British Journal of Dermatology最新文献

Background: Patients with Gorlin (basal cell naevus) syndrome (GS) have numerous phenotypic abnormalities due to overactivity of the hedgehog (HH) signalling pathway, most commonly caused by a heritable mutation in PTCH1, which encodes a major inhibitor of this pathway. Oral HH inhibitors (HHi) can reverse some of the manifestations, most prominent of which is the development of numerous cutaneous basal cell carcinomas (BCCs). In order to improve the benefit-risk ratio, we developed a gel containing a small cyclopamine-derived molecule that can be applied topically in expectation that this mode of delivery can reduce the burden of BCCs without producing the systemic adverse effects that cause patients to stop oral HHi treatment.

Objectives: To determine whether or not patidegib topical gel 2% or 4% can accumulate in high enough concentrations to have local anti-BCC efficacy but not so high that systemic drug levels produce the adverse effects typical of oral HHi treatment.

Methods: We conducted a small randomized double-blinded phase IIA trial at two sites in the UK, to assess the clinical and molecular efficacy and adverse effects of 6 months of twice-daily application of patidegib topical gel to the entire face, as well as to treatment-targeted surgically eligible BCCs at other anatomical sites.

Results: Post hoc analyses suggested that patidegib topical gel reduced the number of new, surgically eligible BCCs and the level of HH signalling, with minimal adverse effects.

Conclusions: Patidegib topical gel warrants further clinical development.

Background: Discrete choice experiments (DCEs) are increasingly used to understand and quantify patient preferences for a variety of treatments, services or screening in order to analyse the choices patients make when faced with different alternatives.

Objectives: The aim of this DCE was to examine patient preferences for the treatment of Bowen disease.

Methods: A DCE was conducted alongside a randomized controlled noninferiority trial comparing the effectiveness of surgical excision, methyl aminolaevulinate photodynamic therapy (MAL-PDT) and 5-fluorouracil (5-FU) cream as treatments for Bowen disease. Preferences were elicited by presenting patients with choice tasks between surgical excision, MAL-PDT and 5-FU cream with the following attributes: effectiveness, cosmetic outcome, side-effects, treatment duration and process. A mixed logit model was used to account for the panel nature of the data (repeated choices for each respondent) and heterogeneity in preference.

Results: A total of 215 patients completed the DCE. Patients have a clear preference for excision and noninvasive therapies were less valued, as indicated by the large and negative label effect. Both moderate and good-to-excellent cosmetic outcomes were accepted and preferred to poor cosmetic outcomes for all treatments. In addition, none or mild-to-moderate side-effects were considered acceptable and preferred to severe side-effects.

Conclusions: Patients show a clear preference for surgical excision, and of the two noninvasive treatments, 5-FU cream is preferred to MAL-PDT. Treatment choice is also determined by attributes such as effectiveness, cosmetic outcome and side-effects. In the context of shared decision making for Bowen disease, it is important to discuss the elements of treatment that patients value to ensure that an informed decision is made.

Background: Moderate-to-severe atopic dermatitis (AD) affects the quality of life of patients. More treatment options are urgently needed to manage this chronic disease. Lebrikizumab is a monoclonal antibody that binds to interleukin-13, a key mediator in AD pathogenesis. In Japanese patients, lebrikizumab has been evaluated through week 16 in the randomized placebo-controlled phase III ADhere-J study.

Objectives: To evaluate the long-term efficacy and safety of lebrikizumab in combination with topical corticosteroids (TCS) in the ADhere-J study.

Methods: Patients aged ≥12 years weighing ≥ 40 kg with moderate-to-severe AD and receiving either subcutaneous lebrikizumab 250 mg -every 2 weeks (Q2W)/every 4 weeks (Q4W) or placebo during the 16-week induction period were evaluated during the long-term maintenance period from week 16 to week 68. Responders achieved the co-primary endpoints at week 16: an Investigator's Global Assessment score of 0 or 1 [IGA (0,1)] with ≥ 2-point improvement from baseline and/or ≥ 75% improvement from baseline in Eczema Area and Severity Index (EASI 75). In this analysis, week 16 responders received lebrikizumab 250 mg Q2W or Q4W combined with TCS during the maintenance period (maintenance primary population; MPP); week 16 per-protocol nonresponders received lebrikizumab Q2W with TCS (maintenance escape population; MEP). Major endpoints included IGA (0,1) with ≥ 2-point improvement from baseline and EASI 75 through week 68. Other outcomes included quality of life, itch and serum thymus and activation-regulated chemokine. The trial was registered with ClinicalTrials.gov (NCT04760314).

