Dear Editors, Janus kinase (JAK) inhibitors have emerged as key treatments for several dermatological diseases, including atopic dermatitis (AD) and alopecia areata (AA).1 However, their use is associated with adverse events (AEs), which may affect the continuation of therapy and the overall quality of life of patients.2 A case of amenorrhea was recently reported in a patient treated with upadacitinib for AD.3 The mechanism underlying this AE is not fully understood. Leptin may play a crucial role in regulating the hypothalamic-pituitary-ovarian (HPO) axis through the JAK2/STAT3 pathway. JAK inhibitors may alter leptin signaling, disrupting gonadotropin-releasing hormone (GnRH) secretion and gonadotropin release, leading to menstrual alterations.4, 5 Baricitinib (2/4 mg) inhibits JAK1/2 and is approved for moderate-to-severe AD and severe AA.1 Abrocitinib (100/200 mg) selectively inhibits JAK1 for moderate-to-severe AD. Upadacitinib, a JAK1 inhibitor, is approved for moderate-to-severe AD at 15 mg and 30 mg doses, with in vitro studies suggesting that 30 mg may also inhibit JAK2 signaling.1, 6, 7 AEs commonly associated with JAK inhibitors are generally mild-to-moderate and include non-infectious and infectious cutaneous events, and laboratory abnormalities.1 We report a case series of 16 female patients who developed menstrual alterations during treatment with JAK inhibitors for AA or AD. We excluded patients who had reported irregular menstrual cycles before the start of JAK inhibitor therapy. Patients’ characteristics at baseline were retrospectively retrieved from the medical records of the IRCCS Humanitas Research Hospital (Milan, Italy). Each patient was assessed for menstrual cycle alterations (including amenorrhea, hyper/hypomenorrhea, poly/oligomenorrhea, and dysmenorrhea) at each follow-up visit.8 Continuous variables were reported as mean and standard deviation (SD), while categorical variables were expressed as absolute numbers and percentages. Institutional review board approval was not required because the study procedures did not deviate from good clinical practice. The study was conducted in accordance with the Helsinki Declaration of 1964 and its later amendments. All included patients provided written informed consent for the retrospective analysis of their clinical data. Our population included 16 female patients with AA or AD treated with JAK inhibitors (Table 1). The mean age at baseline was 35 years (SD 10), with a mean Body Mass Index (BMI) of 20 (SD 2). Three patients (19%) were already taking oral contraceptives. Nine patients (56%) received baricitinib 4 mg for severe AA, while the other seven (45%) were treated with upadacitinib (5 patients 15 mg; 2 patients 30 mg) for moderate-to-severe AD. The most reported menstrual cycle alteration was amenorrhea (8 patients, 50%), followed by polymenorrhea (6 Patients, 38%). Our patients developed menstrual irregularities after a mean time of 5 months (SD 4) since the start of the treatment. All patients who developed amenorrhea discontinued the medication, underwent a gynecological examination with negative results regarding organic alterations, and experienced a natural restoration of their menstrual cycle. Our case series study highlights a potential association between JAK inhibitors and menstrual cycle alterations in female patients treated for AD or AA. Amenorrhea was the most frequently reported alteration, suggesting a possible impact on the HPO axis. Most patients (11, 69%) received therapy that also acted on the signaling of JAK2 (9 with baricitinib 4 mg and 2 with upadacitinib 30 mg). JAK2 signaling is involved in leptin-mediated effects at the hypothalamic level, and its inhibition may disrupt GnRH pulsatility, leading to menstrual irregularities.4, 5 A recent study showed that suppression of this pathway may induce metabolic dysregulation of leptin activity, leading to significant weight gain in patients treated with agents that interfere with JAK2-mediated signaling.9 Menstrual disorders occurred at a mean of 5 months after starting the JAK inhibitor, suggesting a delayed impact on hormonal regulation. Amenorrhea resolved naturally in eight patients after discontinuing JAK inhibitors, suggesting a reversible drug-related effect. Our study has several limitations, including its retrospective design and the relatively small sample size. Moreover, the retrospective nature of the analysis and variability in patient-reported data did not allow for the establishment of a consistent and reliable time course. Nonetheless, all patients had returned to their normal menstrual cycle by the first follow-up visit, conducted 6 months after discontinuation of the medication. Although patients with known pre-existing menstrual irregularities were excluded, the presence of unrecognized endocrine disorders or the influence of concomitant medications cannot be fully ruled out. In conclusion, JAK inhibitors, particularly those blocking JAK1/2 signaling, may disrupt the HPO axis and contribute to menstrual cycle alterations. Clinicians should be aware of these potential AEs and monitor menstrual cycles in patients using these drugs. Larger and longer studies with hormonal profiling are needed to confirm these findings. Institutional review board approval was not required because the study procedures did not deviate from good clinical practice. The study was conducted in accordance with the Helsinki Declaration of 1964 and its later amendments. All patients included in the study provided written informed consent for the retrospective analysis of their clinical data. L.I. has served as a consultant for Almirall. L.G. has served as a consultant and/or speaker and has participated in advisory boards for AbbVie, Almirall, Eli Lilly, Pfizer, Sanofi and UCB. M.V. has served as a consultant and/or speaker for Sanofi, LEO Pharma, Eli Lilly, Novartis, Janssen, AbbVie, Boehringer Ingelheim, Almirall, UCB and Difa Cooper. P.F. has served as a consultant for Eli Lilly and as a speaker for UCB, Pfizer and AbbVie. A.N. has served on advisory boards and has received honoraria for lectures and research grants from Almirall, AbbVie, LEO Pharma, Celgene, Eli Lilly, Janssen, Novartis, Sanofi Genzyme, Amgen and Boehringer Ingelheim. A.C. has served as an advisory board member and consultant and has received fees and speaker's honoraria or has participated in clinical trials for AbbVie, Almirall, Biogen, LEO Pharma, Eli Lilly, Janssen, Novartis, Pfizer, Sanofi Genzyme and UCB. All other authors declare no conflict of interest.
Ibba et al. (Thu,) studied this question.
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