Two Phase 3 Trials of Baricitinib for Alopecia Areata.

BACKGROUND: Alopecia areata is an autoimmune condition characterized by rapid hair loss in the scalp, eyebrows, and eyelashes, for which treatments are limited. Baricitinib, an oral, selective, reversible inhibitor of Janus kinases 1 and 2, may interrupt cytokine signaling implicated in the pathogenesis of alopecia areata. METHODS: We conducted two randomized, placebo-controlled, phase 3 trials (BRAVE-AA1 and BRAVE-AA2) involving adults with severe alopecia areata with a Severity of Alopecia Tool (SALT) score of 50 or higher (range, 0 [no scalp hair loss] to 100 [complete scalp hair loss]). Patients were randomly assigned in a 3:2:2 ratio to receive once-daily baricitinib at a dose of 4 mg, baricitinib at a dose of 2 mg, or placebo. The primary outcome was a SALT score of 20 or less at week 36. RESULTS: We enrolled 654 patients in the BRAVE-AA1 trial and 546 in the BRAVE-AA2 trial. The estimated percentage of patients with a SALT score of 20 or less at week 36 was 38.8% with 4-mg baricitinib, 22.8% with 2-mg baricitinib, and 6.2% with placebo in BRAVE-AA1 and 35.9%, 19.4%, and 3.3%, respectively, in BRAVE-AA2. In BRAVE-AA1, the difference between 4-mg baricitinib and placebo was 32.6 percentage points (95% confidence interval [CI], 25.6 to 39.5), and the difference between 2-mg baricitinib and placebo was 16.6 percentage points (95% CI, 9.5 to 23.8) (P<0.001 for each dose vs. placebo). In BRAVE-AA2, the corresponding values were 32.6 percentage points (95% CI, 25.6 to 39.6) and 16.1 percentage points (95% CI, 9.1 to 23.2) (P<0.001 for each dose vs. placebo). Secondary outcomes for baricitinib at a dose of 4 mg but not at a dose of 2 mg generally favored baricitinib over placebo. Acne, elevated levels of creatine kinase, and increased levels of low- and high-density lipoprotein cholesterol were more common with baricitinib than with placebo. CONCLUSIONS: In two phase 3 trials involving patients with severe alopecia areata, oral baricitinib was superior to placebo with respect to hair regrowth at 36 weeks. Longer trials are required to assess the efficacy and safety of baricitinib for alopecia areata. (Funded by Eli Lilly under license from Incyte; BRAVE-AA1 and BRAVE-AA2 ClinicalTrials.gov numbers, NCT03570749 and NCT03899259.).

Efficacy and safety of ritlecitinib in adults and adolescents with alopecia areata: a randomised, double-blind, multicentre, phase 2b-3 trial.

