Patient Considerations when Using Ritlecitinib for Alopecia Areata in Adolescents: Guidance for the Clinicians

Alopecia areata (AA) is a T-cell-mediated autoimmune disease characterized by partial or complete non-scarring hair loss affecting the scalp, face, and/or body [1]. The cumulative incidence of AA in children and adolescents is 2.5%, which is significantly higher than that in adults (0.4%) [2]. AA can cause significant emotional and psychosocial distress and is associated with psychiatric comorbidities, including depression, anxiety, and adjustment disorder [3]. The impairment of health-related quality of life (QoL) in children and adolescents with AA has been well documented [4].

Ritlecitinib, an oral, selective dual inhibitor of the Janus kinase (JAK) 3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family, has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treatment of severe AA in patients aged 12 and older [5]. It is currently the only FDA-approved treatment for adolescents (aged 12–17 years) with severe AA. This review aimed to summarize the mechanism of action, clinical trial evidence, and factors associated with treatment response and provide clinical considerations and management recommendations for adolescents with AA using ritlecitinib.

The pathogenesis of AA involves the immune privilege collapse of the hair follicle, leading to the autoimmune attack by NKG2D⁺ CD8⁺ T cells and natural killer (NK) cells in inflammatory infiltrates around the hair bulb [6]. The upregulation of interferon-γ (IFN-γ) and common γ-chain (γc) cytokines, including interleukin (IL)-2, IL-7, IL-15, and IL-21, has been demonstrated as the key driver for the activation and proliferation of the immune cells involved in AA [7, 8]. The inflammatory signals of these cytokines are transmitted and amplified by the JAK/signal transducers and activators of transcription pathway. The JAK family comprising cytoplasmic JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) plays a pivotal role in IFN-γ (JAK1/2) and IL-15 (JAK1/3) signaling, which provides a strong therapeutic rationale for JAK inhibitors [9, 10].

The cytotoxic effects of autoreactive CD8⁺ T cells in AA are medicated by T-cell receptor-major histocompatibility complex signaling [11]. The TEC family consists of five members: TEC, Bruton’s tyrosine kinase (BTK), IL-2-inducible T-cell kinase (ITK), resting lymphocyte kinase (RLK), and bone marrow tyrosine kinase gene on chromosome X (BMX) [12]. TEC, ITK, and RLK have been identified as central components of T-cell activation via T-cell receptor signaling [12], therefore indicating therapeutic potential for targeting TEC-family kinases.

Ritlecitinib is a dual JAK3/TEC-family kinase inhibitor that irreversibly binds to JAK3, demonstrating high selectivity over JAK1, JAK2, and TYK2, as well as five TEC-family kinases (TEC, BTK, ITK, RLK, BMX) [13]. JAK3 is essential for γc receptor-dependent signaling, and selective JAK3 inhibition blocks the positive feedback loop driven by IFN-γ in AA by disrupting IL-15 signaling and downstream STAT5 phosphorylation [14]. Ritlecitinib preserves the immunoregulatory cytokines, including IL-10, IL-27, and IL-35 by sparing JAK1 signaling [13]. Additionally, it also spares JAK2 function, which has been linked to cholesterol elimination via IL-6/JAK2/STAT3 signaling [15]. Preclinical data showed blockade of TEC-family kinases inhibit the cytotoxicity of CD8⁺ T cells and NK cells by reducing degranulation and IFN-γ production [13].

Consistent with the mechanism of action, translational evidence from a randomized, double-blind, placebo-controlled, phase 2a clinical trial of ritlecitinib in patients with AA (NCT02974868) demonstrated decreased infiltrating NKG2D⁺- and CD8⁺ T-cell count in the lesional scalp and downregulated biomarkers of T helper (Th)1 axis and NK-/T-cell activation after receiving ritlecitinib for 24 weeks compared to baseline [16]. Furthermore, treatment with ritlecitinib resulted in significant upregulation of hair keratin (KRT) and keratin-associated protein (KRTAP) and 160% and 52% improvement of Severity of Alopecia Tool (SALT) scores in patients with short (<3.36 years) and long (≥3.36 years) duration of the current episode of hair loss, respectively [16].

