Tapinarof for psoriasis and atopic dermatitis: 15 years of clinical research.

Tapinarof is a topical, aryl-hydrocarbon receptor agonist that has recently received FDA-approval for the treatment of psoriasis. This novel therapeutic has also been shown to be effective for atopic dermatitis and is currently in phase 3 for this indication. Beyond good efficacy and fast onset of action in patients with psoriasis, the clinical response to tapinarof is notable for durable remission or near remission, maintained for an average of 130 days beyond treatment discontinuation in patients with psoriasis in phase 3 studies. Tapinarof is usually well tolerated but can induce a follicular inflammatory reaction and dermatitis in some patients. This narrative review covers the historical development of this molecule, safety and efficacy data from clinical trials conducted with various topical formulations, and practical considerations derived from our 15 years of clinical trial experience with the drug.

Position statement for a pragmatic approach to immunotherapeutics in patients with inflammatory skin diseases during the coronavirus disease 2019 pandemic and beyond.

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, a novel RNA virus that was declared a global pandemic on 11 March 2020. The efficiency of infection with SARS-CoV-2 is reflected by its rapid global spread. The SARS-CoV-2 pandemic has implications for patients with inflammatory skin diseases on systemic immunotherapy who may be at increased risk of infection or more severe infection. This position paper is a focused examination of current evidence considering the mechanisms of action of immunotherapeutic drugs in relation to immune response to SARS-CoV-2. We aim to provide practical guidance for dermatologists managing patients with inflammatory skin conditions on systemic therapies during the current pandemic and beyond. Considering the limited and rapidly evolving evidence, mechanisms of action of therapies, and current knowledge of SARS-CoV-2 infection, we propose that systemic immunotherapy can be continued, with special considerations for at risk patients or those presenting with symptoms.

Impact of baricitinib in combination with topical steroids on atopic dermatitis symptoms, quality of life and functioning in adult patients with moderate-to-severe atopic dermatitis from the BREEZE-AD7 Phase 3 randomized trial.

BACKGROUND: Baricitinib is an oral, selective, reversible Janus kinase 1/2 inhibitor approved in the European Union and Japan and under investigation in the United States for treatment of atopic dermatitis (AD). OBJECTIVES: To evaluate the impact of baricitinib plus background topical corticosteroids (TCS) on health-related quality of life (HRQoL), how AD symptoms impact work productivity and life functioning, and treatment benefit using patient-reported outcome (PRO) assessments in patients with moderate-to-severe AD previously experiencing inadequate response to TCS. METHODS: Adult patients with AD in BREEZE-AD7, a Phase 3, multicentre, double-blind trial, were randomised 1 : 1 : 1 to daily oral placebo (control) or baricitinib 4- or 2-mg plus TCS. PROs reported Week 1 through Week 16: Dermatology Life Quality Index (DLQI), Work Productivity and Activity Impairment-AD (WPAI-AD); Patient-Reported Outcomes Measurement Information System (PROMIS) Itch and Sleep measures, and Patient Benefit Index (PBI). Data were analysed using logistic regression (categorical) and mixed model repeated measures (continuous). PBI scores were analysed using analysis of variance. RESULTS: A total of 329 patients were randomised. Treatment with baricitinib 4-mg (N = 111) or 2 mg (N = 109) plus TCS led to rapid, statistically significant improvements [vs. TCS plus placebo (N = 109)] in DLQI ≥4-point improvement starting at Week 2 (4-mg plus TCS, P ≤ 0.001; 2-mg plus TCS P ≤ 0.05), change from baseline in WPAI-AD presenteeism at Week 1 (4-mg plus TCS, P ≤ 0.01; 2-mg plus TCS P ≤ 0.05) and PROMIS itch interference at Week 2 (4-mg plus TCS P ≤ 0.01). Improvements were sustained through Week 16 for baricitinib 4-mg. Statistically significant improvements were observed at Week 16 for PBI global score (4-mg plus TCS, P ≤ 0.001; 2-mg plus TCS P ≤ 0.05). CONCLUSIONS: Baricitinib plus TCS vs. placebo plus TCS showed significant improvements in treatment benefit at Week 16 and rapid significant improvements in HRQoL and impact of AD symptoms on work productivity and functioning through 16 weeks.

