Safety of upadacitinib in moderate-to-severe atopic dermatitis: An integrated analysis of phase 3 studies.

BACKGROUND: Upadacitinib is a selective reversible Janus kinase (JAK) inhibitor with established efficacy in moderate-to-severe atopic dermatitis (AD). OBJECTIVE: We evaluated the safety of upadacitinib in patients with moderate-to-severe AD. METHODS: Integrated safety data from the 16-week placebo-controlled periods of 1 phase 2b and 3 ongoing phase 3 studies (16 weeks) and longer-term safety data from patients receiving upadacitinib during the blinded extension periods of the three phase 3 studies were analyzed (all upadacitinib exposure). Treatment-emergent adverse events (TEAEs) were presented as exposure-adjusted rates per 100 patient-years (PY). RESULTS: Safety results were similar between the 16-week and all upadacitinib exposure groups. The latter group included 2485 patients (333 adolescents), receiving upadacitinib 15 mg (n = 1239) or 30 mg (n = 1246) for a mean duration of approximately 1 year. Upadacitinib was well tolerated by both adults and adolescents. TEAEs and discontinuation due to AEs were reported more frequently in patients receiving 30 mg upadacitinib (respectively, 311.9 and 5.7 events per 100 PY) versus 15 mg (respectively, 274.6 and 4.4 events per 100 PY). Serious adverse event rates (15/30 mg, 7.1/7.7 events per 100 PY) were similar in both groups. Acne was the most frequently reported adverse event (15/30 mg, 13.3/20.2 events per 100 PY). Serious infection rates were similar across treatment groups. Adjudicated major adverse cardiovascular event and venous thromboembolic event rates were ≤0.1 events per 100 PY. Rates of malignant neoplasms were within the expected range for the general population. CONCLUSIONS: Upadacitinib was well tolerated, and no new important safety risks were observed among adults and adolescents with moderate-to-severe AD treated for approximately 1 year compared to the known safety profile of upadacitinib.

Efficacy and safety of switching from dupilumab to upadacitinib versus continuous upadacitinib in moderate-to-severe atopic dermatitis: Results from an open-label extension of the phase 3, randomized, controlled trial (Heads Up).

BACKGROUND: Characterization of upadacitinib use and switching from dupilumab to upadacitinib among patients with moderate-to-severe atopic dermatitis (AD) is needed. OBJECTIVE: To evaluate the long-term safety and efficacy of continuous upadacitinib 30 mg and switching to upadacitinib after 24 weeks of dupilumab. METHODS: Adults who completed the phase 3b clinical trial of oral upadacitinib 30 mg vs injectable dupilumab 300 mg (Heads Up) and entered a 52-week open-label extension (OLE) (NCT04195698) were included. All patients received 30-mg upadacitinib during the open-label period. We report results of a prespecified interim OLE 16-week analysis. RESULTS: Patients (n = 239) continuing upadacitinib maintained high levels of skin and itch response. Patients (n = 245) switching from dupilumab experienced additional incremental improvements in clinical responses within 4 weeks of starting upadacitinib. Most patients who did not achieve adequate clinical responses with dupilumab did so with upadacitinib. The safety profile of upadacitinib up to 40 weeks (week 16 of OLE) was consistent with previous phase 3 AD studies, with no new safety risks observed. LIMITATIONS: Open-label study design. CONCLUSIONS: Clinical responses are maintained with continuous upadacitinib through 40 weeks and patients regardless of prior dupilumab response experienced improved outcomes when switched to upadacitinib. No new safety risks were observed.

Upadacitinib plus topical corticosteroids in atopic dermatitis: Week 52 AD Up study results.

