Two Phase 3, Randomized, Controlled Trials of Ruxolitinib Cream for Vitiligo.

BACKGROUND: Vitiligo is a chronic autoimmune disease that causes skin depigmentation. A cream formulation of ruxolitinib (an inhibitor of Janus kinase 1 and 2) resulted in repigmentation in a phase 2 trial involving adults with vitiligo. METHODS: We conducted two phase 3, double-blind, vehicle-controlled trials (Topical Ruxolitinib Evaluation in Vitiligo Study 1 [TRuE-V1] and 2 [TRuE-V2]) in North America and Europe that involved patients 12 years of age or older who had nonsegmental vitiligo with depigmentation covering 10% or less of total body-surface area. Patients were randomly assigned in a 2:1 ratio to apply 1.5% ruxolitinib cream or vehicle control twice daily for 24 weeks to all vitiligo areas on the face and body, after which all patients could apply 1.5% ruxolitinib cream through week 52. The primary end point was a decrease (improvement) of at least 75% from baseline in the facial Vitiligo Area Scoring Index (F-VASI; range, 0 to 3, with higher scores indicating a greater area of facial depigmentation), or F-VASI75 response, at week 24. There were five key secondary end points, including improved responses on the Vitiligo Noticeability Scale. RESULTS: A total of 674 patients were enrolled, 330 in TRuE-V1 and 344 in TRuE-V2. In TRuE-V1, the percentage of patients with an F-VASI75 response at week 24 was 29.8% in the ruxolitinib-cream group and 7.4% in the vehicle group (relative risk, 4.0; 95% confidence interval [CI], 1.9 to 8.4; P<0.001). In TRuE-V2, the percentages were 30.9% and 11.4%, respectively (relative risk, 2.7; 95% CI, 1.5 to 4.9; P<0.001). The results for key secondary end points showed superiority of ruxolitinib cream over vehicle control. Among patients who applied ruxolitinib cream throughout 52 weeks, adverse events occurred in 54.8% in TRuE-V1 and 62.3% in TRuE-V2; the most common adverse events were application-site acne (6.3% and 6.6%, respectively), nasopharyngitis (5.4% and 6.1%), and application-site pruritus (5.4% and 5.3%). CONCLUSIONS: In two phase 3 trials, application of ruxolitinib cream resulted in greater repigmentation of vitiligo lesions than vehicle control through 52 weeks, but it was associated with acne and pruritus at the application site. Larger and longer trials are required to determine the effect and safety of ruxolitinib cream in patients with vitiligo. (Funded by Incyte; TRuE-V1 and TRuE-V2 ClinicalTrials.gov numbers, NCT04052425 and NCT04057573.).

Secukinumab in moderate-to-severe hidradenitis suppurativa (SUNSHINE and SUNRISE): week 16 and week 52 results of two identical, multicentre, randomised, placebo-controlled, double-blind phase 3 trials.

BACKGROUND: Few therapeutic options are available for patients with moderate-to-severe hidradenitis suppurativa. We aimed to assess the efficacy of secukinumab in patients with moderate-to-severe hidradenitis suppurativa in two randomised trials. METHODS: SUNSHINE and SUNRISE were identical, multicentre, randomised, placebo-controlled, double-blind phase 3 trials done in 219 primary sites in 40 countries. Patients aged 18 years old or older with the capacity to provide written informed consent and with moderate-to-severe hidradenitis suppurativa (defined as a total of ≥5 inflammatory lesions affecting ≥2 distinct anatomical areas) for at least 1 year were eligible for inclusion. Included patients also agreed to daily use of topical over-the-counter antiseptics on the areas affected by hidradenitis suppurativa lesions while on study treatment. Patients were excluded if they had 20 or more fistulae at baseline, had ongoing active conditions requiring treatment with prohibited medication (eg, systemic biological immunomodulating treatment, live vaccines, or other investigational treatments), or met other exclusion criteria. In both trials, patients were randomly assigned (1:1:1) by means of interactive response technology to receive subcutaneous secukinumab 300 mg every 2 weeks, subcutaneous secukinumab 300 mg every 4 weeks, or subcutaneous placebo all via a 2 mL prefilled syringe in a double-dummy method as per treatment assignment. The primary endpoint was the proportion of patients with a hidradenitis suppurativa clinical response, defined as a decrease in abscess and inflammatory nodule count by 50% or more with no increase in the number of abscesses or in the number of draining fistulae compared with baseline, at week 16, assessed in the overall population. Hidradenitis suppurativa clinical response was calculated based on the number of abscesses, inflammatory nodules, draining fistulae, total fistulae, and other lesions in the hidradenitis suppurativa affected areas. Safety was assessed by evaluating the presence of adverse events and serious adverse events according to common terminology criteria for adverse events, which were coded using Medical Dictionary for Regulatory Activities terminology. Both the SUNSHINE, NCT03713619, and SUNRISE, NCT03713632, trials are registered with ClinicalTrials.gov. FINDINGS: Between Jan 31, 2019, and June 7, 2021, 676 patients were screened for inclusion in the SUNSHINE trial, of whom 541 (80%; 304 [56%] women and 237 [44%] men; mean age 36·1 years [SD 11·7]) were included in the analysis (181 [33%] in the secukinumab every 2 weeks group, 180 [33%] in the secukinumab every 4 weeks group, and 180 [33%] in the placebo group). Between the same recruitment dates, 687 patients were screened for inclusion in the SUNRISE trial, of whom 543 (79%; 306 [56%] women and 237 [44%] men; mean age 36·3 [11·4] years) were included in the analysis (180 [33%] in the secukinumab every 2 weeks group, 180 [33%] in the secukinumab every 4 weeks group, and 183 [34%] in the placebo group). In the SUNSHINE trial, significantly more patients in the secukinumab every 2 weeks group had a hidradenitis suppurativa clinical response (rounded average number of patients with response in 100 imputations, 81·5 [45%] of 181 patients) compared with the placebo group (60·7 [34%] of 180 patients; odds ratio 1·8 [95% CI 1·1-2·7]; p=0·0070). However, there was no significant difference between the number of patients in the secukinumab every 4 weeks group (75·2 [42%] of 180 patients) and the placebo group (1·5 [1·0-2·3]; p=0·042). Compared with the placebo group (57·1 [31%] of 183 patients), significantly more patients in the secukinumab every 2 weeks group (76·2 [42%] of 180 patients; 1·6 [1·1-2·6]; p=0·015) and the secukinumab every 4 weeks group (83·1 [46%] of 180 patients; 1·9 [1·2-3·0]; p=0·0022) had a hidradenitis suppurativa clinical response in the SUNRISE trial. Patient responses were sustained up to the end of the trials at week 52. The most common adverse event by preferred term up to week 16 was headache in both the SUNSHINE (17 [9%] patients in the secukinumab every 2 weeks group, 20 [11%] in the secukinumab every 4 weeks group, and 14 [8%] in the placebo group) and SUNRISE (21 [12%] patients in the secukinumab every 2 weeks group, 17 [9%] in the secukinumab every 4 weeks group, and 15 [8%] in the placebo group) trials. No study-related deaths were reported up to week 16. The safety profile of secukinumab in both trials was consistent with that previously reported, with no new or unexpected safety findings detected. INTERPRETATION: When given every 2 weeks, secukinumab was clinically effective at rapidly improving signs and symptoms of hidradenitis suppurativa with a favourable safety profile and with sustained response up to 52 weeks of treatment. FUNDING: Novartis Pharma.