Clinical evidence from previous open-label studies and phase 2–3 trials with baricitinib (JAK1/2 inhibitor) [17, 18], tofacitinib (JAK1/3 inhibitor) [19, 20], ruxolitinib (JAK1/2 inhibitor) [21], and deuruxolitinib (JAK1/2 inhibitor) [22] supports JAK inhibitor use for treating adults with AA. The ALLEGRO phase 2b–3 trial was the first international, randomized, double-blind, placebo-controlled trial that included adolescents as well as adults with at least 50% scalp hair loss (NCT03732807) [5, 23]. This study involved the administration of ritlecitinib in 30 mg and 50 mg daily doses, with or without a 200 mg loading dose every day for 4 weeks. At 24 weeks, 17–28% of adolescent patients receiving ritlecitinib 30 mg or higher achieved a SALT score ≤20, and 0% of those receiving placebo achieved this score. Regarding adolescent patients with alopecia totalis (AT) or alopecia universalis (AU), 50% on 50 mg ritlecitinib achieved a SALT score ≤20 at week 48. Additionally, at week 24, there was eyelash regrowth observed in 17–62% of patients on ≥30 mg ritlecinitib who did not have a normal eyelash assessment score at baseline, compared to 0–13% in the placebo cohort [23]. Adverse events commonly reported in adolescents included headache, acne, and nasopharyngitis, occurring in ≥10% of patients on any treatment dose. Headache, acne, and nasopharyngitis were reported in 16.7%, 11.1%, and 11.1% of patients receiving 50 mg of ritlecitinib, respectively, compared to 10.5%, 5.3%, and 0% reported in the placebo group up to week 24 [23]. Urticaria was found in 1 patient (5.6%) on 50 mg ritlecitinib and resulted in discontinuation from the study. Mildly decreased platelets and lymphocyte counts were seen in all treatment groups, less notably in placebo groups, but these changes were subtle and returned to a stable baseline after initial reduction following the start of ritlecitinib treatment. No cases of grade 2 or higher decreases in platelet counts (<75,000/mm³) were observed, and 8% of adolescents treated with ritlecitinib experienced a grade 2 decrease in lymphocyte count (500–799/mm³). There was no case of serious infection leading to halting of treatment. There were mild elevations in low-density lipoprotein (LDL) cholesterol and total cholesterol and decreases in high-density lipoprotein (HDL) cholesterol observed in 3.9%, 2.6%, and 2.6% of the adolescents receiving 30 mg and more of ritlecitinib, respectively. Elevated creatine kinase was observed in 7 patients (9.1%) in the 30 mg and higher ritlecitinib group compared to 1 patient (10%) in the placebo to ritlecitinib 200/50 mg group, but no cases of rhabdomyolysis were present. There were no serious neurological, thromboembolic, or cardiovascular adverse effects observed. Ritlecitinib was shown to be efficacious and generally well tolerated in adolescents with AA.

The severity of hair loss at baseline and the duration of the current episode have been correlated to treatment response to JAK inhibitors and are important factors for selecting the appropriate initiation dose and setting treatment expectations. Post hoc analyses of the phase 3 trials of baricitinib for AA, BRAVE-AA1, and BRAVE-AA2 demonstrated a lower response rate in the very severe AA group (patients with a SALT score 95–100 at baseline) than in the severe AA group (patients with a SALT score 50–94 at baseline), with 27.7% and 41.5–57.6% of the patients achieving a SALT score ≤20 after treating with baricitinib 4 mg for 52 weeks, respectively [24]. Additionally, there was a delayed onset of the treatment response in the very severe AA group. The proportions of patients on baricitinib 4 mg achieving a SALT score ≤20 at week 24 to those at week 52 were 50.0% and 81.9% in the very severe AA group and severe AA group, respectively [24]. Furthermore, a higher and faster response rate was seen in the severe and very severe AA group treated with baricitinib 4 mg compared to baricitinib 2 mg [24].

For patients with a longer duration of current episode of hair loss (>4 years), the response rate was lower than those with a shorter duration of current episode of hair loss (≤4 years) [25]. However, there was no association observed between the onset of efficacy (defined as the time to achieve ≥30% improvement from baseline in SALT score) and the duration of current episode of hair loss. Similar findings were also documented in studies with tofacitinib showing that patients with a current episode of AT/AU >10 years in duration had a lower response rate [19, 20, 26], underscoring the importance of early intervention of severe and very severe AA with JAK inhibitors. As noted previously, baricitinib was studied in adults only, so data are needed to understand if these same observations are seen in adolescent patients and/or those treated with ritlecitinib. Post hoc analyses of the ritlecitinib trial are required to identify factors associated with treatment response in adolescents.

Adolescence is a critical phase for bone development and puberty. Oral or intravenous corticosteroid therapy is used to treat adolescents with moderate to severe AA [27]. Nonetheless, long-term use of systemic corticosteroids in adolescents has been documented to affect bone growth and delay pubertal growth, leading to osteopenia/osteoporosis and compromised final height [28, 29]. In contrast, there is limited clinical evidence on potential effects of JAK inhibitors on puberty and bone development in adolescents.

The physiological function of growth hormone (GH) is mediated by JAK2 signaling upon binding of GH to GH receptor [30], which is crucial for regulating pubertal bone metabolism. Inhibition of the JAK2/STAT3 signaling pathway has been demonstrated to diminish bone marrow stromal cell proliferation and osteogenic differentiation in vitro [31]. The selective inhibition of JAK3/TEC by ritlecitinib spares the JAK2-driven GH signaling and is thus unlikely to result in retardation of bone growth in adolescents, although this has not been shown conclusively.

