Post-marketing safety concerns with abrocitinib: a real-world pharmacovigilance analysis of the FDA adverse event reporting system.

BACKGROUND: Abrocitinib was newly approved for treatment of moderate-to-severe atopic dermatitis. The present study was to assess abrocitinib-related adverse events (AEs) using the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms, were employed to quantify the signals of abrocitinib-related AEs. RESULTS: A total of 3,177,744 reports of AEs were collected from the FAERS database, of which 1370 reports were identified with abrocitinib as the primary suspect drug. Abrocitinib-induced adverse events (AEs) occurred across 27 system organ classes (SOCs). A total of 68 preferred terms (PTs) with significant disproportionality, meeting the criteria of all four algorithms simultaneously, were identified. Unexpected significant AEs, such as increased blood cholesterol, venous embolism, hypoacusis, cellulitis, and tuberculosis, might also occur. The median onset time for abrocitinib-associated AEs was 182 days (interquartile range [IQR] 47-527 days). CONCLUSIONS: The results of this study were consistent with clinical observations. Additionally, unexpected safety signals for abrocitinib were identified, which provided supportive information for the safety profile of abrocitinib. Prospective clinical studies are warranted to validate these findings.

Effects of two commonly used antidepressants amitriptyline and fluoxetine on the pharmacokinetics of abrocitinib in rats.

Abrocitinib is approved to treat moderate-to-severe atopic dermatitis and eliminated mainly through cytochrome P450 (CYP450) enzyme. Two commonly used antidepressants, amitriptyline and fluoxetine, could inhibit the activities of CYP2C19 and CYP3A4. In this study, we developed a new and quick ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for quantitatively analyzing the plasma concentration of abrocitinib, and further investigated the effects of amitriptyline or fluoxetine on the pharmacokinetics of abrocitinib in rats. The selectivity, linearity, recovery, accuracy, precision, matrix effect and stability of UPLC-MS/MS assay were satisfied according to the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. Our result showed that when co-administered with amitriptyline and fluoxetine, the CLz/F of abrocitinib was reduced by 44.4% and 33.3%, respectively, while the AUC(0-t) of abrocitinib was increased by 77.7% and 49.4%, respectively. It indicated that amitriptyline and fluoxetine could significantly increase the plasma concentration of abrocitinib in rats. Thus, dose adjustment of abrocitinib may be required when it is combined with amitriptyline or fluoxetine in ongoing clinical practice.

Abrocitinib-associated adverse events: a real-world pharmacovigilance study using the FAERS database.

BACKGROUND: Atopic dermatitis (AD) is a common chronic inflammatory skin disease. Janus kinase (JAK) modulates cytokines involved in AD pathophysiology, and JAK inhibitors have emerged as effective pharmacotherapeutic remedies for AD. Abrocitinib, an oral selective inhibitor of JAK1, is indicated for the management of moderate-to-severe AD. The current study evaluated the adverse events (AEs) associated with abrocitinib in a real-world setting. METHODS: To quantify the signals of abrocitinib-associated AEs, we used the US Food and Drug Administration Adverse Event Reporting System (FAERS) for this pharmacovigilance study with two established pharmacovigilance methods. RESULTS: A total of 1071 AEs of abrocitinib were investigated as the primary suspected from the FAERS to detect and characterize relevant safety signals. The analysis revealed 85 signals for abrocitinib. The most common AE for abrocitinib was drug ineffective. The signal strength of eczema herpeticum was 515.87 (277.80-957.98) and 510.59 (5148.65) and exhibited the highest strength for abrocitinib. Rare AEs such as aggravated condition, pruritus, and hypersensitivity were not listed on the label, and attention to these AEs is required. CONCLUSION: The analysis of the AE signals may provide support for clinical monitoring and risk identification of abrocitinib.

Plant-based zinc nanoflowers assisted molecularly imprinted polymer for the design of an electrochemical sensor for selective determination of abrocitinib.