Secukinumab in adult patients with lichen planus: Efficacy and safety results from the randomised, placebo-controlled, proof-of-concept PRELUDE study.

BACKGROUND: Patients with lichen planus (LP) refractory to available therapies often experience a high disease burden; representing a population with a clear unmet need for new treatments. OBJECTIVES: To evaluate the efficacy and safety of secukinumab 300 mg over 32 weeks in adult patients with biopsy-proven cutaneous LP (CLP), mucosal LP (MLP) or lichen planopilaris (LPP), inadequately controlled by topical corticosteroids. METHODS: PRELUDE was a, randomised, double-blind, placebo-controlled, Phase 2 proof-of-concept study that enrolled patients with CLP, MLP or LPP. Eligible patients were randomised to eithersecukinumab 300 mg every 4 weeks for 32 weeks (SECQ4W), or placebo for 16 weeks followed by secukinumab 300 mg every 2 weeks (SECQ2W) for 16 weeks. The primary endpoint was achievement of the newly designed Investigator's Global Assessment (IGA) score ≤2 at Week 16. RESULTS: Overall, 111 patients were randomised (n=37 each) to CLP, MLP and LPP cohorts. As the proof-of-concept criteria were not met for any of the 3 cohorts, the primary objective was not met. A numerically higher proportion of patients achieved IGA ≤2 response at Week 16 with SECQ4W vs. placebo in the MLP (37.5% [95% credibility interval (Crl): 20.3-57.2] vs. 23.1% [95% Crl: 6.5-49.2]) and LPP cohorts (37.5% [95% Crl: 20.2-57.3] vs. 30.8% [95% Crl: 10.8-57.6]). In the LPP cohort, a sustained response for IGA ≤2 from Week 16 to Week 32 was achieved with SECQ4W (Week 16: 37.5%; Week 32: 45.8%), and a substantial improvement was observed in IGA ≤2 response in patients of this cohort switching from placebo (Week 16: 30.8%) to SECQ2W after Week 16 (Week 32: 63.6%). The safety profile was consistent with the known profile of secukinumab and showed no new or unexpected signals. CONCLUSIONS: PRELUDE is the first randomised controlled basket trial evaluating interleukin-17A inhibition with secukinumab across 3 subtypes of LP. Secukinumab was well-tolerated and safe, showing different response rates across the 3 subtypes, with numerical IGA improvements in MLP and LPP, and no response in CLP. The study raises the question of a differential role of interleukin-17A across LP subtypes. The novel IGA score showed significant correlation with patient as well as physician reported outcome measurements. TRIAL REGISTRATION NUMBER: NCT04300296.