On the other hand, baricitinib and tofacitinib have been shown to significantly reduce serum receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG) ratio in mouse models, where RANKL promotes osteoclastogenesis and bone resorption, while OPG enhances osteoblastogenesis and bone formation [32]. In addition, baricitinib and tofacitinib both increase trabecular bone mass with upregulation of the Wnt signaling pathway and improve pathological bone loss in the context of arthritis [32, 33].

The growth analysis of a randomized, controlled phase 3 clinical trial of upadacitinib (JAK1 inhibitor) in adolescents with moderate to severe atopic dermatitis (NCT03661138) demonstrated normal growth curve, growth velocity, and biomarkers of bone metabolism (alkaline phosphatase, calcium, and phosphate) at week 52, indicating no negative effects of upadacitinib on adolescent growth [34]. To the best of our knowledge, there is currently no study reporting the adverse effects of JAK inhibitors on growth and pubertal development in adolescents. Future research and surveillance are required to better understand the long-term safety profile of ritlecitinib regarding puberty and growth.

The ORAL Surveillance study, a randomized, open-label, noninferiority, phase 3b–4 safety end-point trial in patients with active rheumatoid arthritis (RA) (NCT02092467), demonstrated higher incidences of major adverse cardiovascular events (MACE, including cardiovascular mortality, myocardial infarction, and stroke) and cancer in patients receiving tofacitinib (3.4% and 4.2%, respectively) compared to those receiving tumor necrosis factor (TNF) inhibitor (2.5% and 2.9%, respectively) [35]. These findings led to the black box warning, a safety-related notice intended to highlight the serious adverse events of the drug, on both oral and topical JAK inhibitors placed by the FDA.

To understand the implication of the box warning on ritlecitinib use in adolescents with AA, it is important to examine the study population of the ORAL Surveillance trial. The trial comprised patients aged 50 years or older with at least one additional cardiovascular risk factor (current cigarette smoker, hypertension, diabetes mellitus, high-density lipoprotein cholesterol level <40 mg/dL, history of coronary artery disease, or family history of premature coronary artery disease) [35]. Additionally, all patients were on other concomitant immunosuppressive medications, with >99.9% of the patients also receiving methotrexate and 57% using oral corticosteroids.

RA is associated with higher risks of MACE and cancer compared to the general population [36, 37], while the association of AA with MACE and cancer is minimal [38, 39]. A systematic review including five randomized controlled trials and 23 case series investigating the safety of six JAK inhibitors (baricitinib, brepocitinib, deuruxolitinib, ritlecitinib, ruxolitinib, and tofacitinib) for AA treatment demonstrated no significantly elevated risk of MACE and cancer among this patient population and no case of death [40]. Additionally, a current meta-analysis found that JAK inhibitor use for dermatologic condition was not associated with increased risk of MACE, venous thromboembolic events, and all-cause mortality [41]. While limited by the lack of post-market surveillance data, these findings provide insight into the safety profile of JAK inhibitor use in patients with AA and raise questions about whether the signals observed in the ORAL Surveillance trial stemmed from the study population’s older age and higher baseline risk of MACE and cancer and may have been confounded by concomitant immunosuppressant use.

Post hoc analyses of the ORAL Surveillance trial showed increased risks of MACE and cancer in patients with a baseline history of atherosclerotic cardiovascular disease (including history of coronary artery disease, cerebrovascular disease, and peripheral artery disease) compared to those without [42, 43]. The majority of patients who experienced serious adverse events had pre-existing risk factors related to the events. These findings lay emphasis on screening and monitoring adverse events associated with JAK inhibitors for adolescents with AA. We develop a checklist for JAK inhibitors (Table 1) to facilitate the initial screening and identification of the subpopulations more susceptible to severe adverse events before starting ritlecitinib. The checklist encompasses risk factors associated with serious infections, cancer, MACE, and VTE. It assists clinicians in evaluating the risk-benefit ratio of ritlecitinib for adolescents with AA based on the presence or absence of these underlying risk factors and enhances the shared decision-making process.

Ritlecitinib is not recommended for patients with active cancer, active/recurrent shingles or other serious infections, concurrent use of other immunosuppressive therapies, or previous VTE and/or high risk for VTE [44]. Prior to treatment with ritlecitinib, it is recommended to perform baseline laboratory tests, including complete blood count, complete metabolic panel (including liver and kidney function tests), and screening for hepatitis B, hepatitis C, and tuberculosis [45]. Subsequent monitoring of complete blood count and complete metabolic panel 1 month after starting ritlecitinib and then every 6 months thereafter is advised (Table 2). Fasting lipid panel might not be necessary because ritlecitinib spares the JAK2 signaling, which involves the leptin pathway and cellular cholesterol transportation [46].