The first electrochemical sensor application in the literature is described for the sensitive and selective determination of the selective Janus kinase (JAK)-1 inhibitor abrocitinib (ABR). ABR is approved by the U.S. Food and Drug Administration (FDA) for the treatment of atopic dermatitis. The molecularly imprinted polymer (MIP)-based sensor was designed to incorporate zinc nanoflower (ZnNFs)-graphene oxide (GO) conjugate (ZnNFs@GO), synthesized from the root methanolic extract (RME) of the species Alkanna cappadocica Boiss. et Bal. to improve the porosity and effective surface area of the glassy carbon electrode (GCE). Furthermore, the MIP structure was prepared using ABR as a template molecule, 4-aminobenzoic acid (4-ABA) as a functional monomer, and other additional components. Scanning electron microscopy (SEM), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR) were used to characterize the surface and structure of the synthesized nanomaterial and MIP-based surface. Among the electrochemical methods, cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) were preferred for detailed electrochemical characterization, and differential pulse voltammetry (DPV) was preferred for all other electrochemical measurements using 5.0 mM [Fe(CN)6]3-/4- solution as the redox probe. The MIP-based sensor, which was the result of a detailed optimization phase, gave a linear response in the 1.0 × 10-13 - 1.0 × 10-12 M range in standard solution and serum sample. The obtained limit of detection (LOD) and limit of quantification (LOQ) values and recovery studies demonstrated the sensitivity, accuracy, and applicability of the sensor. Selectivity, the most important feature of the MIP-based sensor, was verified by imprinting factor calculations using ibrutinib, ruxolitinib, tofacitinib, zonisamide, and acetazolamide.

A Case of Persistent Pityriasis Rosea Successfully Treated by a Short Course of Therapy with Abrocitinib.

Pityriasis rosea (PR) is a common inflammatory, erythematous and scaly skin condition that usually affects individuals aged from 20 to 40 years old. The disease often exhibits a self-limiting course up to 6-8 weeks. We report a 25-year-old female patient with a six-month history of red scaly rashes on the trunk and proximal limbs, accompanied by severe pruritus that has been remained ineffective conventional treatments. She was diagnosed as persistent pityriasis rosea. As abrocitinib has been proved to be effective for many inflammatory diseases, therefore in this case, we tried abrocitinib for the patient, and a good result had been achieved.

Case report: Treatment of psoriasiform dermatitis in patients with malignancy.

Psoriasis and atopic dermatitis (AD) are prevalent inflammatory skin disorders, each stemming from diverse factors, and characterized by recurring episodes. In certain complex cases, the clinical and pathological features exhibit overlapping and atypical characteristics, making accurate clinical diagnosis and targeted treatment a challenge. Psoriasiform dermatitis is the term used to describe such cases. Moreover, when patients have a history of malignancy, the situation becomes even more intricate, resulting in limited treatment options. Biologic therapies have transformed the management of immune-mediated inflammatory diseases, including psoriasis and AD. Meanwhile, the safety of biologics in special populations, especially among patients with a history of malignancy, should be underlined. The selective Janus kinase 1 (JAK1) inhibitor abrocitinib has been approved for the treatment of AD and has showed satisfying efficacy and safety in the treatment of psoriasis in clinical trials. Although unreported, JAK1 inhibitors are thought to have the potential to increase the risk of potential tumors. Apremilast, an oral phosphodiesterase (PDE)-4 inhibitor, is approved for moderate to severe plaque psoriasis. It has been investigated for its efficacy in AD, and is not contraindicated in malignancy. This report presents three cases of psoriasiform dermatitis in patients with a history of malignancy, showcasing significant improvement following treatment with systemic glucocorticoid, abrocitinib, or apremilast.

Cost-effectiveness analysis of abrocitinib compared with standard of care in adult moderate-to-severe atopic dermatitis in Japan.

