LITFULOTM (Ritlecitinib) Capsules: A Janus Kinase 3 Inhibitor for the Treatment of Severe Alopecia Areata.

LITFULOTM (ritlecitinib) capsules were recently approved for the treatment of severe alopecia areata in adolescents and adults, aged ≥12 years. Ritlecitinib is the active ingredient and a dual inhibitor of Janus kinase 3 and the tyrosine kinase expressed in hepatocellular carcinoma kinase family. It prevents immune attack on the hair follicles that leads to hair loss. In a phase 2b-3 dose-dependant study, five doses of oral ritlecitinib and placebo administered once daily (QD) were investigated. Ritlecitinib demonstrated efficacy in achieving the primary outcome, Severity of Alopecia Tool (SALT) score of ≤20, at week 24 (31% [38/124] 200-mg ritlecitinib QD for 4 weeks, then 50 mg QD for 20 weeks; 22% [27/121] 200-mg ritlecitinib QD for 4 weeks, then 30 mg QD for 20 weeks; 23% [29/124] 50-mg ritlecitinib QD; 14% [17/119] 30-mg ritlecitinib QD; 2% [1/59] 10-mg ritlecitinib QD; and 2% [2/130] placebo). Mild to moderate common adverse effects were observed, which included headache, nasopharyngitis, and upper respiratory tract infection. The recommended regimen of ritlecitinib capsules is 50 mg QD with without food and swallowed whole.

A Retrospective Review of Anthralin in Petrolatum in the Treatment of Alopecia Areata in the Pediatric Population.

BACKGROUND/OBJECTIVES: Alopecia areata (AA) is a T-cell driven autoimmune disease, which results in hair loss. This study aims to determine the efficacy, tolerability and safety of different concentrations of anthralin in the treatment of pediatric AA. METHODS: A retrospective cohort study of patients < 18 yo diagnosed with AA treated with anthralin at SickKids Hospital, Toronto dermatology outpatient clinic in 2016 - 2018. Anthralin used at 0.1%, 0.2%, 0.5% and 1% in petrolatum at short contact, at increments of 15 minutes every week until a 1 hr maximum contact achieved. No other treatment was used in conjunction. Severity of Alopecia Tool (SALT) scores (SS) were determined using photographs and descriptions to assess severity of alopecia at baseline and post anthralin treatment. RESULTS: A total of 11 charts were reviewed in this retrospective cohort. Hair loss pattern; 3 patients with patchy, 6 had mixed (patchy and ophiasis), and 2 were totalis. All except for 1 patient had failed traditional treatments. One patient had complete hair regrowth, 3 showed more than 85% hair re-growth and 7 patients showed more than 75% hair regrowth, the average time for this to occur was 6.5 months. None of the patients experience serious side effects. CONCLUSIONS: Our study demonstrated the efficacy and tolerability of topical anthralin 0.1% to 1% in pediatric alopecia areata. In our study, anthralin 0.2% appears to offer the best performance and tolerability profile among the different concentrations used, with treatment course of at least 6 months in order to achieve more than 75% hair regrowth.

Safety of Janus Kinase inhibitors in Patients with Alopecia Areata: A Systematic Review.

BACKGROUND AND OBJECTIVES: Janus kinase (JAK) inhibitors are emerging as a therapeutic option for alopecia areata. The risk of potential adverse events is currently debated. In particular, several safety data for JAK inhibitors are extrapolated from a single study in elderly patients with rheumatoid arthritis treated with tofacitinib or adalimumab/etanercept as a comparator. The population of patients with alopecia areata is clinically and immunologically different from persons with rheumatoid arthritis and tumor necrosis factor (TNF) inhibitors are not effective in these patients. The objective of this systematic review was to analyze available data on the safety of various JAK inhibitors in patients with alopecia areata. METHODS: The systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature review was performed by searching PubMed, Scopus and EBSCO databases with the last search on March 13, 2023. RESULTS: In total, 36 studies were included. The frequency and odds ratio (OR) for most common adverse events versus placebo were: for baricitinib hypercholesterolemia (18.2% vs 10.5%, OR = 1.9) and headache (6.1% vs 5.1%, OR = 1.2), for brepocitinib elevated creatinine level (27.7% vs 4.3%, OR = 8.6) and acne (10.6% vs 4.3%, OR = 2.7), for ritlecitinib acne (10.4% vs 4.3%, OR = 2.6) and headache (12.5% vs 10.6%, OR = 1.2) and for deuruxolitinib headache (21.4% vs 9.1%, OR = 2.7) and acne (13.6% vs 4.5%, OR = 3.3). The respective numbers for upper respiratory infections were: baricitinib (7.3% vs 7.0%, OR = 1.0) and brepocitinib (23.4% vs 10.6%, OR = 2.6); for nasopharyngitis: ritlecitinib (12.5% vs 12.8%, OR = 1.0) and deuruxolitinib (14.6% vs 2.3%, OR = 7.3). CONCLUSIONS: The most common side effects of JAK inhibitors in patients with alopecia areata were headache and acne. The OR for upper respiratory tract infections varied from over 7-fold increased to comparable to placebo. The risk of serious adverse events was not increased.