BACKGROUND: Alopecia areata is characterised by non-scarring loss of scalp, face, or body hair. We investigated the efficacy and safety of ritlecitinib, an oral, selective dual JAK3/TEC family kinase inhibitor, in patients with alopecia areata. METHODS: In this randomised, double-blind, multicentre, phase 2b-3 trial done at 118 sites in 18 countries, patients aged 12 years and older with alopecia areata and at least 50% scalp hair loss were randomly assigned to oral ritlecitinib or placebo once-daily for 24 weeks, with or without a 4-week loading dose (50 mg, 30 mg, 10 mg, 200 mg loading dose followed by 50 mg, or 200 mg loading dose followed by 30 mg), followed by a 24-week extension period during which ritlecitinib groups continued their assigned doses and patients initially assigned to placebo switched to ritlecitinib 50 mg or 200 mg loading dose followed by 50 mg. Randomisation was done by use of an interactive response system and was stratified by baseline disease severity and age. The sponsor, patients, and investigators were masked to treatment, and all patients received the same number of tablets to maintain masking. The primary endpoint was Severity of Alopecia Tool (SALT) score 20 or less at week 24. The primary endpoint was assessed in all assigned patients, regardless of whether they received treatment. This study was registered with ClinicalTrials.gov, NCT03732807. FINDINGS: Between Dec 3, 2018, and June 24, 2021, 1097 patients were screened and 718 were randomly assigned to receive ritlecitinib 200 mg + 50 mg (n=132), 200 mg + 30 mg (n=130), 50 mg (n=130), 30 mg (n=132), 10 mg (n=63), placebo to 50 mg (n=66), or placebo to 200 mg + 50 mg (n=65). 446 (62%) of 718 patients were female and 272 (38%) were male. 488 (68%) were White, 186 (26%) were Asian, and 27 (4%) were Black or African American. Of 718 patients randomly assigned, 104 patients discontinued treatment (34 withdrew, 19 adverse events [AEs], 12 physician decision, 12 lack of efficacy, 13 lost to follow up, five rolled over to long-term study transfer, four pregnancies, two protocol deviations, one declined to attend follow-up due to COVID-19, one attended last visit very late due to COVID-19, and one non-compliance). At week 24, 38 (31%) of 124 patients in the ritlecitinib 200 mg + 50 mg group, 27 (22%) of 121 patients in the 200 mg + 30 mg group, 29 (23%) of 124 patients in the 50 mg group, 17 (14%) of 119 patients in the 30 mg group, and two (2%) of 130 patients in the placebo group had a response based on SALT score 20 or less. The difference in response rate based on SALT score 20 or less between the placebo and the ritlecitinib 200 mg + 50 mg group was 29·1% (95% CI 21·2-37·9; p<0·0001), 20·8% (13·7-29·2; p<0·0001) for the 200 mg + 30 mg group, 21·9% (14·7-30·2; p<0·0001) for the 50 mg group, and 12·8% (6·7-20·4; p=0·0002) for the 30 mg group. Up to week 48 and including the follow-up period, AEs had been reported in 108 (82%) of 131 patients in the ritlecitinib 200 mg + 50 mg group, 105 (81%) of 129 patients in the 200 mg + 30 mg group, 110 (85%) of 130 patients in the 50 mg group, 106 (80%) of 132 patients in the 30 mg group, 47 (76%) of 62 patients in the 10 mg group, 54 (83%) of 65 patients placebo to ritlecitinib 200 mg + 50 mg in the extension period, and 57 (86%) of 66 patients in the placebo to 50 mg group. The incidence of each AE was similar between groups, and there were no deaths. INTERPRETATION: Ritlecitinib was effective and well tolerated in patients aged 12 years and older with alopecia areata. Ritlecitinib might be a suitable treatment option for alopecia areata in patients who are candidates for systemic therapy. FUNDING: Pfizer.

Reflectance Confocal Microscopy, Optical Coherence Tomography, and Multiphoton Microscopy in Inflammatory Skin Disease Diagnosis.

BACKGROUND AND OBJECTIVES: Technological advances in medicine have brought about many novel skin imaging devices. This review aims to evaluate the scientific evidence supporting the use of noninvasive optical imaging techniques to aid in the diagnosis and prognosis of inflammatory skin diseases. STUDY DESIGN/MATERIALS AND METHODS: PubMed and Scopus were searched in September 2020 according to PRISMA guidelines for articles using reflectance confocal microscopy (RCM), optical coherence tomography (OCT), and multiphoton microscopy (MPM) in inflammatory skin diseases, excluding studies monitoring treatment efficacy. RESULTS: At the time of the study, there were 66 articles that addressed the utilization of noninvasive imaging in interface, spongiotic, psoriasiform, vesiculobullous, and fibrosing/sclerosing inflammatory skin dermatoses: RCM was utilized in 46, OCT in 16, and MPM in 5 articles. RCM was most investigated in psoriasiform dermatoses, whereas OCT and MPM were both most investigated in spongiotic dermatoses, including atopic dermatitis and allergic contact dermatitis. CONCLUSIONS: There is preliminary evidence to support the diagnostic potential of noninvasive optical imaging techniques in inflammatory skin diseases. Improvements in the devices and further correlation with histology will help broaden their utility. Additional studies are needed to determine the parameters for diagnostic features, disease differentiation, and staging of inflammatory skin conditions. Lasers Surg. Med. © 2021 Wiley Periodicals LLC.

Combining Deep Learning With Optical Coherence Tomography Imaging to Determine Scalp Hair and Follicle Counts.

