Alopecia areata (AA) is a commonly occurring autoimmune disorder, with a prevalence rate of 2% in the United States (1). Persistent AA and its variants can lead to significant scalp hair loss, adversely impacting the patient’s quality of life and psychological well-being (2). Currently, there are no available drugs for permanent AA treatment. Clinical drug regimens mainly rely on intra-lesion or systemic corticosteroids, minoxidil, and methotrexate. However, patients with moderate to severe alopecia areata (SALT score≥50%), especially those with alopecia totalis or universalis, require more effective, better tolerated, and safer alternative drugs (3–5).

AA is a degenerative disease that affects hair follicles and is characterized by inflammatory cell infiltration around lesion follicles. The clinical manifestations include sudden, circular patchy hair loss on the scalp and other areas such as eyebrows, eyelashes, beard, and body hair, along with dotted depression of finger/toe nails (6). Some oral JAK inhibitors (JAKi) have been approved by the FDA for the treatment of autoimmune diseases such as rheumatoid arthritis, psoriasis, and allergic dermatitis; however, as of June 2022, only Baricitinib had garnered approval from FDA (7–10). Pfizer’s new oral JAKi PF-06651600 and Concert Pharmaceuticals’ CTP-543 and topical ATI-502 have received ‘Fast Track’ from the FDA and completed Phase III RCTs to generate efficacy and safety data for future JAKi applications in AA. Additional studies are required to establish their effectiveness and safety. To that end, we undertook a systematic review and meta-analysis of published RCTs and OSs to evaluate the effectiveness and safety of JAKi in AA treatment.

This investigation was conducted in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (11) ( Supplemental Table 1 in Supplement material). The primary design was registered on PROSPERO (CRD42022334326).

Our study examined the impact of pre- and post-JAKi therapies on AA patients’ outcomes. The primary evaluation was the variation in Severity in Alopecia Tool (SALT) score, comparing the experimental group to the placebo group in the randomized controlled trials (RCTs), and post-treatment values to the baseline in the observation studies (OSs). Secondary measurements included the proportion of patients achieving improvements of 5%, 50%, and 90% in the SALT score (SALT₅, SALT₅₀, SALT₉₀) and adverse event rates.

The current systematic review reveals that the analysis of RCTs and OSs outcome indicators presents statistically significant evidence that JAKi significantly promotes hair regrowth in patients with AA. Notably, subgroup analysis demonstrates a positive effect on hair regrowth for female patients, with Ruxolitinib showing superiority over tofacitinib, and higher Tofacitinib daily dosing having a more significant impact on efficacy. Concerning safety assessment, the observed frequency of adverse reactions was 61.1%, while severe adverse reactions were negligible, with a mere 1.7% of all documented cases. Notably, 30 patients withdrew from the trial due to adverse reactions. Finally, the review was conducted to determine frequencies of typical mild adverse events; the outcomes fetched were within tolerable ranges.

Currently, first-line treatments for AA consist of a range of drugs including compound glycopyrrolate, topical or systemic steroid hormones, topical or oral minoxidil. Second-line treatment options, such as JAK inhibitors, diphenylcyclopropenone, and immunosuppressants, are typically reserved for severe cases where the lesion areas exceed 50%. It is important to note that presently, only Baricitinib has received FDA approval for treating AA (47). While fast-acting, glucocorticoids can be associated with significant pain and severe side effects due to their non-selective targeting of immune cells (48). Off-label immunosuppressive drugs like methotrexate and cyclosporine A constitute systemic therapies, with the latter being recommended in combination with steroids to manage intractable AA cases (49, 50). In summary, given the associated risks, systemic therapies should be reserved for patients with refractory AA and significant psychosocial stress. Low-risk local management represents a reasonable option for instances where AA is localized or limited in extent, particularly in the long run (51).

The JAK/STAT signaling pathway serves as a crucial intersection for numerous inflammatory factors, with JAK inhibitors offering the advantages of swift onset, notable effectiveness, and minimal adverse effects (52). JAKi application has been shown to promote hair regrowth in various areas such as the eyelashes, eyebrows, beards on the face, arms, legs, armpits, and groin region (53). Laboratory findings demonstrated increased hair keratin levels and reduced perifollicular T-lymphocyte infiltration following JAKi therapy, with treatment-related downregulation of inflammatory markers evident in gene expression profiles (17, 43).While JAKi’s effectiveness in treating alopecia areata may not exceed that of systemic glucocorticoids in present evidence, their targeted immunosuppressive properties may offer a safer alternative to long-term systemic therapy (54). Currently, JAKi usage in clinical practice is supplemented with other drugs, such as topical hormones and minoxidil, resulting in significant gains in refractory AA therapy (23). Given that approved JAKi are metabolized by CYP3A4 enzymes, caution must be taken when used in conjunction with inducers such as rifampin or inhibitors such as ketoconazole (48). However, due to data limitations, our study did not evaluate the impact of concomitant therapy with multiple agents.

This meta-analysis has several limitations that should be acknowledged. Firstly, despite our effort to include all randomized controlled trials assessing oral JAK inhibitors, the number of placebo-controlled studies with full reporting is scarce, which precluded us from conducting subgroup and sensitivity analyses. Additionally, this systematic review encompassed many case series and reports characterized by small scale, low quality, high risk of bias, and limited statistical power analysis. Secondly, the present study, along with most of the clinical trials examined, encompassed severe alopecia areata, comprising alopecia totalis and alopecia universalis. Patients with alopecia universalis and alopecia totalis exhibited superior outcomes in response to JAK inhibitors compared to those individuals afflicted with patchy alopecia areata. Our analysis suggests that outcome indicators such as SALT₅₀ obtained by observation studies may be higher than RCTs, given that patients’ disease severity in case reports or series may be severe, and display a marked inflammatory response to JAKi and more overt symptoms. Thirdly, observer bias may limit our results due to the lack of blinding in observational studies’ treatment and outcome assessment process. Lastly, the studies we included in our analysis did not provide sufficient data on the long-term efficacy, safety, and disease recurrence of JAKi drugs; hence, future large-scale, long-term RCTs are imperative to validate the efficacy and safety of these drugs.

In this systematic evaluation and meta-analysis, we demonstrated the effectiveness of oral JAK inhibitors in patients with alopecia areata and that adverse effects were within manageable limits. However, we regard additional high-quality randomized controlled trials involving larger samples as crucial steps towards the identification of the ideal drug types and doses that would optimize therapeutic efficiency while limiting potential harm posed by JAK suppression.

M-QM gathered the information and wrote the original draft. JJ is responsible for funding acquisition and modification. All authors are contributed to the article, participated in resources, wrote the review and edited. All authors contributed to the article and approved the submitted version.