just some of the hair and what we can’t predict is whether pregnancy will alter this (as some patients have reduced activity of alopecia areata in pregnancy). But in general, there is a very high chance of losing at least some hair when the tofacitinib is stopped. Some women do get it back again when tofacitinib is restarted at a later date. But not every single patient who stops tofacitinib and loses hair and then restarts tofacitinib at a later date gets back all the hair again. These are tough issues but important to review in exhaustive detail with your doctors.
REFERENCE
Clowse ME, Feldman SR, Isaacs JD, et al. Pregnancy outcomes in the tofacitinib safety databases for rheumatoid arthritis and psoriasis. Drug Saf. 2016;39:755–62. 22. Sandborn WJ, Gh
Mahadevan U et al.Outcomes of Pregnancies With Maternal/Paternal Exposure in the Tofacitinib Safety Databases for Ulcerative Colitis. Inflamm Bowel Dis. 2018 Nov 29;24(12):2494-2500.
Pfizer Inc. Xeljanz prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/203214s018lbl.pdf. Accessed aug 5 2023.
Carina Götestam Skorpen et al. The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Ann Rheum Dis. 2016 May;75(5):795-810.
Laube R et al. Use of medications during pregnancy and breastfeeding for Crohn's disease and ulcerative colitis. Expert Opin Drug Saf. 2021 Mar;20(3):275-292.