BACKGROUND AND OBJECTIVES: One of the challenges in developing effective hair loss therapies is the lack of reliable methods to monitor treatment response or alopecia progression. In this study, we propose the use of optical coherence tomography (OCT) and automated deep learning to non-invasively evaluate hair and follicle counts that may be used to monitor the success of hair growth therapy more accurately and efficiently. STUDY DESIGN/MATERIALS AND METHODS: We collected 70 OCT scans from 14 patients with alopecia and trained a convolutional neural network (CNN) to automatically count all follicles present in the scans. The model is based on a dual approach of both detecting hair follicles and estimating the local hair density in order to give accurate counts even for cases where two or more adjacent hairs are in close proximity to each other. RESULTS: We evaluate our system on 70 OCT manually labeled scans taken at different scalp locations from 14 patients, with 20 of those redundantly labeled by two human expert OCT operators. When comparing the individual human predictions and considering the exact locations of hair and follicle predictions, we find that the two human raters disagree with each other on approximately 22% of hairs and follicles. Overall, the deep learning (DL) system predicts the number of follicles with an error rate of 11.8% and the number of hairs with an error rate of 18.7% on average on the 70 scans. The OCT system can capture one scalp location in three seconds, and the DL model can make all predictions in less than a second after processing the scan, which takes half a minute using an unoptimized implementation. CONCLUSION: This approach is well-positioned to become the standard for non-invasive evaluation of hair growth treatment progress in patients, saving significant amounts of time and effort compared with manual evaluation. Lasers Surg. Med. © 2020 Wiley Periodicals, Inc.

Optical Coherence Tomography in the Evaluation of the Scalp and Hair: Common Features and Clinical Utility.

BACKGROUND AND OBJECTIVE: Early diagnosis and treatment of hair loss disorders is vital in providing patients with improved psychological outcomes. Non-invasive imaging with optical coherence tomography (OCT) may be useful in characterizing and managing alopecia. Despite expanding clinical applications of OCT in dermatology, guidelines demonstrating in vivo features of normal and alopecic scalp images remain scant. This pilot study aims to provide an atlas of OCT findings of healthy and alopecia subjects, explore diagnostic quantitative endpoints of alopecia, and compare epidermal thickness and follicular density between scalp regions. STUDY DESIGN/MATERIALS AND METHODS: A total of 32 patients (19-76 years old) were enrolled in the study, including healthy patients (n = 6), and patients with scarring alopecia (n = 12) or non-scarring alopecia (n = 14). An in-line fiber-based swept source OCT was used to image five scalp locations at baseline and 6-month visits. Three investigators evaluated each image for gross features, epidermal thickness, and follicular density. RESULTS: Only data from baseline imaging analysis is discussed in this manuscript. Qualitative differences of OCT images are identified in sample images from healthy scalp and each subtype of alopecia studied. Scarring alopecia is characterized by significantly increased epidermal thickness (average Image J pixel units 32 ± 2 compared with non-scarring alopecia [average 28 ± 3] and control [average 27 ± 3]) (P = 0.022) and decreased follicle count (average 35 ± 5 in a 5 × 7 mm2 area compared with control (50 ± 3) and non-scarring patients (47 ± 6)) (P = 0.0052). Scalp location had no impact on epidermal thickness (P = 0.861) or follicular density (P = 0.15). CONCLUSION: OCT holds promise as a non-invasive technique to further characterize and objectively measure alopecia. Larger sample sizes and longitudinal data are needed to improve reliability and determine if additional distinction between alopecia subtypes and treatment monitoring is possible. Lasers Surg. Med. © 2020 Wiley Periodicals, Inc.

Safety Profile of Thread Lifts on the Face and Neck: An Evidence-Based Systematic Review.

BACKGROUND: "Thread lifting" has quickly gained popularity as a minimally invasive treatment for facial rejuvenation. However, the effectiveness is questionable, and the safety and adverse effects are often not discussed. OBJECTIVE: To identify and discuss the adverse effects associated with various types of threads. MATERIALS AND METHODS: Studies describing the use of thread lifts were identified using a PubMed search. Inclusion criteria included studies in which barbed and nonbarbed threads were used for the face and neck. RESULTS: Fifty-nine articles consisting of 14,222 patients (14,134 barbed, 81 nonbarbed, and 7 combined cases) were included. The most common side effects overall were facial asymmetry (n = 6,143), edema/tumefaction (n = 453), and ecchymosis (n = 407). Serious adverse effects were rare and consisted of paresthesias, alopecia, and injuries to vessels/glands. Most adverse effects were transient and self-resolving, with the exception of contour irregularities, injuries to vessels/glands, infections, and inflammatory reactions. CONCLUSION: Most side effects associated with threads were self-resolving, whereas more serious cases subsided with treatment. Future studies are critical to further determine whether thread lifting provides long-lasting, safe, and satisfying results.