An indirect comparison of long-term efficacy of every-2-week dosing vs. recommended dosing of ixekizumab in patients who had static Physician's Global Assessment > 1 at week 12.

BACKGROUND: Long-term efficacy and safety of ixekizumab [160 mg at week 0, then 80 mg every 2 weeks (Q2W) for 12 weeks, followed by every 4 weeks (Q4W) thereafter (i.e. Q2W/Q4W), which is the labelled psoriasis dosing where approved, except in Japan] have been established for the treatment of adults with moderate-to-severe plaque psoriasis. However, some patients may benefit from remaining on Q2W dosing beyond 12 weeks. METHODS: Among patients who had static Physician's Global Assessment (sPGA) > 1 at week 12, efficacy through week 52 of continuous Q2W dosing in the IXORA-P study was compared indirectly with Q2W/Q4W in the integrated data from the UNCOVER-1, UNCOVER-2 and UNCOVER-3 studies. The continuous Q4W dose group, which had comparable results across studies, was used as the common comparator. RESULTS: In the IXORA-P study, among patients with sPGA > 1 at week 12, 64% of patients in the continuous Q2W group achieved sPGA ≤ 1 at week 52, which was statistically significantly higher than the 36% of patients with sPGA > 1 in the Q2W/Q4W group based on the integrated data from the UNCOVER studies (P = 0·0007). There were no clinically meaningful differences in frequencies of safety events between patients with sPGA ≤ 1 and patients with sPGA > 1 at week 12 in the IXORA-P study. CONCLUSIONS: Among patients who did not have clear or almost clear skin at week 12, nearly 30% more patients who were treated continuously with ixekizumab Q2W in IXORA-P had clear or almost clear skin at week 52 when compared indirectly with those who were treated using the labelled psoriasis dosing in integrated UNCOVER studies. What's already known about this topic? Most patients with moderate-to-severe psoriasis who were given the labelled psoriasis dosing of ixekizumab [160-mg loading dose at week 0, 80 mg every 2 weeks (Q2W) through week 12, and 80 mg every 4 weeks (QW4) thereafter] respond quickly with a high percentage of skin clearance. Additionally, patients who achieve static Physician's Global Assessment (sPGA) ≤ 1 by week 12 tend to maintain this response, even after switching to Q4W. What does this study add? Here, we assessed whether patients with sPGA > 1 at week 12 benefited from receiving more frequent dosing beyond the first 12 weeks. The results showed that Q2W dosing beyond 12 weeks resulted in more patients achieving sPGA ≤ 1 by week 52 than the labelled psoriasis dosing among patients with sPGA > 1 at week 12.

A head-to-head comparison of ixekizumab vs. guselkumab in patients with moderate-to-severe plaque psoriasis: 12-week efficacy, safety and speed of response from a randomized, double-blinded trial.