Selective Delivery of Tofacitinib Citrate to Hair Follicles Using Lipid-Coated Calcium Carbonate Nanocarrier Controls Chemotherapy-Induced Alopecia Areata.

Chemotherapy-induced alopecia (CIA) is one of the common side effects in cancer treatment. The psychological distress caused by hair loss may cause patients to discontinue chemotherapy, affecting the efficacy of the treatment. The JAK inhibitor, Tofacitinib citrate (TFC), showed huge potential in therapeutic applications for treating baldness, but the systemic adverse effects of oral administration and low absorption rate at the target site limited its widespread application in alopecia. To overcome these problems, we designed phospholipid-calcium carbonate hybrid nanoparticles (PL/ACC NPs) for a topical application to target deliver TFC. The results proved that PL/ACC-TFC NPs showed excellent pH sensitivity and transdermal penetration in vitro. PL/ACC NPs offered an efficient follicular targeting approach to deliver TFC in a Cyclophosphamide (CYP)-induced alopecia areata mouse model. Compared to the topical application of TFC solution, PL/ACC-TFC NPs significantly inhibited apoptosis of mouse hair follicles and accelerated hair growth. These findings support that PL/ACC-TFC NPs has the potential for topical application in preventing and mitigating CYP-induced Alopecia areata.

TNFα inhibitor biosimilars associated with alopecia areata. Case-based review.

Alopecia areata (AA) is a common non-scaring hair loss associated with many inflammatory and autoimmune disorders. Anti-tumor necrosis factor alpha (TNFα) therapy is used to treat many chronic inflammatory disorders and has been proven to be effective and relatively safe. However, several immune-mediated skin reactions have been described with the use of TNFα inhibitors, among them AA. In this report, we describe two patients, a 32-year-old woman with ankylosing spondylitis and a 48-year-old man with rheumatoid arthritis who were both treated with SB4 (Benepali®), an etanercept biosimilar, and developed AA, 6 and 12 months respectively after the initiation of TNFα blocker biosimilar. These, are the first two cases of AA development during TNFα inhibitors biosimilar. Thus, physicians when dealing with patients treated with these agents, should be aware of possible immune skin reactions, among them AA. To this end, a close follow-up and monitoring is mandatory.

Transient chemotherapy-induced alopecia after successful reversal of 5-fluorouracil myelosuppression and neurotoxicosis in a 9-month-old dog.

BACKGROUND: 5-Fluorouracil (5-FU) cream is a common human topical chemotherapy agent with potentially fatal neurotoxic effects on dogs if accidentally ingested. There are seldom reports in veterinary literature describing the successful outcome of intervention after accidental ingestion of 5-FU cream. CASE SUMMARY: A 9-month-old spayed female labradoodle presented 14 h after ingesting an unknown amount of 40 g tube of Efudex cream (5% 5-FU). The dog presented in status epilepticus, which was managed with benzodiazepines and levetiracetam in conjunction with induced coma and mechanical ventilation. No further seizure activity occurred throughout the ensuing 5 days of hospitalisation; however, myelosuppression was featured. The dog was discharged home after 5 days of hospitalisation. Three days post discharge, the dog was noted to develop focal alopecia around the eyes and temporal region. 14 days after discharge, the alopecia progressed to a majority of the head and body. CONCLUSION: To the authors' knowledge, this is the first report that documents the enduring adverse effects of 5-FU cream after survival of the initial episode, including an earlier onset of myelosuppression and diffuse alopecia. Successful treatment of accidental 5-FU ingestion is possible several hours after the initial event with minimal long-term consequences.