The effect of gluten on skin and hair: a systematic review.

Non-celiac gluten sensitivity is often clinically indistinguishable from celiac disease, and patients show improvement or resolution of their symptoms with a gluten-free diet. In contrast to celiac disease, the effects of gluten on the skin and hair in the context of non-celiac gluten sensitivity are not as clear. This review aims to describe the impact of gluten on the skin and hair in patients with non-celiac gluten sensitivity and those without a definitive celiac disease diagnosis. A literature search was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) reporting guidelines for systematic reviews. Forty-two publications met inclusion criteria with five studies describing the skin manifestations of non-celiac gluten sensitivity. Trials identifying the impact of a gluten-free diet on skin disease, as well as dermatologic conditions and their associations with antigliadin antibodies were also identified. Dermatologic manifestations in patients with non-celiac gluten sensitivity vary and may be non-specific. It may be appropriate for some of these patients with skin manifestations to trial a gluten-free diet. Dermatologic conditions that may respond positively to a gluten-free diet include psoriasis, atopic dermatitis, vitiligo, and palmoplantar pustulosis, while linear IgA disease does not appear to improve with this dietary change.

Forging the Future: 2018 Alopecia Areata Research Summit Summary Report.

Alopecia areata (AA) is a common autoimmune skin disease resulting in the loss of hair on the scalp and elsewhere on the body that affects over 146 million people worldwide at some point in their lives. Founded in 1981, the National AA Foundation (NAAF) is a nonprofit organization that supports research to find a cure or acceptable treatment for AA, supports those with the disease, and educates the public about AA. NAAF conducts research summits every two years to review progress and create new directions in its funded and promoted research. This report from the seventh AA Research Summit, Forging the Future, held December 4-5, 2018 in New York City provides highlights of the research presented and future research priorities identified during targeted discussion sessions.

The Role of Patients in Alopecia Areata Endpoint Development: Understanding Physical Signs and Symptoms.

Meaningful patient input to understand disease experience and patient expectations for improvement with treatment is essential for the selection and development of outcome measures for alopecia areata (AA) clinical trials. This study explored the physical signs and symptoms of AA through 30 semistructured interviews with adult (n = 25) and adolescent (n = 5) patients experienced with severe or very severe AA. Scalp hair loss was overwhelmingly the most important sign and symptom of AA. Nearly all patients (90%) considered scalp hair loss in their top three most bothersome physical signs and symptoms of AA, with 77% (n = 23) naming scalp hair loss as the most bothersome symptom. Other identified signs and symptoms in the top three most bothersome included eyebrow, eyelash, nose, body, and facial hair loss, as well as eye irritation and nail damage and/or appearance. Eyebrow (16%, n = 4), eyelash (4%, n = 1), nasal (4%, n = 1), and body (4%, n = 1) hair loss were identified by seven adult patients as the most bothersome signs and symptoms of AA. Conceptual saturation confirmed that a comprehensive understanding of this patient population's physical AA-related signs and symptoms was obtained. These findings indicate that the primary objective for new AA treatments for this patient population should be meaningful improvement in scalp hair growth to address the most troubling unmet need.

Characterizing the adverse dermatologic effects of hydroxychloroquine: A systematic review.