Secukinumab in patients with moderate-to-severe hidradenitis suppurativa based on prior biologic exposure: an efficacy and safety analysis from the SUNSHINE and SUNRISE phase III trials.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with a substantial disease burden. Secukinumab has previously been reported to have sustained efficacy with a favourable safety profile in patients with moderate-to-severe HS. It is unknown whether prior biologic exposure affects the efficacy and safety of secukinumab. OBJECTIVES: To investigate the efficacy and safety of secukinumab in patients with moderate-to-severe HS based on prior exposure to -biologics. METHODS: This was an analysis of the SUNSHINE and SUNRISE phase III trials of secukinumab in patients with moderate-to-severe HS. Patients were randomized at baseline to receive secukinumab every 2 (SECQ2W) or 4 weeks (SECQ4W), or placebo for 16 weeks. After week 16, patients on the SECQ2W and SECQ4W schedules remained on the same treatment regimen, while patients randomized to placebo were switched to either SECQ2W or SECQ4W up to week 52. Assessments based on prior exposure to biologics included Hidradenitis Suppurativa Clinical Response (HiSCR), abscess and inflammatory nodule (AN) count, flare rates, HS-related pain [numerical rating scale 30 (NRS30)], 55% reduction in the International Hidradenitis Suppurativa Severity Score System (IHS4-55), Dermatology Life Quality Index, EuroQol-5D and safety. RESULTS: Overall, 1084 patients were randomized in the SUNSHINE and SUNRISE trials and included in this analysis; 255 (23.5%) were biologic-experienced [SECQ2W (n = 80); SECQ4W (n = 81); placebo (n = 94)] and 829 (76.5%) were biologic-naïve [SECQ2W (n = 281); SECQ4W (n = 279); placebo (n = 269)]. At week 16, responses were more efficacious for secukinumab than for placebo with regard to HiSCR in patients who were biologic-experienced {SECQ2W 37.0% [odds ratio (OR) 1.60, 95% confidence interval (CI) 0.83-3.08]; SECQ4W 38.8% [OR 1.67, 95% CI 0.86-3.22]; placebo 27.3%} and biologic-naïve [SECQ2W 45.6% (OR 1.64, 95% CI 1.15-2.33); SECQ4W 45.4% (OR 1.61, 95% CI 1.13-2.29); placebo 34.2%]. Similar results were observed for AN count, NRS30 and IHS4-55. The higher response seen at week 16 with secukinumab was sustained, with a trend toward improvement over time, through to week 52 in both subgroups. Additional efficacy was observed for quality-of-life assessments, and no differences in safety between subgroups were observed. CONCLUSIONS: Regardless of prior biologic exposure, secukinumab was efficacious in improving the signs and symptoms of HS. This finding positions secukinumab as the first option in patients who are biologic-naïve, as well as in patients who have previously been treated with other biologic therapy, based on individual patient needs.

Hidradenitis suppurativa (HS) is a chronic skin disease that causes painful boils. HS is common and affects about 0.4% of the world's population. Treating the condition is difficult, but drugs called 'biologics' can help to improve the symptoms. For example, secukinumab is a biologic drug that has been shown to be effective and well-tolerated for the treatment of HS. In this analysis, we investigated whether previous treatment with biologics could affect the effectiveness and tolerability of secukinumab. This analysis included data from two identical clinical trials (called SUNSHINE and SUNRISE) that recruited adult patients with HS who had moderate-to-severe disease. In these trials, patients took secukinumab 300 mg every 2 weeks or every 4 weeks for 1 year, or a placebo for 4 months and then switched to secukinumab until 1 year. At regular intervals, the effectiveness and tolerability of secukinumab were examined and the results were compared between patients who had previously used another biologic and patients who had never used a biologic before. After 16 weeks, patients who took secukinumab had better results than the patients who took a placebo, independent of previous biologic use. Secukinumab was still effective and had improved results over 1 year of treatment in both subgroups. Regardless of whether patients had previously been taking another biologic, secukinumab was just as tolerable as placebo and there were no new safety risks. Our analysis shows that secukinumab is effective and tolerable, regardless of whether patients have previously used another biologic drug.

Deucravacitinib in plaque psoriasis: 2-year safety and efficacy results from the phase III POETYK trials.

BACKGROUND: In the phase III POETYK PSO-1 and PSO-2 trials, deucravacitinib, an oral selective allosteric tyrosine kinase 2 inhibitor, was well tolerated and efficacious over 1 year in patients with psoriasis. OBJECTIVE: To evaluate deucravacitinib safety and efficacy over 2 years in patients participating in the phase III trials. METHODS: In the POETYK long-term extension (LTE), an ongoing phase IIIb open-label trial, adults with moderate-to-severe plaque psoriasis who completed PSO-1 or PSO-2 receive deucravacitinib 6 mg once daily. Safety was assessed via adverse events (AEs) and laboratory parameter abnormalities. Efficacy endpoints, including ≥ 75% reduction from baseline Psoriasis Area and Severity Index score (PASI 75) and static Physician's Global Assessment (sPGA) score of 0/1 (clear/almost clear), were evaluated in patients originally randomized to deucravacitinib, patients who crossed over from placebo at week 16 and patients who achieved PASI 75 at week 24 (peak efficacy). RESULTS: At data cutoff (1 October 2021), 1519 patients had received at least one dose of deucravacitinib; 79.0% and 39.9% had ≥ 52 weeks and ≥ 104 weeks of total deucravacitinib exposure, respectively. Exposure-adjusted incidence rates (EAIRs) per 100 person-years were similar at 1 year and 2 years for any AEs (229.2 vs. 154.4, respectively), serious AEs (5.7 vs. 6.1), discontinuations (4.4 vs. 2.8), deaths (0.2 vs. 0.4), serious infections (1.7 vs. 2.6), herpes zoster (0.9 vs. 0.8), major adverse cardiovascular events (0.3 vs. 0.4), venous thromboembolic events (0.2 vs. 0.1) and malignancies (1.0 vs. 0.9). EAIRs for COVID-19 infections were higher at 2 years than at 1 year (5.1 vs. 0.5) owing to the peak of the global COVID-19 pandemic occurring during the LTE. No clinically meaningful changes from baseline or trends were observed over 2 years in haematological, chemistry or lipid parameters. Clinical responses were maintained in patients who received continuous deu-cravacitinib treatment from baseline [PASI 75: week 52, 72.4%; week 112, 79.7%; sPGA 0/1: week 52, 57.9%; week 112, 61.1% (as observed)]. Responses at week 52 were also maintained in placebo crossovers and in week-24 PASI-75 responders. CONCLUSIONS: Deucravacitinib maintained efficacy and demonstrated consistent safety with no new safety signals observed through 2 years.