Alemtuzumab-induced Alopecia areata - a case report and systematic literature review of adverse events associated with Alemtuzumab.

Alemtuzumab is currently approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS). Despite the efficacy of this therapy several side effects in the skin have been noted during or after infusion including vitiligo, alopecia areata, malignant skin tumors and infections. Awareness of these effects and their treatment is of essential interdisciplinary importance. This minireview provides an overview of the dermatological side effects described in the current literature. We also suggest pathomechanisms underlying these phenomena. To introduce this review, we present the case of a woman with RRMS who developed severe alopecia areata for the first time on alemtuzumab.

Cutaneous Immune-Related Adverse Events (irAEs) to Immune Checkpoint Inhibitors: A Dermatology Perspective on Management [Formula: see text].

Immune checkpoint inhibitors have proven to be efficacious for a broad spectrum of solid organ malignancies. These monoclonal antibodies lead to cytotoxic T-cell activation and subsequent elimination of cancer cells. However, they can also lead to immune intolerance and immune-related adverse event (irAEs) that are new and specific to these therapies. Cutaneous irAEs are the most common, arising in up to 34% of patients on PD-1 inhibitors and 43% to 45% on CTLA-4 inhibitors. The most common skin manifestations include maculopapular eruption, pruritus, and vitiligo-like lesions. A grading system has been proposed, which guides management of cutaneous manifestations based on the percent body surface area (BSA) involved. Cutaneous irAEs may prompt clinicians to reduce drug doses, add systemic steroids to the regiment, and/or discontinue lifesaving immunotherapy. Thus, the goal is for early identification and concurrent management to minimize treatment interruptions. We emphasize here that the severity of the reaction should not be graded based on BSA involvement alone, but rather on the nature of the primary cutaneous pathology. For instance, maculopapular eruptions rarely affect <30% BSA and can often be managed conservatively with skin-directed therapies, while Stevens-Johnson syndrome (SJS) affecting even 5% BSA should be managed aggressively and the immunotherapy should be discontinued at once. There is limited literature available on the management of the cutaneous irAEs and most studies present anecdotal evidence. We review the management strategies and provide recommendations for psoriatic, immunobullous, maculopapular, lichenoid, acantholytic eruptions, vitiligo, alopecias, vasculitides, SJS/toxic epidermal necrolysis, and other related skin toxicities.

Alopecia areata as an immune-related adverse event of immune checkpoint inhibitors: A review.

Immune checkpoint inhibitors (ICI) improve the ability of the immune system to target cancer cells by blocking signaling through either the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death (PD-1) receptor, or its ligand (PD-L1). They have been found to cause a variety of immune-related adverse events (irAEs) including a form of nonscarring alopecia that resembles alopecia areata (AA) in presentation and histology. Clinical features of ICI-induced AA are poorly described. We queried the Pubmed database for cases of AA secondary to ICI use reporting on extent of hair loss, treatments attempted, alopecia outcome, and time of follow-up with 13 cases identified. Although most patients had localized hair loss with subsequent regrowth, four of them experienced extensive and persistent AA, lasting up to a year. All but one patient continued ICI after the onset of hair loss. Many used topical corticosteroids with varying outcomes. Possible prognostic factors for severe and persistent disease may include young age and male sex. However, the low number of reported cases limits the generalizability of these findings. Tumor response was positive in every case of immune-induced AA where it was reported. Further investigation will be needed to better characterize clinical features of this irAE, risk factors for persistent disease, and determine its optimal management.

Remote-onset alopecia areata attributed to ipilimumab.

Ipilimumab is a fully humanized monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and one of a growing class of immunomodulatory therapies for melanoma. The most common toxicities are immune-related adverse effects (irAEs), which manifest most frequently in the skin as rash and pruritus. We report a case of alopecia areata (AA) attributed to ipilimumab that presented 1.5 years after treatment. Because CTLA-4 dysregulation has been increasingly linked to AA, the incidence of this irAE may increase following US Food and Drug Administration approval of a higher dose of ipilimumab for adjuvant treatment of stage III melanoma.