Adolescents are advised to receive all age-appropriate vaccinations before starting JAK inhibitors [47]. According to the information leaflet of ritlecitinib, prophylactic herpes zoster vaccinations before treatment commencement are also recommended [48]. Influenza and pneumococcal vaccines should be administered according to the recommended schedule. It is advisable to discontinue JAK inhibitors for 1–2 weeks following each COVID-19 vaccination [49]. Live vaccines should be avoided during JAK inhibitor treatment, but they can be given 2–4 weeks prior to the initiation of treatment [47].

AA can impact patients’ QoL interpersonally, economically, and psychologically. A study implemented the Cumulative Life Course Impairment (CLCI) model, which aggregates the stigmatization, the physical and psychosocial burden, and the adopted coping mechanisms that patients with AA develop [3]. The study summarized that pediatric patients with AA were associated with a significantly increased risk of depression, anxiety, and intentional self-harm, as well as reduced QoL, lower educational attainment, and a higher likelihood of experiencing bullying [3]. The CLCI provides a clearer, more holistic view of the implications of the disease over a lifetime. Although AA is not largely associated with physical burden, the loss of hair that AA patients, particularly those with AU, experience reduces their protection from various elements like sun and substances in the air [50]. This can leave these patients more vulnerable to skin and eye irritation, burns, and allergies, which can be uncomfortable. Aside from hair loss, patients with AA can present with pitting nails or trachyonychia, which can be seen higher in pediatric patients with AA (46%) than adults (14–19%) [51, 52]. Because AA is an autoimmune disease, it often arises with other autoimmune pathologies, such as diabetes mellitus, RA, multiple sclerosis, and thyroid disease [53]. Aside from symptoms and associated disease, these patients often carry the burden of stigmatization against their condition due to their physical appearance. Patients often mention how the culture around hair contributes to the stigma as hair is often revered and seen as a symbol of beauty, especially for women. In a qualitative survey, patients reported feeling “alien” or “ugly or unfeminine” due to societal standards of beauty and misconceptions regarding their diagnosis [54]. The social consequences of AA are evident, particularly in the pediatric population, as AA often develops during childhood and adolescence. Adolescents with AA more commonly reported bullying due to their condition, with 40% of high school and college adolescents (aged 15–19 years) having been bullied [55]. However, pediatric patients of all ages with AA were found to be affected by bullying, with boys being bullied significantly more frequently than girls [55]. This occurrence is also critical because this younger population is at a pivotal time regarding self-esteem development and self-perception. Psychological comorbidities were found to be commonly associated with AA. Patients with AA showed increased rates of psychological comorbidities such as depression and anxiety, and obsessive-compulsive disorder, alongside their condition. In young adult patients with more severe AA, such as AT and AU, the risk of suicide and self-harm was 2-fold higher [56, 57]. A qualitative study showed significantly higher rates of trait and state anxiety in children with AA and reduced QoL [58]. The chronicity of AA can also result in long-term financial strain. Many patients opt to use hair prostheses, which can be costly, and 65% of patients have concerns about the affordability of wigs long term [59]. The CLCI also explored how coping strategies mediated the mental, social, and financial stressors caused by AA. Methods of coping can be adaptive such as acceptance and humor – improving the QoL in patients with this condition. Maladaptive coping can hinder QoL and further perpetuate the CLCI [3]. Adolescents with AA may encounter difficulties forming adequate coping mechanisms to manage their condition, further emphasizing the importance of early medical intervention and accessible treatment options.

Ritlecitinib offers an efficacious treatment with a favorable safety profile for adolescents with severe AA, which is associated with impaired QoL and psychological comorbidities. Before initiating ritlecitinib, clinicians should present clinical evidence regarding its efficacy and safety profile, assess patients’ risk factors associated with JAK inhibitors, and engage in risk-benefit profile assessment with patients. Appropriate laboratory monitoring and active shared decision-making are crucial for managing adolescents with AA using ritlecitinib as long-term use will likely be necessary to maintain benefits in severe cases. Future studies exploring strategies to help adolescents with AA maintain the lowest effective dose of JAK inhibitors, such as adjunctive use of low-dose oral minoxidil or every-other-day dosing, would be valuable.

The authors have no conflicts of interest to declare.

The authors do not receive any external funding.

Conceptualization and design of the manuscript: M.M.S. and L.-C.C.; supervision and validation: M.M.S.; writing – original draft preparation: L.-C.C. and C.O.; writing – review and editing: M.M.S. and K.J.K.; and final approval of the version to be published: L.-C.C., C.O., K.J.K., and M.M.S.