Psoriasis is a chronic inflammatory skin condition. Many available treatments for psoriasis are injected, but can be inadequate in terms of effectiveness, and/or cause serious side-effects. Deucravacitinib is a recently approved oral medicine that interferes with an enzyme involved in inflammation called 'tyrosine kinase 2' (TYK2). Deucravacitinib has been shown to improve psoriatic patches and symptoms (such as itching) through 1 year in two global clinical trials in adults with moderate-to-severe plaque psoriasis (POETYK PSO-1 and PSO-2). This study was an analysis of the safety and efficacy of deu­cravacitinib for up to 2 years. To do this, the researchers used data from approximately 1500 people who completed both trials and continued into an ongoing, long-term extension trial (POETYK LTE). Overall, there were no new side-effects, and the number, type and severity of side-effects, as well as the number of patients who stopped treatment because of these side-effects, remained low. The most frequent side-effects included common cold symptoms and COVID-19. Rates of shingles and serious side-effects were comparable to rates reported in the real world. Improvements in psoriasis symptoms seen at 1 year were maintained for up to 2 years in patients receiving deucravacitinib treatment from the start of PSO-1 or PSO-2, or who crossed over from placebo to deucravacitinib at 4 months. Long-term treatment with deucravacitinib improved psoriasis symptoms and resulted in mostly mild side-effects. The study findings suggest that deucravacitinib could be a well-tolerated and effective treatment for people with psoriasis.

A Bayesian network meta-analysis of 14 molecules inhibiting UV daylight-induced pigmentation.

INTRODUCTION: Hyperpigmentation disorders are very frequent, affect the quality of life and may become a psychological burden for afflicted patients. Many anti-pigmenting or depigmenting agents are available with various efficacy and almost no comparative data. 2-mercaptonicotinoyl glycine (2-MNG) was recently proposed as a viable candidate showing safe and effective results on hyperpigmentation control in vitro and in vivo. OBJECTIVES: A Bayesian network meta-analysis (BNMA) was conducted to map and rank the anti-pigmenting and depigmenting efficacy of 2-MNG 0.5% on UV daylight (UVDL)-induced pigmentation together with 13 other reference molecules. A comparison in the kinetics of 2-MNG 0.5% was also performed. METHODOLOGY: Fourteen studies were conducted, for each, on 15-30 women of skin phototype III in Shanghai, China and Paris, France. The products were applied on mini zone, in randomized and blinded protocol, on the back, 5 days a week during 6 weeks, at a dose of 4 mg/cm2. During the second week, volunteers were exposed under to varying minimum erythemal dose of UVDL during 4 consecutive days-adapted to obtain a similar induction of skin pigmentation regardless of the population. Assessments were performed instrumentally using Chromameter®. Ascorbic acid 7% was used as a positive control for all experiments. A Bayesian network meta-analysis was then established to map and follow the kinetics of 2-MNG 0.5% performance with 13 reference molecules (glutathione 2%, kojic acid 1%, hydroquinone 4%, ascorbyl glucoside 2%, niacinamide 4%, etc.). RESULTS: 2-MNG 0.5% dominated the ranking at all time points with a significant high probability of strong efficacy against UVDL-induced pigmentation. Ascorbic acid 7% ranks second after 4 days of irradiations (D12) whereas hydroquinone 4% ranks second 1 month after irradiations (D40). In the kinetics, 2-MNG at 0.5% was effective as from the end of irradiations (D12) to the study endpoint (D40). This suggested an immediate and persistent efficacy across all timepoints evaluated. CONCLUSION: The BNMA revealed a rapid and lasting efficacy of 2-MNG 0.5% on the anti-pigmenting and depigmenting phases of the clinical protocol. 2-MNG 0.5% ranked first, with immediate and lasting effect compared to 13 other references. This study is the first allowing comparison between reference anti-pigmenting and depigmenting agents and will help clinicians for proposing the most effective approach for their patients.

Photoprotection for people with skin of colour: needs and strategies.

Skin of colour or pigmented skin has unique characteristics: it has a higher eumelanin-to-pheomelanin ratio, more mature melanosomes, an increased amount of melanin distributed in the upper layers of the epidermis, and more efficient DNA repair compared with lighter skin. However, individuals with skin of colour are at a significant risk of skin damage caused by ultraviolet radiation, including the development of photodermatoses and photoageing changes such as uneven skin tone, and are predisposed to pigmentary disorders. In fact, one of the most common conditions leading to dermatology consultations by patients with skin of colour is photoexacerbated pigmentary disorders. Unfortunately, individuals with skin of colour may be less prone to engage in photoprotective measures, including the use of sunscreens. Physicians are also less likely to prescribe sunscreens for them. There is thus a clear need for better education on photodamage and for more efficient and suitable photoprotection in populations with skin of colour. However, this need has thus far only partially been met, and the development of sunscreen products designed to provide optimal photoprotection for people with skin of colour remains a challenge. Targeted sunscreens for individuals with skin of colour require optimal cosmetic appeal (leaving no white residue and not disrupting skin tone). They should include broad-spectrum [ultraviolet (UV)B/UVA] protection with high sun protection factor, as well as protection against long-wave UVA (UVA1) and visible light, as these wavelengths are capable of inducing or augmenting pigmentary disorders. They may also contain depigmenting agents for patients with pigmentary disorders.

Impact of house dust mite in vitiligo skin: environmental contribution to increased cutaneous immunity and melanocyte detachment.