BACKGROUND: Hydroxychloroquine is associated with myriad adverse dermatologic effects, most of which are poorly characterized by the literature, with unknown frequencies and risk factors. OBJECTIVE: To conduct a systematic review of the adverse dermatologic effects and predisposing factors of hydroxychloroquine toxicity. RESULTS: The review included 94 articles comprising 689 dermatologic adverse effects. A total of 21 unique dermatologic reactions were reported, most commonly drug eruption or rash (358 cases), cutaneous hyperpigmentation (116), pruritus (62), acute generalized exanthematous pustulosis (27), Stevens-Johnson syndrome or toxic epidermal necrolysis (26), hair loss (12), and stomatitis (11). Almost all underlying conditions were rheumatologic or autoimmune in nature, composed primarily of lupus erythematous (72% of all cases) and rheumatoid arthritis (14%). The range of reported mean cumulative dosages was wide, with some adverse reactions found after as little as 3 g or as much as 2500 g. LIMITATIONS: Dermatologic adverse events and primary diagnoses related to the use of hydroxychloroquine may be under-reported as only case reports and clinical trials that reported at least 1 dermatologic adverse effect were included. CONCLUSION: Although hydroxychloroquine is generally well tolerated, dermatologic adverse effects involving the skin, hair, or nails are a frequent and significant complication. Most of these reactions occurred after treatment of autoimmune conditions, often manifesting on the skin after a wide range of cumulative dosages.

Incidence and outcomes of cutaneous angiosarcoma: A SEER population-based study.

BACKGROUND: Cutaneous angiosarcoma (CAS) is a rare, malignant tumor of vascular mesenchymal origin accounting for less than 1% of all sarcomas. OBJECTIVE: To examine epidemiologic trends and outcomes in CAS. METHODS: In this retrospective, population-based study, patients with CAS were identified from the Surveillance Epidemiology and End Results database. Age, sex, and race-standardized incidence rates (IRs) were calculated. Survival was assessed with Kaplan-Meier curves and Cox proportional hazards models. RESULTS: Of 811 patients with CAS, 43% had a prior primary cancer. CAS IR for patients without prior primary cancers dropped from 5.88 per 100,000 in 1973 to 1984 to 2.87 per 100,000 in 2005 to 2014. In those with prior primary cancers, IR rose from 0.03 per 100,000 in 1973 to 1984 to 2.25 per 100,000 in 2005 to 2014. On multivariate analysis, patients older than 70 years of age had a higher risk of death compared with those younger than 50 years (hazard ratio, 2.16; 95% confidence interval 1.33-3.57; P = .002), and distant disease was associated with increased risk of death compared with localized disease (hazard ratio, 1.50; 95% confidence interval, 1.11-2.03; P = .008). Receipt of surgery and/or radiation therapy was not associated with survival. LIMITATIONS: Potential selection and miscoding bias, retrospective nature. CONCLUSION: CAS rates are rising among those with other prior primary cancers. Survival is not affected by current therapeutic strategies, highlighting the need for additional treatment options.

Adverse Events of Injectable Deoxycholic Acid.

BACKGROUND: Injectable deoxycholic acid (DCA) may be used to remove excess submental fat and off-label for local adipose reduction. Despite DCA's widespread use, rare incidences of severe, systemic, long-term adverse events (AEs) have been reported. OBJECTIVE: To evaluate the potential side effects associated with injectable DCA. METHODS AND MATERIALS: A systematic review was conducted using PubMed, Cochrane, CINAHL, and Web of Science using PRISMA guidelines to gather the literature relating to DCA or deoxycholate-associated AEs and their management. RESULTS: Twenty-eight manuscripts were included after full article review. Most commonly, patients experienced mild localized AEs, whereas a small number of patients experienced severe pain, alopecia, nasopharyngitis, dysphagia, dizziness/lightheadedness, and gastrointestinal upset. Severe, long-term AEs were reported as rare in the evaluated literature. Deoxycholic acid injections in large volumes were more likely to cause severe adverse effects. CONCLUSION: Self-resolving, mild side effects and severe but rare adverse effects have been reported with DCA use making it a safe treatment for local adipose reduction. Further studies are necessary to determine its safety profile, especially when using DCA in off-label areas.

Building and Crossing the Translational Bridge: 2016 Alopecia Areata Research Summit Highlights.

Alopecia areata (AA) is a common autoimmune skin disease that results in the loss of hair on the scalp and elsewhere on the body and affects over 146 million people worldwide at some point in their lives. Founded in 1981, the National Alopecia Areata Foundation is a nonprofit organization that supports research to find a cure or acceptable treatment for AA, supports those with the disease, and educates the public about AA. The National Alopecia Areata Foundation conducts research summits every 2 years to review progress and create new directions in its funded and promoted research. The Foundation brings together scientists from all disciplines to get a broad and varied perspective. These AA research summits are part of the Foundation's main strategic initiative, the AA Treatment Development Program, to enhance the understanding of AA and accelerate progress toward a viable treatment.