BACKGROUND: Primary (week 16) results from the ongoing phase 3, double-blind AD Up study (NCT03568318) demonstrate a positive benefit-risk profile for upadacitinib + topical corticosteroid (TCS) in patients with moderate-to-severe atopic dermatitis. OBJECTIVE: We evaluated the efficacy and safety of upadacitinib + TCS through 52 weeks. METHODS: Patients aged 12 to 75 years with chronic moderate-to-severe atopic dermatitis (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] ≥16, Validated Investigator's Global Assessment for atopic dermatitis [vIGA-AD] ≥3, and Worst Pruritus Numerical Rating Scale [WP-NRS] score ≥4) were randomized 1:1:1 to once-daily upadacitinib 15 mg + TCS, upadacitinib 30 mg + TCS, or placebo (PBO) + TCS (rerandomized at week 16 to upadacitinib + TCS). Safety and efficacy, including proportion of patients experiencing ≥75% improvement in EASI (EASI-75), vIGA-AD of clear/almost clear with improvement ≥2 grades (vIGA-AD 0/1), and WP-NRS improvement ≥4, were assessed through week 52. Missing data were primarily handled by nonresponse imputation incorporating multiple imputation for missing values due to coronavirus disease 2019 (COVID-19). RESULTS: Of 901 patients, 300 were randomized to upadacitinib 15 mg + TCS, 297 to upadacitinib 30 mg + TCS, and 304 to PBO + TCS. For all end points, efficacy for upadacitinib 15 mg + TCS and upadacitinib 30 mg + TCS at week 16 was maintained through week 52. At week 52, the proportions of patients treated with upadacitinib 15 mg + TCS and upadacitinib 30 mg + TCS who experienced EASI-75 were 50.8% and 69.0%, respectively; 33.5% and 45.2%, respectively, experienced vIGA-AD 0/1; and 45.3% and 57.5%, respectively, experienced WP-NRS improvement ≥4. Upadacitinib + TCS was well tolerated through 52 weeks; no new important safety risks beyond the current label were observed. No deaths were reported; major adverse cardiovascular events and venous thromboembolic events were infrequent (≤0.2/100 patient-years). CONCLUSIONS: Results through 52 weeks demonstrate long-term maintenance of efficacy and a favorable safety profile of upadacitinib + TCS in patients with moderate-to-severe AD.

Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Systemic therapies are typically combined with topical corticosteroids for the management of moderate-to-severe atopic dermatitis. Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 that is being tested for atopic dermatitis. We aimed to assess the efficacy and safety of upadacitinib plus topical corticosteroids compared with placebo for the treatment of moderate-to-severe atopic dermatitis. METHODS: In this randomised, double-blind, placebo-controlled, phase 3 trial (AD Up) adults (aged 18-75 years) and adolescents (aged 12-17 years) with chronic atopic dermatitis that was moderate to severe (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for atopic dermatitis [vIGA-AD] score of ≥3, and weekly average Worst Pruritus Numerical Rating Scale score of ≥4 at baseline) were enrolled at 171 clinical centres across 22 countries in the Asia-Pacific region, Europe, the Middle East, North America, and Oceania. Patients were randomly assigned (1:1:1) to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily, all in combination with topical corticosteroids for 16 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity, geographical region, and age. Study investigators, study site personnel, and patients were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved at least a 75% reduction in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of improvement from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03568318, and is active, but not recruiting. FINDINGS: Between Aug 9, 2018, and Dec 20, 2019, 901 patients were randomly assigned to receive upadacitinib 15 mg plus topical corticosteroids (n=300), upadacitinib 30 mg plus topical corticosteroids (n=297), or placebo plus topical corticosteroids (n=304). At week 16, the proportion of patients who had achieved EASI-75 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (194 [65%] of 300 patients) and the upadacitinib 30 mg plus topical corticosteroids group (229 [77%] of 297 patients) than the placebo group (80 [26%] of 304 patients; adjusted difference in EASI-75 response rate vs placebo, 38·1% [95% CI 30·8-45·4] for the upadacitinib 15 mg group and 50·6% [43·8-57·4] for the upadacitinib 30 mg group; p<0·0001 for both doses). The proportion of patients who had achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (119 [40%] patients) and upadacitinib 30 mg plus topical corticosteroid group (174 [59%] patients) than the placebo group (33 [11%] patients; adjusted difference in vIGA-AD response vs placebo, 28·5% [22·1-34·9] for the upadacitinib 15 mg group and 47·6% [41·1-54·0] for the upadacitinib 30 mg group; p<0·0001 for both doses). During the double-blind period, upadacitinib 15 and 30 mg were well tolerated in combination with topical corticosteroids. The most frequently reported treatment-emergent adverse events (≥5% in any treatment group) were acne, nasopharyngitis, upper respiratory tract infection, oral herpes, elevation of blood creatine phosphokinase levels, headache, and atopic dermatitis. The incidence of acne was higher in the upadacitinib 15 mg (30 [10%] of 300 patients) and upadacitinib 30 mg (41 [14%] of 297 patients) groups than the placebo group (six [2%] of 304 patients). The incidence of adverse events leading to discontinuation of study drug (four [1%] patients in the upadacitinib 15 mg plus topical corticosteroids group, four [1%] patients in the upadacitinib 30 mg plus topical corticosteroids group, and seven [2%] patients in the placebo plus topical corticosteroids group) and serious adverse events (seven [2%] patients, four [1%] patients, and nine [3%] patients) were similar among treatment groups. No deaths were reported in any treatment group. INTERPRETATION: Upadacitinib plus topical corticosteroids was well tolerated and superior to placebo plus topical corticosteroids. Upadacitinib as combination therapy had a positive benefit-risk profile in adults and adolescents with moderate-to-severe atopic dermatitis. FUNDING: AbbVie.