BACKGROUND: Patients with psoriasis value rapid and complete skin clearance. No head-to-head studies have focused on early responses to interleukin (IL)-17 vs. IL-23 inhibitors. OBJECTIVES: To compare early and complete skin clearance by the IL-17A inhibitor ixekizumab vs. the IL-23p19 inhibitor guselkumab. METHODS: IXORA-R, a 24-week, randomized, double-blinded study, enrolled adults with moderate-to-severe plaque psoriasis [static Physician's Global Assessment of Disease (sPGA) score of ≥ 3, Psoriasis Area and Severity Index (PASI) ≥ 12, and ≥ 10% body surface area]. Patients were randomized (1 : 1) to receive the approved dose of subcutaneous ixekizumab or guselkumab. Primary end point was 100% improvement in PASI (PASI 100) at week 12. Major secondary end points included other levels of improved PASI and sPGA at different time points. Comparisons were made using the Cochran-Mantel-Haenszel test with a multiple testing strategy. Nonresponder imputation was used for missing data. After the completion of the study, the final secondary end point (PASI 100 at 24 weeks) and safety data through week 24 will be reported. RESULTS: In total, 1027 patients were randomized. The primary end point PASI 100 at week 12 was met [215/520 ixekizumab (41%); 126/507 guselkumab (25%); P < 0·001]. All major secondary end points measured up to week 12 were met, including PASI 50 at week 1 and PASI 75 at week 2. Serious adverse event frequency was 3% for each group; no new safety signals were identified. CONCLUSIONS: Ixekizumab was superior to guselkumab for rapidly improving signs and symptoms in patients with moderate-to-severe plaque psoriasis by week 12. Adverse events were similar to previous ixekizumab and guselkumab studies. Compared with the IL-23 inhibitor guselkumab, ixekizumab can offer complete skin clearance more rapidly to patients with moderate-to-severe plaque psoriasis. What's already known about this topic? Patients with plaque psoriasis desire both high levels of clearance and rapid onset of treatment effects. Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin (IL)-17A, has demonstrated greater and faster skin clearance than etanercept and ustekinumab, with consistent long-term efficacy, safety and durability of response. Clinical trial data and systematic reviews have suggested that IL-17 inhibitors can improve a patient's psoriasis more rapidly than IL-23 inhibitors. What does this study add? The head-to-head study design directly compares the efficacy and speed of response of ixekizumab and the IL-23 inhibitor guselkumab in moderate-to-severe plaque psoriasis. The primary end point was met, showing superiority of ixekizumab over guselkumab for achieving complete skin clearance at week 12. The safety profile of ixekizumab was consistent with previous studies. Ixekizumab can deliver patients complete skin clearance and improved quality of life more rapidly than guselkumab.

Efficacy and safety of mirikizumab (LY3074828) in the treatment of moderate-to-severe plaque psoriasis: results from a randomized phase II study.

BACKGROUND: Inhibiting interleukin (IL)-23 in patients with psoriasis has demonstrated high levels of skin clearance. OBJECTIVES: To investigate, in a phase II (AMAF; NCT02899988), multicentre, double-blind trial, the efficacy and safety of three doses of mirikizumab (LY3074828), a p19-directed IL-23 antibody, vs. placebo in patients with moderate-to-severe plaque psoriasis. METHODS: Adult patients were randomized 1 : 1 : 1 : 1 to receive placebo (n = 52), mirikizumab 30 mg (n = 51), mirikizumab 100 mg (n = 51) or mirikizumab 300 mg (n = 51) subcutaneously at weeks 0 and 8. The primary objective was to evaluate the superiority of mirikizumab over placebo in achieving a 90% improvement in the Psoriasis Area and Severity Index (PASI 90) response at week 16. Comparisons were done using logistic regression analysis with treatment, geographical region and previous biological therapy in the model. Missing data were imputed as nonresponses. RESULTS: Ninety-seven per cent of patients completed the first 16 weeks of the study. The primary end point was met for all mirikizumab dose groups vs. placebo, with PASI 90 response rates at week 16 of 0%, 29% (P = 0·009), 59% (P < 0·001) and 67% (P < 0·001) for patients receiving placebo, and mirikizumab 30 mg, 100 mg and 300 mg, respectively. There were two (1%) serious adverse events in mirikizumab-treated patients vs. one (2%) in a placebo-group patient. CONCLUSIONS: At week 16, 67% of patients treated with mirikizumab 300 mg at 8-week intervals achieved PASI 90. The percentage of patients reporting at least one treatment-emergent adverse event was similar among patients treated with placebo or mirikizumab.

The oral Janus kinase/spleen tyrosine kinase inhibitor ASN002 demonstrates efficacy and improves associated systemic inflammation in patients with moderate-to-severe atopic dermatitis: results from a randomized double-blind placebo-controlled study.

