Assessment of Clinician-Reported Outcome Measures for Alopecia Areata: A Systematic Scoping Review.

Clinician-reported outcome measures (ClinROMs) are an important part of disease assessment in daily practice and clinical trials. There is a broad disagreement on the most appropriate ClinROM for a comprehensive assessment of alopecia areata (AA) severity. This paper aims to identify the currently available ClinROMs for AA through a systematic literature search, address their practical strengths and weaknesses, and identify the road ahead for future research. A search was conducted of the published, peer-reviewed literature via PubMed (Medline) and EMBASE (via Ovid) databases. Articles published in English within the last 23 years (post-2000) that objectively measured AA severity were included. We did not select scoring systems that were solely based on patient-reported outcomes (PROs). The literature search identified 1376 articles, of which 27 were chosen for full-text review. Based on our eligibility criteria, fourteen articles were identified, describing sixteen different ClinROMs. Five ClinROMs solely measured scalp hair loss (SALT, SALTⅡ, ALODEX, pSALT, and AA-IGA). Three trichoscopy-based ClinROMs assessed disease activity (AAPI, AAPS, and Coudability hair score). Six ClinROMs exclusively assessed non-scalp areas (BETA, BELA, ALBAS, ClinRO for Eyelash, Eyebrow, and Nail assessment). Two ClinROMs assessed both the scalp and beyond-scalp areas (AASI and AASc). The practical strengths and weaknesses of each assessment tool were described. Various practical limitations associated with established tools have impeded their universal implementation in routine clinical practice. There is a significant need for a holistic clinical severity scoring system to capture all the key severity identifiers beyond the involvement of the scalp.

Isotretinoin as a promising option in the treatment of facial papules of frontal fibrosing alopecia.

Frontal fibrosing alopecia (FFA) is a primary cicatricial alopecia characterized by hairline recession, pruritus, and facial papules (FP). Various therapies are used to stabilize disease activity and induce remission. However, FP of FFA is resistant to treatment in many cases. In this review, we searched the PubMed and Google Scholar databases to screen the published literature on treatment options for FP in the context of FFA. Overall, 12 studies were included in this review. Available literature suggests a noticeable improvement in resistant-to-treatment FP in FFA patients with oral isotretinoin. The available evidence is limited and is derived from retrospective studies and case reports/series. Systemic isotretinoin can be considered a promising therapeutic regimen for treating resistant-to-treatment FP of FFA patients. However, more extensive, well-designed studies are necessary for confirmatory evidence.

Real-world effectiveness and safety of tofacitinib for alopecia areata: A retrospective cohort study of 202 patients.

BACKGROUND: Alopecia areata (AA) is an autoimmune hair loss disorder characterised by collapse of hair follicle immune privilege and mediated by autoreactive CD8+ T lymphocytes and natural killer cells. Treatment is often unsatisfactory. The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is implicated in the pathogenesis of AA and Janus Kinase inhibitor (JAKi) medications are promising emerging treatments for AA. OBJECTIVES: We evaluated the safety and effectiveness of tofacitinib in a real-world setting over 18 months of treatment. METHODS: A retrospective cohort study of all patients with scalp AA commenced on tofacitinib between 1 November 2016 and 31 May 2019. The primary endpoint was the percent change in Severity of Alopecia Tool (SALT) score at 18 months. RESULTS: Two hundred and two patients were included. After 18 months of treatment, 55.9%, 42.6% and 29.2% achieved 50%, 75% and 90% reductions in their SALT scores respectively. Increased duration of AA was a negative predictor of hair regrowth. Males and patients with baseline SALT ≥90 were slower to respond to treatment in the first 12 months. One hundred and twenty-four patients and 168 patients received concomitant systemic corticosteroids or low-dose oral minoxidil during tofacitinib therapy respectively. There were no serious adverse events. CONCLUSION: Tofacitinib was a safe and effective treatment for patients with moderate-to-severe AA. Further randomised controlled studies are needed to establish the optimal treatment regimen.

Patient-Reported Satisfaction with Hair Regrowth in a Study of Ritlecitinib in Alopecia Areata: Results from ALLEGRO-2b/3.