Characterization of acne associated with upadacitinib treatment in patients with moderate-to-severe atopic dermatitis: A post hoc integrated analysis of 3 phase 3 randomized, double-blind, placebo-controlled trials.

BACKGROUND: Acne is the most frequent adverse event associated with upadacitinib treatment in patients with moderate-to-severe atopic dermatitis. OBJECTIVE: To characterize the adverse event of acne associated with upadacitinib. METHODS: This was a post hoc integrated analysis of 3 phase 3 randomized, double-blind, placebo-controlled trials of upadacitinib, alone (NCT03569293 and NCT03607422) or in combination with topical corticosteroids (NCT03568318). Data included were from the 16-week placebo-controlled period. RESULTS: Over 16 weeks, 84 of 857 (9.8%), 131 of 864 (15.2%), and 19 of 862 (2.2%) patients randomized to receive upadacitinib 15 mg, upadacitinib 30 mg, and placebo, respectively, experienced acne. All cases of acne, except 1, were mild/moderate in severity; 2 patients discontinued treatment due to moderate acne. Acne occurred at higher rates among younger, female, and non-White patients. Acne required no intervention in 40.5% and 46.6% of patients receiving upadacitinib 15 and 30 mg, respectively; most remaining cases were managed with topical antibiotics, benzoyl peroxide, and/or retinoids. Acne also had no impact on patient-reported outcomes. LIMITATIONS: This study was relatively short in duration and had a small patient population. CONCLUSIONS: Acne associated with upadacitinib for atopic dermatitis treatment is usually mild/moderate in severity and managed with topical therapies or no intervention.

Wound-Related Allergic/Irritant Contact Dermatitis.

PURPOSE: To provide information from a literature review about the prevention, recognition, and treatment for contact dermatitis. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES: After participating in this educational activity, the participant should be better able to:1. Identify signs and symptoms of and diagnostic measures for contact dermatitis.2. Identify causes and risks for contact dermatitis.3. Select appropriate treatment for contact dermatitis and its prevention. ABSTRACT: Contact dermatitis to wound care products is a common, often neglected problem. A review was conducted to identify articles relevant to contact dermatitis.A PubMed English-language literature review was conducted for appropriate articles published between January 2000 and December 2015.Contact dermatitis is both irritant (80% of cases) or allergic (20% of cases). Frequent use of potential contact allergens and impaired barrier function of the skin can lead to rising sensitization in patients with chronic wounds. Common known allergens to avoid in wound care patients include fragrances, colophony, lanolin, and topical antibiotics.Clinicians should be cognizant of the allergens in wound care products and the potential for sensitization. All medical devices, including wound dressings, adhesives, and bandages, should be labeled with their complete ingredients, and manufacturers should be encouraged to remove common allergens from wound care products, including topical creams, ointments, and dressings.

Mucocutaneous manifestations of helminth infections: Nematodes.

In the 21st century, despite increased globalization through international travel for business, medical volunteerism, pleasure, and immigration/refugees into the United States, there is little published in the dermatology literature regarding the cutaneous manifestations of helminth infections. Approximately 17% of travelers seek medical care because of cutaneous disorders, many related to infectious etiologies. This review will focus on the cutaneous manifestations of helminth infections and is divided into 2 parts: part I focuses on nematode infections, and part II focuses on trematode and cestode infections. This review highlights the clinical manifestations, transmission, diagnosis, and treatment of helminth infections. Nematodes are roundworms that cause diseases with cutaneous manifestations, such as cutaneous larval migrans, onchocerciasis, filariasis, gnathostomiasis, loiasis, dracunculiasis, strongyloidiasis, ascariasis, streptocerciasis, dirofilariasis, and trichinosis. Tremadotes, also known as flukes, cause schistosomiasis, paragonimiasis, and fascioliasis. Cestodes (tapeworms) are flat, hermaphroditic parasites that cause diseases such as sparganosis, cysticercosis, and echinococcus.

Gynecomastia: etiologies, clinical presentations, diagnosis, and management.