BACKGROUND: Vitiligo is an autoimmune skin disorder characterized by loss of melanocytes. Protease-mediated disruption of junctions between keratinocytes and/or keratinocyte intrinsic dysfunction may directly contribute to melanocyte loss. House dust mite (HDM), an environmental allergen with potent protease activity, contributes to respiratory and gut disease but also to atopic dermatitis and rosacea. OBJECTIVES: To verify if HDM can contribute to melanocyte detachment in vitiligo and if so, by which mechanism(s). METHODS: Using primary human keratinocytes, human skin biopsies from healthy donors and patients with vitiligo, and 3D reconstructed human epidermis, we studied the effect of HDM on cutaneous immunity, tight and adherent junction expression and melanocyte detachment. RESULTS: HDM increased keratinocyte production of vitiligo-associated cytokines and chemokines and increased expression of toll-like receptor (TLR)-4. This was associated with increased in situ matrix-metalloproteinase (MMP)-9 activity, reduced cutaneous expression of adherent protein E-cadherin, increased soluble E-cadherin in culture supernatant and significantly increased number of suprabasal melanocytes in the skin. This effect was dose-dependent and driven by cysteine protease Der p1 and MMP-9. Selective MMP-9 inhibitor, Ab142180, restored E-cadherin expression and inhibited HDM-induced melanocyte detachment. Keratinocytes from patients with vitiligo were more sensitive to HDM-induced changes than healthy keratinocytes. All results were confirmed in a 3D model of healthy skin and in human skin biopsies. CONCLUSIONS: Our results highlight that environmental mite may act as an external source of pathogen-associated molecular pattern molecules in vitiligo and topical MMP-9 inhibitors may be useful therapeutic targets. Whether HDM contributes to the onset of flares in vitiligo remains to be tested in carefully controlled trials.

Integrated safety analysis of baricitinib in adults with severe alopecia areata from two randomized clinical trials.

BACKGROUND: Baricitinib, an oral, selective, reversible Janus kinase (JAK)1/JAK2 inhibitor, is an approved treatment for adults with severe alopecia areata (AA) in the USA, European Union and Japan. OBJECTIVES: To report safety data for baricitinib in patients with severe AA from two clinical trials including long-term extension periods. METHODS: This analysis includes pooled patient-level safety data from two trials, an adaptive phase II/III trial (BRAVE-AA1) and a phase III trial (BRAVE-AA2) (ClinicalTrials.gov, NCT03570749 and NCT03899259). Data are reported in three datasets: (i) the placebo-controlled dataset (up to week 36): baricitinib 2 mg and 4 mg vs. placebo; (ii) the extended dataset (up to the data cutoff): patients remaining on continuous treatment with baricitinib 2 mg or 4 mg from baseline; and (iii) the all-baricitinib dataset (all-BARI, up to the data cutoff): all patients receiving any dose of baricitinib at any time during the trials. Safety outcomes include treatment-emergent adverse events (TEAEs), adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates (IR) were calculated. RESULTS: Data were collected for 1303 patients who were given baricitinib, reflecting 1868 patient-years of exposure (median 532 days). The most frequently reported TEAEs during the placebo-controlled period (based on the baricitinib 4-mg group) were upper respiratory tract infection, nasopharyngitis, headache, acne and elevated blood creatine phosphokinase (CPK). During the placebo-controlled period, the frequency of acne was higher with baricitinib than placebo, and elevated CPK was higher with baricitinib 4 mg than placebo and baricitinib 2 mg. In all-BARI, the IR of serious infections was low (n = 16, IR 0.8). There was one opportunistic infection (IR 0.1), and 34 cases of herpes zoster (IR 1.8). There was one positively adjudicated major adverse cardiovascular event (myocardial infarction) (IR 0.1), one pulmonary embolism (IR 0.1), three malignancies other than nonmelanoma skin cancer (IR 0.2) and one gastrointestinal perforation (IR 0.1). No deaths were reported. CONCLUSIONS: This integrated safety analysis in patients with severe AA is consistent with the overall safety profile of baricitinib. Some differences with atopic dermatitis were noted that may be attributable to the disease characteristics of AA.

Reliability and agreement testing of a new automated measurement method to determine facial vitiligo extent using standardized ultraviolet images and a dedicated algorithm.

BACKGROUND: Facial repigmentation is the primary outcome measure for most vitiligo trials. The Facial Vitiligo Area Scoring Index (F-VASI) score is often chosen as the primary outcome measure to assess the efficacy of treatments for facial vitiligo. Although useful, this scoring system remains subjective and has several limitations. OBJECTIVES: To assess the agreement and reliability of an algorithmic method to measure the percentage depigmentation of vitiligo on the face. METHODS: We developed a dedicated algorithm called Vitil-IA® to assess depigmentation on standardized facial ultraviolet (UV) pictures. We then conducted a cross-sectional study using the framework of the ERASE trial (NCT04843059) in 22 consecutive patients attending a tertiary care centre for vitiligo. Depigmentation was analysed before any treatment and, for 7 of them, after 3 and 6 months of narrowband UVB treatment combined with 16 mg methylprednisolone, both used twice weekly. Interoperator and interacquisition repeatability measures were assessed for the algorithm. The results of the algorithmic measurement were then compared with the F-VASI and the percentage of depigmented skin scores assessed by 13 raters, including 7 experts in the grading of vitiligo lesions. RESULTS: Thirty-one sets of pictures were analysed with the algorithmic method. Internal validation showed excellent reproducibility, with a variation of < 3%. The percentage of depigmentation assessed by the system showed high agreement with the percentage of depigmentation assessed by raters [mean error (ME) -11.94 and mean absolute error (MAE) 12.71 for the nonexpert group; ME 0.43 and MAE 5.57 for the expert group]. The intraclass correlation coefficient (ICC) for F-VASI was 0.45 [95% confidence interval (CI) 0.29-0.62] and 0.52 (95% CI 0.37-0.68) for nonexperts and experts, respectively. When the results were analysed separately for homogeneous and heterogeneous depigmentation, the ICC for homogeneous depigmentation was 0.47 (95% CI 0.31-0.77) and 0.85 (95% CI 0.72-0.94) for nonexperts and experts, respectively. When grading heterogeneous depigmentation, the ICC was 0.19 (95% CI 0.05-0.43) and 0.38 (95% CI 0.20-0.62) for nonexperts and experts, respectively. CONCLUSIONS: We demonstrated that the Vitil-IA algorithm provides a reliable assessment of facial involvement in vitiligo. The study underlines the limitations of the F-VASI score when performed by nonexperts for homogeneous vitiligo depigmentation, and in all raters when depigmentation is heterogeneous.