INTRODUCTION: Patients with alopecia areata (AA) report high levels of dissatisfaction with commonly used treatments. Patient-reported outcomes are essential to understanding patients' experiences with AA treatments. The objective of this study was to evaluate patient-reported satisfaction with hair growth among patients with AA receiving ritlecitinib or placebo and the correlation between clinician-assessed efficacy and patient-reported satisfaction. METHODS: In the ALLEGRO-2b/3 (NCT03732807) trial, patients with AA and ≥50% scalp hair loss were randomized to daily ritlecitinib or placebo for 24 weeks, with a 24-week extension of continued ritlecitinib or switch from placebo to ritlecitinib. The Patient Satisfaction with Hair Growth (P-Sat) measure evaluated patients' satisfaction with hair growth in 3 domains: amount, quality, and overall satisfaction with hair growth. The prespecified analysis evaluated the proportion of patients who were slightly, moderately, or very satisfied with hair growth. Several post hoc analyses assessed the proportion of patients who were moderately/very satisfied and moderately/very dissatisfied and calculated polyserial correlations between change from baseline (CFB) in Severity of Alopecia Tool (SALT) and P-Sat scores at weeks 24 and 48. RESULTS: At week 24, the proportion of patients (N = 718) reporting satisfaction (slightly, moderately, or very satisfied) overall with their hair growth ranged from 36.4% in the ritlecitinib 10-mg group (evaluated for dose ranging only) to 67.5% in the 200/50-mg group versus 22.6% in the placebo groups. In patients randomized to ritlecitinib, the proportion who were satisfied increased or was maintained at week 48. A substantially greater proportion of placebo patients who switched to ritlecitinib reported satisfaction at week 48 than at week 24. Similar results were observed for patient satisfaction with the amount and quality of hair growth. In the post hoc analyses defining satisfaction as moderately/very satisfied and dissatisfaction as moderately/very dissatisfied, the benefit of ritlecitinib was also observed. All P-Sat domain scores strongly correlated with CFB-SALT scores at weeks 24 (range 0.73-0.76; p < 0.05) and 48 (0.74-0.77; p < 0.05). CONCLUSIONS: Patients receiving active ritlecitinib doses reported favorable results versus placebo in satisfaction with hair growth up to week 48. High concordance was observed between improvement in scalp hair growth evaluated by clinicians and patient-reported satisfaction.

Health-related quality of life of adult and adolescent patients living with alopecia areata in Australia.

INTRODUCTION: To understand the experiences of adolescent and adult patients living with alopecia areata (AA) in Australia regarding symptom severity and the impact on psychosocial well-being and work/classroom productivity. MATERIALS AND METHODS: A cross-sectional online patient survey among adolescent and adult patients diagnosed with AA was recruited via the Australia Alopecia Areata Foundation. Patient-reported outcomes were also assessed. RESULTS: A total of 337 patients (49 adolescents; 288 adults), with a mean ± standard deviation age of 14.7 ± 1.55 and 38.9 ± 13.31 years for adolescents and adults, respectively, were included. In the group with extensive hair loss (Scalp Hair Assessment Patient-Reported Outcome, categories 3 + 4, n = 172), we observed higher emotional symptom and activity limitation scores (Alopecia Areata Patient Priority Outcomes, emotional symptoms: adults 2.5 ± 1.03, adolescents 2.2 ± 1.15; activity limitations: adults 1.4 ± 1.15, adolescents 1.2 ± 0.99). Additionally, in adults, the Alopecia Areata Symptom Impact Scale global score was 4.0 ± 2.10 (symptoms subscale score 4.1 ± 1.91; interference subscale scores 3.8 ± 2.73). Hospital Anxiety and Depression Scale scores were high across participants, irrespective of hair loss extent (adults: anxiety 9.2 ± 3.85, depression 6.6 ± 3.95; adolescents: anxiety 9.7 ± 4.65, depression 5.2 ± 3.59). Work and classroom productivity were substantially impaired due to AA, with 70.5% of adults and 57.1% of adolescents reporting activity impairment, and overall work/classroom impairment reported at 39.2% and 44.9%, respectively. CONCLUSIONS: AA impacts the physical, emotional and psychosocial well-being of both adult and adolescent patients. More extensive hair loss more profoundly impacts those living with AA. Patients may benefit from patient-centred care approaches addressing the impact of hair loss on mental and emotional well-being, daily activities and work productivity.

Cross-sectional burden-of-illness study in atopic dermatitis (MEASURE-AD) in Australia and New Zealand reveals impacts on well-being.