Atopic dermatitis (AD) is a chronic inflammatory skin disease with a significant clinical, economic, and human burden. The JAK1 Atopic Dermatitis Efficacy and Safety (JADE) program's Phase 3 trials demonstrated that as a treatment for moderate-to-severe AD in adults with previous exposure to immunotherapy, abrocitinib showed superior efficacy and safety compared with standard of care (SoC), consisting of topical corticosteroids. This study assessed the cost-effectiveness of abrocitinib with SoC versus SoC alone for this patient population in Japan from a societal perspective. A hybrid decision tree and Markov model were used to capture the initial treatment and long-term maintenance phases. Clinical inputs at 16 weeks were obtained through a Bayesian network meta-analysis of four pivotal trials from the JADE program. Clinical inputs at 52 weeks were derived from the JADE EXTEND trial. Response-specific utility inputs were obtained from published literature. Resource use, costs, and productivity inputs were gathered from Japanese claims analysis, literature, public documents, and expert opinion. Costs and quality-adjusted life years (QALYs) were discounted at 2.0% per year and incremental cost-effectiveness ratios (ICERs) were calculated. Sensitivity and scenario analyses were performed to validate the base case results and explore a payer perspective. Over a lifetime horizon and with the base-case societal perspective, abrocitinib produced a mean gain of 0.75 QALYs, incremental costs of JPY (¥) 2 270 386 (USD [$] 17 265.6), and a resulting ICER of ¥3 034 514 ($23 076.5) per QALY compared with SoC. From a payer perspective, the incremental costs increased to ¥4 476 777 ($34 044.4), with an ICER of ¥5 983 495 ($45 502.6) per QALY. The results were most sensitive to treatment-specific, response-based utility weights, drug costs, and productivity-related inputs. From a Japanese societal perspective, abrocitinib demonstrated superior QALYs and with a willingness-to-pay threshold of ¥5 000 000 ($38 023.4) per QALY, can be considered cost-effective compared with SoC as a treatment for moderate-to-severe AD in adult patients with previous immunosuppressant exposure.

Effects of abrocitinib on pruritus and eczema symptoms and tolerance in patients with moderate­to­severe atopic dermatitis in randomized, double­blind and placebo­controlled trials: A systematic review and a meta­analysis.

Abrocitinib is a highly selective Janus kinase 1 (JAK1) inhibitor that can block a multitude of inflammatory signaling pathways that underlie atopic dermatitis (AD). In addition, abrocitinib inhibits JAK1 signaling in sensory neurons to alleviate acute and chronic pruritus during AD. However, substantial variations in efficacy and safety risks remain due to variations in doses applied in clinical use. Therefore for the present study, differences in the efficacy and tolerability of 100 and 200 mg abrocitinib for treating pruritus and eczema symptoms in patients with moderate-to-severe AD were evaluated compared with placebo. Specifically, randomized controlled trials (RCTs) of abrocitinib compared with placebo for the treatment of moderate-to-severe AD were searched on Pubmed, E.B. Stephens Company, China National Knowledge Infrastructure, Wanfang Medical network, Web of Science and related Clinical Trials Registry up to November 2023. In total, two researchers evaluated the quality of the included literature according to the Cochrane Handbook of Systematic Reviews. RevMan 5.3 software was used to conduct a meta-analysis of the efficacy and safety indicators in a cross-comparison of the effects exerted by placebo and 100 and 200 mg abrocitinib. A total of 1,825 patients with moderate-to-severe AD were included across five double-blind, placebo RCTs. Compared with the placebo group, during the double-blind trial period, significant improvements were observed in the investigator's global assessment score, response rate of eczema area and severity index (EASI)-50, EASI-75, EASI-90 and pruritus numerical rating scale (P-NRS) in the 100 and 200 mg abrocitinib groups (P<0.05). However, pairwise control analysis of the 100 and 200 mg group yielded significant differences (P<0.05) in all of the aforementioned therapeutic indicators except for the P-NRS score. In terms of safety, compared with the placebo group, there were significantly higher incidence of nausea, upper respiratory tract viral infection, infections and infestations in the 100 mg abrocitinib group (P<0.05). In addition, there were significantly higher incidence of nausea, gastrointestinal disorder, headache and dizziness in the 200 mg group (P<0.05). There were also significant differences in the incidence of nausea, gastrointestinal disorder and dizziness between the 100 and 200 mg groups (P<0.05). For patients with moderate-to-severe AD, oral administration of 100 or 200 mg abrocitinib once/day was concluded to ameliorate skin pruritus and eczema symptoms to varying degrees, with the efficacy significantly superior at the 200 mg dose. However, the risk of a number of adverse reactions, such as headache, dizziness, nausea and gastrointestinal dysfunction, is also significantly increased. Therefore, patients should be made aware of the risk of adverse drug effects prior to the administration of long-term high abrocitinib doses. Furthermore, large-scale, multi-center, rigorous clinical trials remain necessary to validate the findings from the present study.