Outdoor clinical testing with reference sunscreens to determine differences in skin response between populations of different ethnicity: A combined data analysis from 128 subjects.

BACKGROUND: Two previously published clinical studies by our group assessed erythema and pigmentation responses in outdoor conditions with three reference sunscreens, comparing their effectiveness under the full spectrum of natural sunlight. These studies followed an almost identical protocol but were conducted in two different locations and in two ethnic groups: broadly, Chinese (Singapore) and White European (Mauritius). We analysed the data from these two study populations to compare differences in skin response according to ethnicity. METHODS: The analysis included 128 subjects (53 were Chinese from Singapore and 75 were White European from Mauritius and Singapore). Products used were the reference sunscreens P3 (sun protection factor [SPF] 15), P5 (SPF 30) and P8 (SPF 50+) from ISO norm 24444:2019. Participants were exposed to outdoor sunlight for 2-3 h, depending on baseline ITA. Endpoints were erythema at 24 h: clinical score and colorimetry (Δa*) and pigmentation at 1 week based on colorimetry (ΔL* and ΔITA). RESULTS: Among those with baseline ITA > 41, there were differences in erythemal response between the Chinese and White European groups, the White European group being more erythematous and also having a higher rate of photoprotection failure particularly at SPFs 15 and 30. CONCLUSION: Differences in skin response to sun influenced by ethnicity should be taken into account when making recommendations on sun safety.

Evaluation of adapted dermocosmetic regimens for perimenopausal and menopausal women using an artificial intelligence-based algorithm and quality of life questionnaires: An open observational study.

BACKGROUND: The decline in estrogen levels from several years before (perimenopause) and during menopause has various negative effects, including skin specific issues, which often receive less attention than other menopausal symptoms despite having a significant negative effect on quality of life (QoL). The objective of this study was to evaluate the effectiveness of anti-aging dermocosmetic products designed for women during the perimenopause and menopause. MATERIALS AND METHODS: An open study of 101 perimenopausal women (no menstruation for 4-12 months or irregular menstruation for <5 years) and 101 menopausal women (no menstruation for >12 months), not taking hormone replacement therapy, was conducted. Adapted dermocosmetic regimens, specific to each group (day cream, night cream and serum), were applied for 56 days. Assessments included automatic artificial intelligence diagnostics of eight clinical facial signs, hydration and transepidermal water loss (TEWL), and a menopause skin QoL questionnaire. RESULTS: Mean age was 50 ± 3.9 years (range 41-57) and 59 ± 3.8 years (range 50-66) for the perimenopause and menopause groups, respectively. Significant improvements in wrinkles and vascular signs, increases in hydration, decreases in TEWL, and a positive impact on QoL were observed after 56 days of application of the respective dermocosmetic regimens for both the perimenopause and menopause groups. CONCLUSION: The anti-aging skin care products designed specifically for perimenopausal and menopausal women increased skin hydration and improved wrinkles with a positive impact on QoL.

Objective and automatic grading system of facial signs from smartphones' pictures in South African men: Validation versus dermatologists and characterization of changes with age.

OBJECTIVE: To evaluate the capacity of the automatic detection system to accurately grade, from selfie pictures, the severity of eight facial signs in South African men. METHODS: Selfie pictures (obtained from frontal and back cameras) of 281 South African men differently aged (20-70 years) were obtained and analyzed by an automatic artificial intelligence (AI)-based automatic grading system. Data were compared with the clinical gradings made by experts and dermatologists. RESULTS: In all facial signs, both series of gradings were found highly correlated with, however, different coefficients (0.59-0.95), those of marionette lines and cheek pores being of lower values. No differences were observed between data obtained by frontal and back cameras. With age, in most cases, gradings show up to the 50-59 year age-class, linear-like changes. When compared to men of other ancestries, South African men present lower wrinkles/texture, pigmentation, and ptosis/sagging scores till 50-59 years, albeit not much different in the cheek pores sign. The early onset (mean age) of visibility of wrinkles/texture for South African men were (i.e., reaching grade >1) 39 and 45 years for ptosis/sagging. CONCLUSION: This study completes and enlarges the previous works conducted on men of other ancestries by showing some South African specificities and slight differences with men of comparable phototypes (Afro American).

Hidradenitis suppurativa and social disadvantage: A nationwide administrative data study of the French hospitalized population.

BACKGROUND: A lower socioeconomical status (SES) has been reported in patients suffering from hidradenitis suppurative (HS). However, limitations in the available studies prevent drawing definitive conclusions. OBJECTIVES: The objective of this study was to assess the SES of HS patients using a specific SES indicator, the French DEPrivation index (FDep), specifically designed and validated for the French population. METHODS: This cross-sectional cohort study compared the HS hospitalized population with the general hospitalized population without HS. Data were extracted from the French national hospital discharge database, an exhaustive database on all reimbursed hospital stay in the country with a rolling 10-year history (2012-2021). We included all patients aged 7-75 years with at least one stay in a French hospital. A 1:40 propensity score matching, adjusted for age, sex, smoking status and obesity, was performed to create 2 groups of comparable patients. Subgroup analysis was done in the minor (7-17 years) and major (25-75 years) populations independently. RESULTS: In the overall population, we identified 33,880 patients with HS and 24,445,337 patients without HS. After propensity score matching, logistic regression showed a significant association between HS and social disadvantage. There is a 22.5% increased risk of developing HS for individuals being in quintile 5 (the most disadvantaged quintile) versus quintile 1 (the least disadvantaged quintile) (p < 0.0001). After propensity score matching, the logistic regression showed no association between HS and social disadvantage in the 7-17 subgroup. In this minor population, an association between HS and social disadvantage was observed when propensity score matching was performed on age and sex only. CONCLUSIONS: We demonstrate a significant association between HS and low SES in the adult population. In children between 7 and 17, low SES was associated with obesity and tobacco consumption, but not with HS when the populations were matched on these confounding factors.