OBJECTIVES: To describe disease burden in individuals with moderate-to-severe atopic dermatitis (AD) in Australia and New Zealand (ANZ) and compare it with other geographic regions. METHODS: This multicentre, cross-sectional, observational study (MEASURE-AD) recruited consecutive adolescent and adult patients attending dermatology clinics in 28 countries. Data collected included scores of pruritus, disease severity, sleep, pain, disease control, work and quality of life. RESULTS: This study included 112 ANZ participants (Australia n = 72; New Zealand n = 40) from December 2019 to December 2020. Treatments included topicals (85.7% of patients), non-biologic systemic therapy (28.6%), phototherapy (9.8%) and dupilumab (4.5%). Mean Eczema Area and Severity Index (EASI) score was 22.3 (95% CI 19.6-25.0) and Patient-Oriented Eczema Measurement (POEM) score was 18.4 (95% CI 16.8-20.0). Pruritus Numerical Rating Scale (NRS) was 6.0 (95% CI 5.5-6.6) (50% had severe pruritus) and Dermatology Life Quality Index (DLQI) 14.3 (95% CI 12.8-15.8). ADerm-Impact sleep domain score was 15.1 (95% CI 13.2-16.9). ADerm-Symptom Scale worst skin pain domain score was 5.0 (95% CI 4.3-5.6). Work Productivity and Activity Impairment (WPAI) percentages indicated work and productivity impairment. Inadequately controlled AD was self-reported by 41%, with 9.7 flares in the past 6 months. Scores of pruritus, disease severity, sleep, pain, disease control and quality of life in ANZ were often the highest of all the geographic regions studied. CONCLUSION: ANZ patients with AD have a high disease burden, which extends across multiple facets of daily life. Many are inadequately controlled with existing therapies.

Novel investigational drugs for alopecia areata and future perspectives.

INTRODUCTION: Alopecia areata (AA) is an immune-mediated disease that causes non-scarring hair loss. While acute, solitary patches often spontaneously remit, developing secondary patches or failure of the disease to resolve within 6-12 months predicts a poor prognosis, with an increased risk of alopecia totalis or universalis. Chronic AA increases the risk of depression and suicidality and reduces quality of life. Treatment options for chronic or acute diffuse AA were previously limited to corticosteroids and traditional immunomodulators. Two Janus Kinase (JAK) inhibitors are now approved for the treatment of chronic AA. AREAS COVERED: The results of landmark phase 3 trials for three JAK inhibitors, baricitinib, ritlecitinib, and deuruxolitinib are discussed. Evidence for other JAK inhibitors, biologics, and phosphodiesterase-4 inhibitors are also presented. Therapies currently undergoing clinical trials are listed. EXPERT OPINION: JAK inhibitors are a safe and efficacious treatment of moderate-to-severe AA. Early intervention, regardless of severity, allows for improved treatment efficacy. It is uncertain how long patients should remain on JAK inhibitors; discontinuation often leads to relapse. A black-box warning for JAK inhibitors was extrapolated from safety data in a rheumatoid arthritis cohort; recent meta-analyses of JAK inhibitors used in dermatology cohorts do not demonstrate the same risk profile.

Integrated Safety Analysis of Ritlecitinib, an Oral JAK3/TEC Family Kinase Inhibitor, for the Treatment of Alopecia Areata from the ALLEGRO Clinical Trial Program.

BACKGROUND: The ALLEGRO phase 2a and 2b/3 studies demonstrated that ritlecitinib, an oral JAK3/TEC family kinase inhibitor, is efficacious at doses of ≥ 30 mg in patients aged ≥ 12 years with alopecia areata (AA). OBJECTIVE: The objective of this study was to evaluate the safety of ritlecitinib in an integrated analysis of four studies in AA. METHODS: Two cohorts were analyzed: a placebo-controlled and an all-exposure cohort. Proportions and study size-adjusted incidence rates (IRs) of adverse events (AEs) of interest and laboratory abnormalities are reported. RESULTS: In the placebo-controlled cohort (n = 881; median exposure: 169 days), the proportion of ritlecitinib-treated patients with AEs was 70.2-75.4% across doses versus 69.5% in the placebo group; serious AEs occurred in 0-3.2% versus 1.9% for the placebo. A total of 19 patients permanently discontinued due to AEs (5 while receiving the placebo). In the all-exposure cohort (n = 1294), median ritlecitinib exposure was 624 days [2091.7 total patient-years (PY)]. AEs were reported in 1094 patients (84.5%) and serious AEs in 57 (4.4%); 78 (6.0%) permanently discontinued due to AEs. The most common AEs were headache (17.7%; 11.9/100 PY), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive test (15.5%; 9.8/100 PY), and nasopharyngitis (12.4%; 8.2/100 PY). There were two deaths (breast cancer and acute respiratory failure/cardiorespiratory arrest). Proportions (IRs) were < 0.1% (0.05/100 PY) for opportunistic infections, 1.5% (0.9/100 PY) for herpes zoster, 0.5% (0.3/100 PY) for malignancies (excluding nonmelanoma skin cancer), and 0.2% (0.1/100 PY) for major adverse cardiovascular events. CONCLUSIONS: Ritlecitinib is well tolerated with an acceptable safety profile up to 24 months in patients aged ≥ 12 years with AA (video abstract and graphical plain language summary available). TRIAL REGISTRIES: ClinicalTrials.gov: NCT02974868 (date of registration: 11/29/2016), NCT04517864 (08/18/2020), NCT03732807 (11/07/2018), and NCT04006457 (07/05/2019).