Gynecomastia is a common finding that is present in up to 57% of men. It is caused by proliferation of the mammary glands, which leads to the development of dense subareolar tissue. The condition results from both physiologic (eg, hypogonadism, altered estrogen-to-androgen ratio) and nonphysiologic (eg, drugs, herbal products) causes. Most cases are benign and resolve spontaneously. Treatment is usually unnecessary, although there are specific signs and symptoms that warrant further workup. Psychosocial effects also are of concern, particularly among adolescents. Knowledge of the possible causes of gynecomastia and a thoughtful approach to the patient presenting with this condition can lead to improved outcomes and patient satisfaction. This concise review of the common presentation, etiologies, diagnosis, and treatment of gynecomastia should aid healthcare professionals who may encounter these patients in their practices.

Cancers mimicking fungal infections.

Primary and metastatic malignancies may occasionally mimic or coexist with cutaneous fungal infections. The authors report 3 cases of cancers that were initially presumed to be cutaneous fungal infections. Dermatologists should maintain a low threshold for skin biopsy in patients with persistent or refractory fungal infections.

Upadacitinib Rapidly Improves Patient-Reported Outcomes in Atopic Dermatitis: 16-Week Results from Phase 3 Clinical Trials (Measure Up 1 and 2).

INTRODUCTION: Atopic dermatitis (AD) is characterized by intense itch and other symptoms that negatively impact quality of life (QoL). This study evaluates the effect of upadacitinib (an oral selective Janus kinase inhibitor) monotherapy on patient-reported outcomes (PROs) among adults and adolescents with moderate-to-severe AD over 16 weeks. METHODS: This integrated analysis of the double-blind, placebo-controlled periods of phase 3 monotherapy clinical trials Measure Up 1 (NCT03569293) and Measure Up 2 (NCT03607422) assessed itch (Worst Pruritus Numerical Rating Scale [WP-NRS] and SCORing Atopic Dermatitis [SCORAD]), skin pain and symptom severity (AD Symptom Scale), symptom frequency (Patient-Oriented Eczema Measure), sleep (AD Impact Scale [ADerm-IS] and SCORAD), daily activities and emotional state (ADerm-IS), QoL (Dermatology Life Quality Index [DLQI] and Children's DLQI), mental health (Hospital Anxiety and Depression Scale), and patient impressions (Patient Global Impression of Severity, Patient Global Impression of Change, and Patient Global Impression of Treatment). RESULTS: Data from 1683 patients (upadacitinib 15 mg, n = 557; upadacitinib 30 mg, n = 567; placebo, n = 559) were analyzed. A greater proportion of patients receiving upadacitinib versus placebo experienced improvements in itch (≥ 4-point improvement on WP-NRS) by week 1 (upadacitinib 15 mg, 11.2%; upadacitinib 30 mg, 17.7%; placebo, 0.5%; P < 0.001), with response rates sustained through week 16 (upadacitinib 15 mg, 47.1%; upadacitinib 30 mg, 59.8%; placebo, 10.4%; P < 0.001). Improvements were similar for PROs assessing skin pain/symptoms, sleep, daily activities, QoL, emotional state, mental health, and patient impressions of disease severity and treatment. Responses generally improved rapidly (within 1-2 weeks), increased through weeks 4-6, and were maintained through week 16. CONCLUSIONS: Once-daily oral upadacitinib monotherapy improved response rates across PROs compared with placebo. Upadacitinib therapy resulted in rapid, sustained improvements in PROs measuring symptom burden and QoL in adults and adolescents with moderate-to-severe AD. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT03569293 and NCT03607422.

Atopic dermatitis, or eczema, is characterized by itchy, dry, inflamed skin. These symptoms often make it difficult for patients to get adequate sleep. Patients with atopic dermatitis may also experience anxiety, depression, reduced self-confidence, social isolation, disruption to daily activities like school and work, and decreased quality of life. Many atopic dermatitis symptoms, including itch and psychological impact, are difficult for doctors to assess. Thus, it is important to consider patients' descriptions of their symptoms and quality of life, particularly when assessing treatment benefit. Upadacitinib is an orally administered drug approved to treat moderate-to-severe atopic dermatitis. We investigated how upadacitinib (15 mg or 30 mg) given once daily to adults and adolescents with moderate-to-severe atopic dermatitis in the Measure Up 1 and 2 clinical trials impacts their symptoms and quality of life over a 16-week period. We compared changes in patient-reported itch, pain, sleep, daily activities, emotional state, mental health, and overall quality of life among patients in the clinical trials who received upadacitinib with those in the same studies who received a dummy (placebo) treatment. Upadacitinib improved patient-reported symptoms and quality of life early in the clinical trials, often within the first 1­2 weeks. The extent of the improvements increased through weeks 4­6 of treatment and lasted through week 16. Patients who received upadacitinib reported greater improvements in symptoms and quality of life than did patients who received placebo. Upadacitinib treatment resulted in rapid and lasting improvements in the well-being of patients with atopic dermatitis.