Efficacy and safety of a novel triple combination cream compared to Kligman's trio for melasma: A 24-week double-blind prospective randomized controlled trial.

BACKGROUND: Kligman's trio (KT), combining hydroquinone, retinoic acid and corticosteroid, is considered as the gold standard treatment of melasma. Its efficacy has never been matched before, but it is tempered by frequent adverse effects. OBJECTIVE: To assess the efficacy and tolerance of a New Trio (NT) combination with isobutylamido-thiazolyl-resorcinol, retinoic acid and cortosteroid compared to KT. METHODS: We conducted a 24-week monocentric trial, randomized, double-blind, controlled versus KT, with 40 melasma patients. NT and KT were applied for 12 weeks and associated with the same sunscreen applied for 24 weeks. The primary endpoint was the modified Melasma Area Severity Index (mMASI) at 12 weeks. Patient quality of life was investigated using MelasQoL. RESULTS: After 12 weeks, KT and NT groups both demonstrated a significant improvement in mMASI, respectively -2.84 (SE 0.69, p < 0.0002) and -4.33 (SE 0.71, p < 0.0001). The mean difference between the two groups was -1.49 (IC 95% -3.52 to 0.54, p = 0.14). MelasQoL improvement was -6.66 (SE 3.29, p = 0.0515) with KT and -12.57 (SE 3.29, p = 0.0006) with NT. CONCLUSION: The NT combination appears to be an effective treatment option for treating melasma and could be considered as a well-tolerated alternative to KT.

Vitiligo patient population and disease burden in France: VIOLIN study results from the CONSTANCES cohort.

BACKGROUND: Vitiligo is a chronic autoimmune disease resulting in skin depigmentation. OBJECTIVES: This study assessed the prevalence, disease burden and treatment of vitiligo in France. METHODS: VIOLIN was a cross-sectional study nested in the national CONSTANCES cohort, which consists of randomly selected adults aged 18-69 years in France. In VIOLIN, longitudinal data were collected prospectively from 158,898 participants during 2012-2018 and linked to the National Health Data System (SNDS), a healthcare utilization database. Patients with physician-diagnosed vitiligo were matched (1:3) with control participants based on age, sex, geographic region, year of inclusion and skin phototype. Patients completed a questionnaire in 2022 to collect disease characteristics, disease burden and quality-of-life (QoL) data. RESULTS: Vitiligo prevalence was 0.71% (681/95,597) in 2018. The mean age in the vitiligo population was 51.2 years; 51.4% were women. Most patients (63%) were diagnosed before age 30 years, mainly by dermatologists (83.5%). Most patients (81.1%) had visible lesions (i.e. on face, hands). Vitiligo was limited to <10% of the body surface area (BSA) in 85.8% of patients. Comorbidities including thyroid disease (18.0% vs. 9.0%), psoriasis (13.7% vs. 9.7%), atopic dermatitis (12.4% vs. 10.3%), depression (18.2% vs. 14.6%) and alopecia areata (4.3% vs. 2.4%) were significantly more common in patients with vitiligo versus matched controls (n = 2043). QoL was significantly impaired in patients with >5% BSA involvement or visible lesions, particularly with ≥10% facial involvement. Vitiligo-specific instruments (i.e. Vitiligo Impact Patient scale and Vitiligo-specific QoL instrument) were more sensitive to QoL differences among subgroups versus general skin instruments, and generic instruments were least sensitive. Most patients (83.8%) did not receive any prescribed treatment. CONCLUSIONS: Patients with vitiligo in France have a high disease burden, particularly those with visible lesions or higher BSA involvement. Most patients are not receiving treatment, highlighting the need for new effective treatments and patient/physician education.

Accuracy and clinical relevance of an automated, algorithm-based analysis of facial signs from selfie images of women in the United States of various ages, ancestries and phototypes: A cross-sectional observational study.

BACKGROUND: Real-life validation is necessary to ensure our artificial intelligence (AI) skin diagnostic tool is inclusive across a diverse and representative US population of various ages, ancestries and skin phototypes. OBJECTIVES: To explore the relevance and accuracy of an automated, algorithm-based analysis of facial signs in representative women of different ancestries, ages and phototypes, living in the same country. METHODS: In a cross-sectional study of selfie images of 1041 US women, algorithm-based analyses of seven facial signs were automatically graded by an AI-based algorithm and by 50 US dermatologists of various profiles (age, gender, ancestry, geographical location). For automated analysis and dermatologist assessment, the same referential skin atlas was used to standardize the grading scales. The average values and their variability were compared with respect to age, ancestry and phototype. RESULTS: For five signs, the grading obtained by the automated system were strongly correlated with dermatologists' assessments (r ≥ 0.75); cheek skin pores were moderately correlated (r = 0.63) and pigmentation signs, especially for the darkest skin tones, were weakly correlated (r = 0.40) to the dermatologist assessments. Age and ancestry had no effect on the correlations. In many cases, the automated system performed better than the dermatologist-assessed clinical grading due to 0.3-0.5 grading unit differences among the dermatologist panel that were not related to any individual characteristic (e.g. gender, age, ancestry, location). The use of phototypes, as discontinuous categorical variables, is likely a limiting factor in the assessments of grading, whether obtained by automated analysis or clinical assessment of the images. CONCLUSIONS: The AI-based automatic procedure is accurate and clinically relevant for analysing facial signs in a diverse and inclusive population of US women, as confirmed by a diverse panel of dermatologists, although skin tone requires further improvement.