Treatment of moderate-to-severe alopecia areata in patients over the age of 65†years with baricitinib.

Baricitinib is a Janus kinase inhibitor that has been approved by the US Food and Drugs Administration for the treatment of severe alopecia areata (AA) in adults. However, the clinical trials that demonstrated the efficacy of baricitinib in the treatment of severe AA did not include men aged > 60 years or women aged > 70 years. We retrospectively assessed the efficacy and safety of baricitinib in 14 patients aged ≥ 65 years with moderate-to-severe AA. After a mean (SD) duration of 18.5 (11.9) months, a 72% reduction in mean Severity of Alopecia Tool score from baseline was observed. Partial or complete eyebrow and eyelash hair was observed in 57% and 43% of patients, respectively. The adverse effects of baricitinib were mild. No cases of venous thromboembolism, major adverse cardiovascular events or malignancy were reported.

Efficacy and safety of ligelizumab in adults and adolescents with chronic spontaneous urticaria: results of two phase 3 randomised controlled trials.

BACKGROUND: Many patients with chronic spontaneous urticaria (CSU) do not achieve complete control of their symptoms with current available treatments. In a dose-finding phase 2b study, ligelizumab improved urticaria symptoms in patients with H1-antihistamine (H1-AH) refractory CSU. Here, we report the efficacy and safety outcomes from two ligelizumab phase 3 studies. METHODS: PEARL-1 and PEARL-2 were identically designed randomised, double-blind, active-controlled and placebo-controlled parallel-group studies. Patients aged 12 years or older with moderate-to-severe H1-AH refractory CSU were recruited from 347 sites in 46 countries and randomly allocated in a 3:3:3:1 ratio via Interactive Response Technology to 72 mg ligelizumab, 120 mg ligelizumab, 300 mg omalizumab, or placebo, dosed every 4 weeks, for 52 weeks. Patients allocated to placebo received 120 mg ligelizumab from week 24. The primary endpoint was change-from-baseline (CFB) in weekly Urticaria Activity Score (UAS7) at week 12, and was analysed in all eligible adult patients according to the treatment assigned at random allocation. Safety was assessed throughout the study in all patients who received at least one dose of the study drug. The studies were registered with ClinicalTrials.gov, NCT03580369 (PEARL-1) and NCT03580356 (PEARL-2). Both trials are now complete. FINDINGS: Between Oct 17, 2018, and Oct 26, 2021, 2057 adult patients were randomly allocated across both studies (72 mg ligelizumab n=614; 120 mg ligelizumab n=616; 300 mg omalizumab n=618, and placebo n=209). A total of 1480 (72%) of 2057 were female, and 577 (28%) of 2057 were male. Mean UAS7 at baseline across study groups ranged from 29·37 to 31·10. At week 12, estimated treatment differences in mean CFB-UAS7 were as follows: for 72 mg ligelizumab versus placebo, -8·0 (95% CI -10·6 to -5·4; PEARL-1), -10·0 (-12·6 to -7·4; PEARL-2); 72 mg ligelizumab versus omalizumab 0·7 (-1·2 to 2·5; PEARL-1), 0·4 (-1·4 to 2·2; PEARL-2); 120 mg ligelizumab versus placebo -8·0 (-10·5 to -5·4; PEARL-1), -11·1 (-13·7 to -8·5; PEARL-2); 120 mg ligelizumab versus omalizumab 0·7 (-1·1 to 2·5; PEARL-1), -0·7 (-2·5 to 1·1; PEARL-2). Both doses of ligelizumab were superior to placebo (p<0·0001), but not to omalizumab, in both studies. No new safety signals were identified for ligelizumab or omalizumab. INTERPRETATION: In the phase 3 PEARL studies, ligelizumab demonstrated superior efficacy versus placebo but not versus omalizumab. The safety profile of ligelizumab was consistent with previous studies. FUNDING: Novartis Pharma.