BACKGROUND: ASN002 is an oral dual inhibitor of Janus kinase and spleen tyrosine kinase, which are involved in the pathogenesis of atopic dermatitis (AD) through their regulatory role on T helper (Th)1, Th2 and Th17/Th22 pathways. OBJECTIVES: The objectives of this study were to evaluate the efficacy, safety, pharmacokinetics and effects on systemic biomarkers of ASN002 in patients with moderate-to-severe AD. Methods A total of 36 patients with moderate-to-severe AD were randomized (3 : 1) to ASN002 or placebo in the phase Ib study. Three dosage cohorts were studied over a 28-day period (20 mg, 40 mg and 80 mg once daily). RESULTS: ASN002 was superior to placebo for the proportion of patients achieving Eczema Area and Severity Index (EASI) 50 (20 mg 20%, P = 0·93; 40 mg 100%, P = 0·003; 80 mg 83%, P = 0·03; placebo 22%), EASI 75 (20 mg 0%, P = 0·27; 40 mg 71%, P = 0·06; 80 mg 33%, P = 0·65; placebo 22%) and in change from baseline in pruritus (20 mg -1·3 ± 2·1, P = 0·81; 40 mg -3·1 ± 2·7, P = 0·27; 80 mg -4·7 ± 2·1, P = 0·01; placebo -1·6 ± 1·8). Adverse events were generally mild and similar across all groups. ASN002 showed dose-dependent plasma exposure with low interpatient variability, significantly downregulated several serum biomarkers involved in Th1, Th2 and Th17/Th22 immunity, and decreased the atherosclerosis-associated biomarker E selectin/SELE. CONCLUSIONS: In patients with moderate-to-severe AD, ASN002 showed strong efficacy with rapid onset of action and associated improvements in systemic inflammation.

A phase 2a randomized controlled study to evaluate the pharmacokinetic, safety, tolerability and clinical effect of topically applied Umeclidinium in subjects with primary axillary hyperhidrosis.

BACKGROUND: Hyperhidrosis is a common medical condition which can have a significant impact on quality of life. Umeclidinium (UMEC) is a long-acting muscarinic antagonist (LAMA) developed as a dermal formulation. OBJECTIVES: This 2-week, double-blind, randomized, vehicle-controlled study evaluated systemic exposure, safety and tolerability of topically administered UMEC in subjects with primary axillary hyperhidrosis. Clinical effect was a secondary objective, measured by gravimetry and the hyperhidrosis disease severity scale (HDSS). Vehicle was included to evaluate safety. METHODS: Twenty-three subjects were randomized to either 1.85% UMEC (N = 18) or vehicle (N = 5) once daily. RESULTS: Measurable plasma concentrations were observed in 78% of subjects after the treatment. Nine subjects (50%) on UMEC and two subjects (40%) on vehicle reported AEs, most commonly application site reactions. At Day 15, seven subjects (41%) in UMEC and two subjects (40%) in vehicle had at least a 50% reduction in sweat production. Eight subjects (47%) in UMEC and one subject (20%) in vehicle had at least a two-point reduction in HDSS. No comparisons of treatment arms were planned prospectively. CONCLUSIONS: The measurable exposure, acceptable safety and preliminary clinical activity observed in this proof-of-concept study suggest the potential clinical utility of topical UMEC in subjects with axillary hyperhidrosis.

Changes in serum free testosterone, sleep patterns, and 5-alpha-reductase type I activity influence changes in sebum excretion in female subjects.

BACKGROUND/PURPOSE: Sebum is thought to play an important role in acne vulgaris and sebum excretion rate (SER) is often used as a marker of efficacy in acne studies. This study explored factors that could induce intra-subject variability in SER. METHODS: SER was measured twice, 7 days apart, on the forehead of 40 healthy subjects. At each visit, the following parameters were also evaluated: serum androgen levels, 5-alpha-reductase type I gene expression, forehead temperature, sleep habits, diet, facial washing routine, and UV exposure. RESULTS: There was a positive correlation between the time subjects fell asleep on Day 0 and the change in SER for the left (P = 0.010; R = 0.402) and right sides (P = 0.002; R = 0.467) of the forehead. There was a significant inverse correlation between SER and 5-alpha-reductase type 1 expression and between free testosterone levels and 5-alpha-reductase type 1 expression. In sub-analyses performed on men and women, these correlations were only significant for women. CONCLUSION: Variations in sleep patterns, free testosterone, and 5-alpha-reductase type 1 activity are associated with changes in sebum excretion in women. This could explain some of the inter-subject variability in SER measured between visits in clinical studies.