Guselkumab for the treatment of patients with moderate-to-severe hidradenitis suppurativa: A phase 2 randomized study.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that causes substantial physical, emotional and psychological burdens. Guselkumab, a monoclonal antibody that binds to the p19 subunit of interleukin-23, has demonstrated high levels of efficacy in the treatment of inflammatory diseases, including psoriasis and psoriatic arthritis. OBJECTIVE: To evaluate the effect of guselkumab on the treatment of HS, a phase 2, multicentre, randomized, placebo-controlled, double-blind, proof-of-concept study was conducted. METHODS: Patients ≥18 years of age with moderate-to-severe HS for ≥1 year were randomized to (1) guselkumab 200 mg by subcutaneous (SC) injection every 4 weeks (q4w) through Week 36 (guselkumab SC); (2) guselkumab 1200 mg intravenously (IV) q4w for 12 weeks, then switched to guselkumab 200 mg SC q4w from Weeks 12 through 36 (guselkumab IV); or (3) placebo for 12 weeks, with re-randomization to guselkumab 200 mg SC q4w at Weeks 16 through 36 (placebo → guselkumab 200 mg) or guselkumab 100 mg SC at Weeks 16, 20, 28 and 36 and placebo at Weeks 24 and 32 (placebo → guselkumab 100 mg). End points included HS clinical response (HiSCR) and patient-reported outcomes. RESULTS: Although guselkumab SC or guselkumab IV resulted in numerically higher HiSCR versus placebo at Week 16 (50.8%, 45.0%, 38.7%, respectively), statistical significance was not achieved. Numerically greater improvements in patient-reported outcomes were also observed for guselkumab SC and guselkumab IV versus placebo at Week 16. Through Week 40, no clear differences to suggest a dose response were observed for HiSCR and patient-reported outcomes. CONCLUSIONS: Despite modest improvements, the primary end point was not met and the overall findings do not support the efficacy of guselkumab in the treatment of HS. CLINICALTRIALS: gov: NCT03628924.

Sun exposure behaviours as a compromise to paradoxical injunctions: Insight from a worldwide survey.

BACKGROUND: Behavioural interventions can improve attitudes towards sun protection but the impact remains inconsistent worldwide. OBJECTIVE: To assess awareness of and attitudes towards the multiple facets of sun exposure and suggest ways to improve prevention from overexposure to the sun in all geographical zones and multiple skin types. METHODS: Online survey was conducted from 28 September to 18 October 2021. Study population was selected from the Ipsos online Panel (3,540,000 panellists), aged ≥18 years, from 17 countries around the five continents. Demographics, sun-exposure habits and practices, understanding of risks and information on phototypes were documented and analysed using descriptive statistics. RESULTS: Eighty-eight per cent of participants knew that sunlight can cause skin health problems (90% phototypes I-II, 82% phototypes V-VI, >90% in American and European countries, 72% in Asia and 85% in Africa). Eighty-five per cent used some form of protection against sunlight, predominantly: Seeking shade (77%), avoiding the midday sun (66%), facial application of sunscreen (60%) and wearing protective clothing (44%). The perception of sunlight itself is positive ('it gives energy' for 82%; 'tanned skin looks attractive' for 72%), although less in Asian countries and among individuals with dark skin phototypes. Eighty-three per cent reported having experienced sunburn, mainly in Australia, Canada, USA, Germany, France and Russia, and among individuals with dark skin phototypes. Only 12% systematically/often used all types of protection during exposure to the sun and 23% believed it is safe to go out in the sun with no protection when their skin is already tanned. From 13% (skin phototype I) to 26% (phototype VI) reported not using any form of protection against the sun. Knowledge and habits were significantly superior among people who are accustomed to seeing a dermatologist for a complete skin exam. CONCLUSIONS: Dermatologists could play a crucial role in relaying novel prevention messages, more finely tailored to specific risks, populations and areas of the world.

Worldwide expert recommendations for the diagnosis and management of vitiligo: Position statement from the international Vitiligo Task Force-Part 2: Specific treatment recommendations.

BACKGROUND: The treatment of vitiligo can be challenging. Up-to-date agreed consensus recommendations on the use of topical and systemic therapies to facilitate the clinical management of vitiligo are currently lacking. OBJECTIVES: To develop internationally agreed-upon expert-based recommendations for the treatment of vitiligo. METHODS: In this consensus statement, a consortium of 42 international vitiligo experts and four patient representatives participated in different online and live meetings to develop a consensus management strategy for vitiligo. At least two vitiligo experts summarized the evidence for different topics included in the algorithms. A survey was then given to a core group of eight experts to resolve the remaining issues. Subsequently, the recommendations were finalized and validated based on further input from the entire group during two live meetings. RESULTS: The recommendations provided summarize the latest evidence regarding the use of topical therapies (steroids, calcineurin inhibitors and Jak-inhibitors) and systemic therapies, including steroids and other systemic immunomodulating or antioxidant agents. The different modalities of phototherapies (NB-UVB, photochemotherapy, excimer devices and home phototherapy), which are often combined with other therapies, are also summarized. Interventional approaches as well as depigmentation strategies are presented for specific indications. Finally, the status of innovative and targeted therapies under development is discussed. CONCLUSIONS: This international consensus statement culminated in expert-based clinical practice recommendations for the treatment of vitiligo. The development of new therapies is ongoing in vitiligo, and this will likely improve the future management of vitiligo, a disease that still has many unmet needs.