Management of Patients Affected by Moderate-to-Severe Atopic Dermatitis with JAK Inhibitors in Real-World Clinical Practice: An Italian Delphi Consensus.

INTRODUCTION: Several systemic therapies have been approved for the treatment of severe AD. In particular, Janus kinase inhibitors (JAKi), including abrocitinib, baricitinib, and upadacitinib, recently received approval for the treatment of patients with severe AD after being evaluated in several clinical trials. However, a few concerns have been raised regarding their long-term safety and the management of these drugs in real-world clinical practice. In this article we described the results of a Delphi consensus aimed at describing the knowledge on JAKi and focusing, in particular, on providing clinical recommendations for dermatologists in daily practice regarding the use of these drugs. METHODS: Twelve Italian dermatologists reviewed the most recent literature regarding the efficacy and safety profiles of JAKi and proposed 24 statements. RESULTS: Agreement was reached for statements focusing on three main topics: (1) place in therapy of JAKi in patients with moderate-to-severe AD; (2) effectiveness and safety of JAK inhibitors in different phenotypes; (3) different approaches to the management of patients treated with JAKi in clinical practice. The panel proposed several recommendations regarding all the statements. CONCLUSION: Given the wide use of JAKi in clinical practice, it is crucial to establish a specific follow-up for each patient's phenotype in order to achieve the best possible clinical outcome and minimize potential adverse events.

Systematic review and network meta-analysis of the risk of Herpes zoster with biological therapies and selective Janus kinase-1 inhibitors in atopic dermatitis.

Introduction: Atopic dermatitis (AD) patients have an increased risk of herpes zoster (HZ). The relationship of dupilumab, tralokinumab, upadacitinib, and abrocitinib to HZ incidence in AD patients remains unclear. Aim: To evaluate and compare the incidence and risk of HZ among patients with moderate to severe atopic dermatitis treated with advanced systemic therapies. Material and methods: Systematic searches were conducted in Ovid Medline and Embase. The primary outcome was incidence of HZ in patients with moderate to severe AD receiving placebo or the aforementioned treatments. A frequentist random-effects NMA was conducted with odds ratio. Results: Our search identified 16 trials comprising 10,689 patients. Upadacitinib was associated with a dose-dependent increase in the incidence of HZ compared to placebo (OR = 2.55 [1.09, 5.95] and (OR = 4.29 [1.89, 9.74], respectively) and compared to various dupilumab doses (OR = 4.48 [1.29, 15.57], 3.61 [1.28, 10.18] and 7.54 [2.21, 25.68], 6.09 [2.24, 16.52], respectively). Upadacitinib 30 mg was associated with a higher incidence of HZ when compared to upadacitinib 15 mg (OR = 1.68 [1.19, 2.38]). Abrocitinib 200 mg was associated with a higher increase in HZ compared to placebo (OR = 3.34 [1.34, 8.31]). According to SUCRA ranks, both JAK-1 inhibitors had a higher cumulative incidence of HZ compared to dupilumab. Conclusions: JAK-1 inhibitors are associated with a significantly higher incidence of HZ compared to dupilumab and placebo. Our results suggest that recombinant HZ vaccination should be highly considered for all adult patients prior to starting oral JAK-1 inhibitors.

Real-world effectiveness and safety of abrocitinib in 12 Japanese patients with atopic dermatitis and transcriptome analysis with peripheral blood.