Mucocutaneous complications of smoking cessation therapies.

Despite widespread knowledge of the morbidity and mortality associated with smoking, this addictive practice continues to be quite prevalent throughout the United States, as about one-fifth of the population smokes cigarettes. Because of the financial burden, and the significant psychosocial and health implications of smoking, many individuals are now attempting to quit, and often using some type of pharmacotherapy for assistance. Given that dermatologists will likely encounter patients using smoking cessation aids, it is important to be aware of their potential mucocutaneous adverse effects. We present a brief review of the dermatologic complications associated with smoking cessation therapies. Hopefully, this article will also remind dermatologists to encourage smoking cessation at every visit.

Frontal fibrosing alopecia: a retrospective review of 19 patients seen at Duke University.

BACKGROUND: Frontal fibrosing alopecia (FFA) is a type of scarring hair loss primarily observed in postmenopausal women and characterized by fronto-tempero-parietal hairline recession, perifollicular erythema, and loss of eyebrows. The incidence is unknown, but the number of women presenting with this condition has significantly increased in recent years. No effective therapy has been established. OBJECTIVE: The purpose of this study is to present pertinent demographic and clinical findings of patients with FFA seen at an academic hair loss clinic and their responses to various therapeutic interventions. METHODS: Patients seen at the Duke University Hair Disorders Research and Treatment Center, Durham, NC, between 2004 and 2011 who met FFA inclusion criteria and signed an informed consent form for participation in the Duke University Hair Disorders Research and Treatment Center database were included in this review. RESULTS: Nineteen female patients with FFA met our inclusion criteria, the majority of whom were white and postmenopausal. A number of treatments, including topical and intralesional steroids, antibiotics, and immunomodulators, were used with disappointing results in most patients. However, the majority of patients on dutasteride experienced disease stabilization. LIMITATIONS: This was a retrospective review and outside clinic records were occasionally incomplete. CONCLUSIONS: FFA is an increasingly common form of scarring hair loss, but the origin remains unknown. Without clear understanding of the pathogenesis and evolution of this condition, it is not surprising that treatments to date have been minimally or not effective. At our institution, dutasteride was most effective in halting disease progression, although no therapy was associated with significant hair regrowth.

Update on necrobiosis lipoidica: a review of etiology, diagnosis, and treatment options.

Necrobiosis lipoidica (NL) is a rare chronic granulomatous disease that has historically been associated with diabetes mellitus. Debate exists regarding the etiology and pathogenesis of NL with a widely accepted theory that microangiopathy plays a significant role. NL typically presents clinically as erythematous papules on the front of the lower extremities that can coalesce to form atrophic telangiectatic plaques. NL is usually a clinical diagnosis, but if the clinical suspicion is uncertain, skin biopsy specimen can help differentiate it from sarcoidosis, necrobiotic xanthogranuloma, and granuloma annulare. NL is a difficult disease to manage despite a large armamentarium of treatment options that include topical and intralesional corticosteroids, immunomodulators, biologics, platelet inhibitors, phototherapy, and surgery. Randomized control trials are lacking to evaluate the many treatment methods and establish a standard regimen of care. Disease complications such as ulceration are common, and lesions should also be monitored for transition to squamous cell carcinoma, a less common sequelae.

Dronaderone-induced phototoxicity.

Phototoxicity is a skin reaction that occurs in patients using photosensitizing drugs in combination with exposure to ultraviolet light. Common photosensitizing pharmacologic agents include antibiotics, non-steroidal anti-inflammatory drugs, diuretics, neuroleptics, retinoids, and amiodarone. Dronaderone is a novel antiarrhythmic that is similar in composition to amiodarone, but is non-iodinated and also has a methane-sulfonyl group, significantly decreasing its incidence of adverse effects as compared to amiodarone. While phototoxicity is a commonly reported complication of amiodarone, this reaction has rarely been documented in patients using dronaderone. We report the case of a 63 year-old woman with a history of atrial fibrillation that presented with a phototoxic drug eruption following use of dronaderone for maintenance of normal sinus rhythm.

Diagnosis of herpes simplex virus-induced erythema multiforme confounded by previous infection with Mycoplasma pneumonia.

Erythema multiforme (EM) is an immune-mediated hypersensitivity reaction often related to viral infection or medications. Infection-induced EM is typically self-limited and commonly caused by herpes simplex virus (HSV) or Mycoplasma pneumoniae (MP); recurrent EM is almost always associated with HSV. We present a concise overview of diagnostic techniques for HSV and MP, as repeatedly elevated MP titers in our case led to a delayed diagnosis of HSV-induced EM.