Clinical Benefits of Baricitinib Therapy According to Scalp Hair Regrowth in Patients with Severe Alopecia Areata.

OBJECTIVES: The present analyses report integrated results from BRAVE-AA1 (NCT03570749) and BRAVE-AA2 (NCT03899259) on the clinical benefits of baricitinib treatment on the basis of the amount of scalp hair regrowth through 52 weeks of treatment. METHODS: This post hoc analysis was conducted with data from patients who were treated continuously for 52 weeks with baricitinib 4 mg or 2 mg. Clinical outcomes were assessed using the Severity of Alopecia Tool (SALT) and Clinician-Reported Outcome (ClinRO) for Eyebrow (EB) and Eyelash (EL) hair. Secondary measures included the Hospital Anxiety and Depression Scale and Skindex-16 adapted for alopecia areata. At week 52, patients were classified into three subgroups: SALT ≤ 20 response, intermediate response (achieved a 30% improvement from baseline (SALT30) without a SALT score ≤ 20), or nonresponse (never achieved SALT30). The criterion of SALT30 approximates a minimal clinical meaningful response to therapy. RESULTS: At week 52, with baricitinib 4 mg treatment, the greatest (70%) improvement in EB and EL was observed in responders, but approximately 50% of patients with intermediate response and 20% of nonresponders experienced complete/nearly complete EB and EL regrowth. Improvement in emotional distress was directionally related to improvements in scalp hair regrowth, while impact on quality of life was proportionately greater for the responder subgroup. CONCLUSIONS: Clinically meaningful regrowth in eyebrow and eyelash hair can occur in the absence of complete scalp hair regrowth after treatment with baricitinib. Emotional distress and quality of life improvement is most associated with obtaining a clinical meaningful improvement in scalp hair. TRIAL REGISTRATION NUMBER: BRAVE-AA1, ClinicalTrials.gov number, NCT03570749, start date, 24 September 2018; BRAVE-AA2, ClinicalTrials.gov number, NCT03899259, start date, 8 July 2019.

Rademikibart (CBP-201), a next-generation monoclonal antibody targeting human IL-4Rα: Two phase I randomized trials, in healthy individuals and patients with atopic dermatitis.

IL-4 and IL-13 signaling via IL-4Rα plays key roles in the pathogenesis of atopic dermatitis (AD) and asthma. Rademikibart (formerly CBP-201), a next-generation human IgG4 kappa monoclonal antibody, blocks IL-4Rα-mediated signal transduction. We performed two phase I, randomized, double-blind, placebo-controlled trials. In a single-ascending dose trial, 40 healthy adults were randomized 3:1 to rademikibart (75-600 mg s.c., 300 mg i.v.) or placebo, with 12 weeks of follow-up. In the multiple-ascending dose trial, 31 adults with moderate-to-severe AD were randomized 4:1 to once weekly rademikibart (75-300 mg s.c.) or placebo for 4 weeks, plus 7 weeks of follow-up. Most treatment-emergent adverse events (TEAEs) were mild; none were serious. Two s.c. injection site reactions and one TEAE of conjunctivitis were reported, all were mild. Rapid and sustained improvements were observed in AD severity and in quality of life (QoL), without plateauing. At week 4, efficacy scores improved by a maximum of -74.4% (Eczema Area and Severity Index), -62.7% (body surface area), -52.8% (Pruritus Numerical Rating Scale [PNRS] severity), -54.4% (PNRS frequency), and - 69.9% (Dermatology Life Quality Index). Thymus activation regulated chemokine inflammatory biomarker concentrations decreased in both trials (-55.4% in the pooled rademikibart arms vs. +18.0% with placebo, at week 5, in patients with AD). Exposure to rademikibart increased in a greater than dose-proportional manner, suggesting nonlinear clearance. In summary, rademikibart was well-tolerated and associated with rapid and sustained improvements in eczematous lesions, pruritus, QoL, and inflammatory biomarker concentrations during 4 weeks of treatment. Efficacy responses did not plateau and were generally dose dependent. These promising findings support further development of rademikibart in patients with AD.