Atopic dermatitis (AD) is a common chronic inflammatory skin disease characterized by recurrent, pruritic, and localized eczema. Various types of new drugs have been recently investigated for treating AD. The efficacy and safety of abrocitinib in treating AD has been reported in clinical trials, but the real-world data from Japan has not been reported. Herein, we analyzed 12 Japanese patients with AD treated with 100 mg of abrocitinib using our real-world data. We also performed transcriptome analysis with peripheral blood to investigate the effects of abrocitinib on cytokine expressions and inflammatory pathways in AD from three patients. This study included patients with moderate to severe AD treated with abrocitinib at Gunma University Hospital, Japan. All patients were systemic treatment-naïve. All patients received a 100-mg dose of abrocitinib daily, and used strong or very strong topical steroids and moisturizers. The Eczema Area and Severity Index (EASI) response analysis revealed that after 4 weeks, 25% (three of 12) of the cases reached a 75% reduction in the EASI score (EASI-75) and a 90% reduction in the EASI score (EASI-90). After 12 weeks, 83.3.% (10 of 12), 41.6% (five of 12), and 16.7% (two of 12) of the patients reached EASI-50, a 75% reduction in the EASI score (EASI-75), and EASI-90. Peak Pruritus Numerical Rating Scale was achieved in nine patients (75%) at week 12. The most frequent adverse reaction was acne (six cases [50%]). Gene Ontology pathway analysis using Differentially expressed genes from RNA sequencing analysis revealed attenuation of defense responses to biotic stimulus, virus, and cytokines. Th2 cytokine expression was not suppressed, but several chemokines, especially CXCL1, were suppressed by abrocitinib treatment. Our results indicate abrocitinib as a fast-acting and highly antipruritic agent that is effective for moderate skin eruptions.

Successful treatment of refractory prurigo nodularis with abrocitinib.

Prurigo nodularis is frequently difficult to manage with conventional therapy. Given the pathogenesis and refractory nature, we demonstrate a case in which inhibition of JAK-STAT signaling may significantly improve prurigo nodularis. Based on the results, we would like to draw a conclusion that abrocitinib as an inhibitor of Jak is a promising choice for the treatment of prurigo nodularis.

Real-Time Experience of Abrocitinib for the Treatment of Mucous Membrane Pemphigoid: A Case Report.

Background: Mucous membrane pemphigoid (MMP), a rare autoimmune vesiculous and erosive disorder, may affect multiple mucous membranes, with the oral cavity being the most commonly affected site. Its treatment depends on the site(s) of mucosal involvement and disease severity. Patients and Methods: A 62-year-old female patient with MMP that predominantly involved the oral cavity strongly rejected systemic corticosteroid or immunosuppressive agents and was successfully treated with abrocitinib, a highly selective JAK-1 inhibitor with a good safety profile. Results: The case demonstrated good efficacy and safety profile of abrocitinib for the treatment of MMP with predominant oral involvement. Conclusion: Abrocitinib is a promising agent for the treatment of MMP with oral involvement.

Rapid resolution of non-segmental vitiligo in a patient treated with abrocitinib: A case report.

Vitiligo is a common, autoimmune, depigmenting disorder of the skin. Janus Kinase inhibitors have emerged as promising topical and oral therapeutic options for vitiligo. There have been no reports of vitiligo being treated with oral Abrocitinib, a selective Janus Kinase 1 inhibitor approved for the treatment of moderate to severe atopic dermatitis. Here, we present a 61-year-old male with acrofacial vitiligo who had repigmentation plateau with twice daily tacrolimus 0.1% ointment, oral ginkgo biloba, and oral minipulse prednisone × 4 months; however, they had significant improvement after taking abrocitinib 100 mg per day for 2 months. He was able to transition topical tacrolimus twice weekly monotherapy for maintenance. This report shows that oral Janus Kinase inhibitors may be a useful option for the treatment of recalcitrant vitiligo. Results of ongoing randomized control trials are needed to determine the durability and safety of oral Janus Kinase inhibitors long-term.

Oral abrocitinib in the treatment of granuloma annulare: a case report.

Aim: To evaluate the therapeutic efficacy and safety of JAK inhibitor abrocitinib in patients with localized granuloma annulare (GA) and to review the available cases documented in English.Methods: We presented a patient who had a persistent, localized granuloma anulare (GA) for one year and did not respond to traditional therapies. This patient was treated with oral abrocitinib at a dosage of 150 mg daily.Results: After 6 weeks of treatment with abrocitinib, the patient exhibited notable symptom improvement with no new lesions. No adverse events or recurrences were reported during the 5-month follow-up period.Conclusions: Abrocitinib may be a promising and safe treatment option for patients with localized GA who do not respond to traditional therapies.