Etanercept for patients with psoriasis who did not respond or who lost their response to adalimumab or infliximab.

BACKGROUND: There is a paucity of data on the use of etanercept in patients who have previously failed a different tumour necrosis factor (TNF) alpha antagonist. OBJECTIVES: To study etanercept in patients who did not achieve a satisfactory response to adalimumab or who lost their response to adalimumab or infliximab and to explore the role of anti-adalimumab and anti-infliximab antibodies in etanercept response. METHODS: Patients with psoriasis who did not achieve a satisfactory response to adalimumab or who lost their response to adalimumab or infliximab were included. All patients received etanercept 50 mg twice a week for 12 weeks followed by 50 mg once a week for 12 more weeks. Anti-infliximab and anti-adalimumab antibodies were measured at baseline. The primary objective was to study the efficacy of etanercept using the proportion of patients who achieved a physician global assessment (PGA) of 0 or 1. RESULTS: A total of 81 patients were included. The proportion of patients who achieved a PGA of 0 or 1 after 24 weeks of etanercept was 20.0% (95% CI 4.8-35.2%) for patients who had an unsatisfactory response to adalimumab, 35.1% (95% CI 19.0-51.3%) and 35.7% (95% CI 7.0-64.4%) for patients who lost their response to adalimumab and infliximab respectively. The proportion of patients who achieved a PGA of 0 or 1 at week 24 was numerically higher for patients who had anti-adalimumab or anti-infliximab antibodies (36.5%) as compared to those without (17.2%; P = 0.08). CONCLUSIONS: Etanercept can be effective in patients with psoriasis who failed a previous TNF alpha antagonist.

Efficacy and safety of topical WBI-1001 in patients with mild to moderate psoriasis: results from a randomized double-blind placebo-controlled, phase II trial.

BACKGROUND: There is a need for the development of novel non-steroidal topical drugs for the treatment of psoriasis. OBJECTIVE: To assess the efficacy and safety of topical 1.0% WBI-1001 in patients with mild to moderate plaque psoriasis. METHODS: A total of 61 patients with 1-10% body surface area (BSA) covered with plaque psoriasis and a physician's global assessment score (PGA) of 2-4 were randomized (2:1) to receive either 1% WBI-1001 in a cream formulation or placebo, applied twice daily for 12 weeks. Efficacy was evaluated using PGA, BSA and Psoriasis Area and Severity Index (PASI). The primary endpoint was the change from baseline (Day 0) in PGA at week 12. RESULTS: The improvement in PGA at week 12 was 62.8% for patients randomized to WBI-1001 when compared with 13.0% for patients randomized to placebo (P<0.0001). At week 12, the proportion of patients who achieved a PGA of clear or almost clear and the mean improvement in BSA were 67.5% and 79.1%, respectively, for patients randomized to WBI-1001, when compared with 4.8% (P<0.0001) and an increase of 9.4% (P<0.0001), respectively, for patients randomized to placebo. More application site adverse drug reactions were observed in patients randomized to WBI-1001 than in those randomized to placebo. These adverse drug reactions were all mild or moderate in intensity. CONCLUSION: Topical WBI-1001 induces rapid and significant improvement in patients with plaque psoriasis.

Kindler syndrome: a focal adhesion genodermatosis.