Cutaneous Hypersensitivity-Like Reactions Associated With Breast Implants: A Review.

BACKGROUND: Breast implantation is an increasingly common procedure for both cosmesis and reconstruction. Risk of cutaneous reactions to breast implants is low and typically described in postsurgical settings. Adverse skin hypersensitivity-like reactions to implants have also been reported but are not well described. OBJECTIVE: To review the scientific literature on cutaneous hypersensitivity-like reactions to breast implants. METHODS: A systematic literature review was conducted using PubMed. Articles pertaining to breast implants and cutaneous hypersensitivity-like reactions in humans were included. RESULTS: In total, 10 studies on hypersensitivity-like reactions from breast implants were included in the review. Potential allergenic compounds in breast implants include silicone, polyurethane texturing, and acellular dermal matrix. Perivascular lymphocytic infiltrate was a common finding on histopathology. Patch testing and preoperative silicone cube implantation were used to determine sensitivity. Attempted treatments included topical and oral corticosteroids, montelukast and antibiotics. Most cases required implant removal for resolution of symptoms. CONCLUSION: Cutaneous hypersensitivity-like reactions to breast implants seem to be rare complications, sometimes necessitating implant removal. Future studies are needed to establish their incidence and etiology, and the diagnostic role of patch testing and preoperative screening.

Polymorphous sweat gland carcinoma: a report of two cases.

Polymorphous sweat gland carcinoma (PSGC) is a rare adnexal neoplasm with characteristic variegated histopathologic findings and low-grade clinical behavior. First described in 1994, only 11 cases have been reported in the literature. It is named for the multiplicity of architectural patterns that may be present: solid, tubular, trabecular, pseudopapillary and cylindromatous. Owing to the multiple architectural patterns, the differential diagnosis is broad, including metastatic adenocarcinoma and other adnexal neoplasms with ductular differentiation. We present two new cases of PSGC and review the literature on this rare tumor.

Clinical Efficacy of Diphenylcyclopropenone in Alopecia Areata: Retrospective Data Analysis of 50 Patients.

Diphenylcyclopropenone (DPCP) is widely considered the most effective topical immunotherapy for refractory or extensive alopecia areata (AA), but questions regarding how long to try DPCP therapy before terminating and what factors are prognostic of therapeutic success still remain unanswered. In this retrospective study of 50 AA patients, we evaluated DPCP efficacy and identified patient factors predictive of therapeutic success/failure. The median duration of DPCP treatment was 3 years, with 47% patients experiencing their first regrowth in the first 6 months of DPCP therapy, 20% between 6 months-1 year, and 8% between 1-2 years. In our study, treatment success, defined as ⩾50% terminal hair regrowth, was reached in 71% of alopecia totalis patients and in 56% of alopecia universalis patients. Three factors were statistically significant predictors of poor treatment outcome-extent of hair loss before DPCP treatment, history of thyroid disease, and extent of body hair involvement. Relapse was observed in 44% of patients and significantly associated with history of thyroid disease. Common side effects were itching, rash, and local lymphadenopathy. The results of this study support our belief that DPCP therapy is a viable treatment option, can be successfully accomplished at home, and should not be terminated before 2 years.

ILK Index and Regrowth in Alopecia Areata.

There is insufficient data in the literature concerning optimal intralesional kenalog (ILK) dosing for the treatment of alopecia areata (AA). The purpose of this pilot study was to evaluate the utility of using the ratio of ILK received to initial Severity of Alopecia Tool (SALT) score to guide ILK dosing in patients with AA. Using photographic data from patients at baseline and 4-months follow-up, hair loss in 15 patients treated with AA was retrospectively graded using the SALT scores. The ILK received/initial SALT score (ILK index) was calculated for each patient, and the mean ILK index for patients who experienced significant (≥50%) and suboptimal (<50%) hair regrowth at 4 months follow-up were compared. Patients who experienced suboptimal hair regrowth had a lower ILK index on average than patients who experienced significant improvement. Although the difference did not meet significance (<0.1), the trend suggests that the ILK index, a novel calculation, may be a useful tool for guiding ILK dosing in the treatment of AA.