PD-1 inhibitor induced alopecia areata.

Immune checkpoint modulators are becoming more prevalent in clinical use for the treatment of metastatic melanoma and other malignancies. These drugs, including programmed death 1 (PD-1) inhibitors, have a high incidence of immune adverse events, including cutaneous manifestations. Alopecia is a known side effect with these drugs, but previous reports describe chemotherapy-induced alopecia. We report a case of alopecia areata in a patient on monotherapy with pembrolizumab (PD-1 inhibitor). It is important for the dermatologist to recognize and appropriately treat to decrease morbidity for these patients.

Immune-related alopecia (areata and universalis) in cancer patients receiving immune checkpoint inhibitors.

Cytotoxic T-lymphocyte-associated protein-4, programmed cell death protein and programmed cell death protein ligand 1 monoclonal antibodies (immune checkpoint inhibitors), are used to treat various malignancies. Their mechanism of action involves the inhibition of negative regulators of immune activation, resulting in immune-related adverse events (irAEs) including endocrinopathies, pneumonitis, colitis, hepatitis and dermatological events. Dermatological irAEs include maculopapular rash, pruritus, vitiligo, blistering disorders, mucocutaneous lichenoid eruptions, rosacea and the exacerbation of psoriasis. Alopecia secondary to immune checkpoint inhibitors has been reported in 1·0-2·0% of treated patients. Our objective is to characterize for the first time the clinicopathology of patients with alopecia areata (AA) secondary to immune checkpoint inhibitors, including the first report of anti-PD-L1 therapy-induced AA, and review of the literature. Four cases of patients who developed partial or complete alopecia during treatment with immune checkpoint inhibitors for underlying cancer were identified from our clinics. Methods include the review of the history and clinicopathologic features. Three patients (75%) had AA and one had universalis. Two patients had a resolution after topical, oral or intralesional therapies and one had a resolution after immunotherapy was discontinued; all regrown hair exhibited poliosis. One of the four patients had coincident onychodystrophy. This report describes a series of four patients who developed partial or complete alopecia (i.e. areata and universalis) during treatment with immune checkpoint inhibitor therapies for cancer. The recognition and management of hair-related irAEs are important for pretherapy counselling and interventions that contribute to maintaining optimal health-related quality of life in patients.

High frequency of cutaneous manifestations including vitiligo and alopecia areata in a prospective cohort of patients with chronic graft-vs-host disease.

AIM: To determine the frequency and the characteristics of cutaneous manifestations, especially vitiligo and alopecia areata, in patients with chronic graft-vs-host disease (cGVHD). METHODS: 50 patients with cGVHD were prospectively enrolled in the observational study protocol and evaluated by an experienced dermatologist. The evaluation was focused on the clinical spectrum of skin and adnexal involvement, and the cutaneous GVHD score was determined according to National Institutes of Health (NIH) Consensus criteria. The presence of vitiligo, alopecia, xerosis, nail changes, and dyspigmentation was also assessed. RESULTS: Out of 50 cGVHD patients, 28 (56%) had skin involvement, and 27 of them (96%) had hypo and/or hyperpigmentations. 11 patients (39%) had a mild cutaneous NIH cGVHD score, 22% moderate, and 39% severe. 15 (30%) patients had nail changes and 10 (20%) had vitiligo or alopecia areata. Univariate analysis showed that patients with vitiligo/alopecia areata received more lines of prior systemic immunosuppressive therapy (P=0.043), had lower Karnofsky performance status (P=0.028), and had a higher B-cell number (P=0.005), platelet count (P=0.022), and total protein (P=0.024). Vitiligo and alopecia areata were associated with higher NIH skin score (P=0.001), higher intensity of immunosuppressive treatment (P=0.020), and total body irradiation conditioning (P=0.040). Multivariate regression model showed that patients with higher NIH skin scoring were 3.67 times more likely to have alopecia and/or vitiligo (odds ratio 3.67; 95% confidence interval 1.26-10.73), controlled for all other factors in the model (age at study entry, number of B-cells, platelet count, and global NIH score). CONCLUSION: These data indicate that vitiligo and alopecia areata occur more frequently in cGVHD than previously reported.