Kindler syndrome (OMIM 173650) is an autosomal recessive genodermatosis characterized by trauma-induced blistering, poikiloderma, skin atrophy, mucosal inflammation and varying degrees of photosensitivity. Although Kindler syndrome is classified as a subtype of epidermolysis bullosa, it has distinct clinicopathological and molecular abnormalities. The molecular pathology of Kindler syndrome involves loss-of-function mutations in a newly recognized actin cytoskeleton-associated protein, now known as fermitin family homologue 1, encoded by the gene FERMT1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix via focal adhesions, and thus the structural pathology differs from other forms of epidermolysis bullosa in which there is a disruption of the keratin intermediate filament-hemidesmosome network and the extracellular matrix. In the skin, fermitin family homologue 1 is mainly expressed in basal keratinocytes and binds to the cytoplasmic tails of beta1 and beta3 integrins as well as to fermitin family homologue 2 and filamin-binding LIM protein 1. It also plays a crucial role in keratinocyte migration, proliferation and adhesion. In this report, we review the clinical, cellular and molecular pathology of Kindler syndrome and discuss the role of fermitin family homologue 1 in keratinocyte biology.

Etanercept in the treatment of palmoplantar pustulosis.

INTRODUCTION: Palmoplantar pustulosis (PPP) is a chronic, recurrent and difficult to treat skin condition characterized by the presence of pustules, erythema, and hyperkeratosis on palms and soles. METHODS: Fifteen subjects with PPP were randomized (2:1) to receive subcutaneous injections of either etanercept 50 mg or a placebo twice a week for 3 months. All subjects then received the etanercept 50 mg injections twice a week for an additional 3 months. RESULTS: Etanercept was well tolerated by subjects with PPP. The decrease in median Palmoplantar Pustulosis Area and Severity Index (PPPASI) score from baseline to 24 weeks was statistically significant for subjects treated with etanercept for 24 weeks (P = 0.038, n = 10) but not for subjects in the placebo/etanercept cross-over group (P = 0.125, n = 5). Comparison of changes in PPPASI from baseline to week 12 was not statistically significant for subjects assigned to etanercept or to placebo. Some subjects treated with etanercept presented good clinical improvements in PPP severity whereas others showed an increase in PPP severity. CONCLUSION: This study showed that etanercept was well tolerated in subjects with PPP and suggests that some PPP subjects might benefit from etanercept therapy. Larger studies are needed to assess PPP response to etanercept including the influence of smoking and the presence or absence of psoriasis outside palms and soles.

Randomized study comparing the efficacy and tolerance of a lipophillic hydroxy acid derivative of salicylic acid and 5% benzoyl peroxide in the treatment of facial acne vulgaris.

BACKGROUND: New topical treatments for acne vulgaris are needed for patients who have tolerance problems with current treatments. AIMS: To compare the efficacy and tolerance of a lipophillic derivative of salicylic acid (lipo hydroxy acid or LHA) containing formulation and 5% benzoyl peroxide in subjects with acne vulgaris. METHODS: Eighty subjects with mild to moderate facial acne were randomized to receive either the LHA formulation twice a day or benzoyl peroxide once a day for 12 weeks. Efficacy and tolerance were evaluated at days 0, 28, 56 and 87. Results LHA formulation and benzoyl peroxide decreased the number of inflammatory lesions from baseline to week 12 by 44% and 47% and noninflammatory lesions by 19% and 23%, respectively. There was no statistically significant difference between the two treatments (P = 0.748; P = 0.445). CONCLUSION: These results suggest that the LHA formulation could be a treatment option to consider in mild to moderate acne vulgaris patients that are intolerant to benzoyl peroxide.

Disseminated linear calcinosis cutis associated with the Koebner phenomenon in an infant with congenital acute monocytic leukaemia.

We present a unique case of an infant with acute monocytic leukaemia who presented at birth with multiple rubbery, erythematous to violaceous subcutaneous nodules secondary to leukaemia cutis. As these infiltrates regressed with chemotherapy, numerous white to yellow linear confluent papules appeared in a scratch-like pattern. These lesions were widely disseminated but were concentrated across her face, trunk and extremities with relative sparing of the napkin area and back. We propose that these lesions represent a form of dystrophic calcinosis cutis that occurred secondary to koebnerization in an infant with congenital leukaemia cutis.