Results: At week 68, 66-81% of 103 patients in the MPP and 32-38% of 168 patients in the MEP achieved IGA (0,1) with ≥ 2-point improvement from baseline. EASI 75 was maintained by 83-89% of patients in the MPP, while 71-80% of patients in the MEP achieved this outcome by week 68. Across treatment arms, patients in the MPP tended to maintain improvements recorded at week 16, while patients in the MEP steadily improved across the maintenance period. No new safety signals were reported, and most treatment-emergent adverse events were mild or moderate in severity in both populations. Safety outcomes were consistent with previous reports for lebrikizumab treatment in global studies.

Conclusions: These results support the use of lebrikizumab in combination with TCS for the treatment of moderate-to-severe AD in the Japanese population in the long term.

Background: Polymorphic light eruption (PLE) is the most frequent photodermatosis in Europe, with an estimated prevalence of 10-20%, particularly in temperate climates. Itching or burning lesions appear only in sun-exposed areas, predominantly on the chest, arms and forearms, within a few hours following exposure. The cause of the disease remains unknown, yet studies have suggested that microbial elements in the skin may play a role in its pathogenesis.

Objectives: To investigate the skin microbiome of a cohort of patients with PLE upon exposure to ultraviolet radiation (UVR), to assess its role in the onset of PLE lesions.

Methods: Forty-one skin swabs were collected from 11 patients with PLE at baseline and after 3 days of exposure to UVR, and from healthy control participants. The collected swabs were analysed for their microbial composition using a 16S amplicon sequencing approach.

Results: PLE skin showed a dysbalanced microbiome at baseline, with significantly reduced microbial diversity and noticeable colonization by bacterial pathogens, including Staphylococcus aureus. Upon UVR exposure, the PLE microbiome exhibited further loss of diversity and a reduction in beneficial skin commensals. In line with this, we found that UVR exerted strong antimicrobial effects in vitro against representative skin residents.

Conclusions: UVR can lead to profound changes in the skin microbiome, allowing the proliferation of dysbiotic members that can release a variety of elements able to trigger PLE lesions. This is the first study to investigate the cutaneous microbiome changes in patients with PLE upon UVR exposure, offering new insights into disease pathogenesis that has so far been unexplored.

Background: Poor adherence to photoprotection in xeroderma pigmentosum (XP) increases morbidity and shortens lifespan due to skin cancers.

Objectives: To test a highly personalized intervention (XPAND) to reduce the dose of ultraviolet radiation (UVR) reaching the face in adults with XP, designed using known psychosocial determinants of poor photoprotection.

Methods: A two-arm parallel group randomized controlled trial, including patients with suboptimal photoprotection to receive XPAND or a delayed-intervention control arm that received XPAND the following year. XPAND comprises seven 1 : 1 sessions targeting photoprotection barriers (e.g. misconceptions about UVR) supported by personalized text messages, activity sheets and educational materials incorporating behaviour change techniques. The primary outcome, mean daily UVR dose to face across 21 days in June-July 2018, was calculated by combining UVR exposure at the wrist with a face photoprotection activity diary. Secondary outcomes were UVR dose to face across 21 days in August 2018, time spent outside, photoprotective measures used outside, mood, automaticity and confidence to photoprotect. Financial costs and quality-adjusted life years (QALYs) were calculated.

Results: Sixteen patients were randomized; 13 provided sufficient data for primary outcome analysis. The XPAND group (n = 8) had lower mean daily UVR dose to face [0.03 standard error of difference (SED) (SD 0.02)] compared with controls (n = 7) [0.43 SED (SD 0.17)] (adjusted difference = -0.25, P < 0.001, Hedge's g = 2.21) at the June 2018 assessment. No significant between-group differences were observed in time spent outside, photoprotection outside, mood or confidence. The delayed-intervention control showed improvements in UVR dose to face (adjusted difference = -0.05; Hedge's g = -0.1), time outside (adjusted difference = -69.9; Hedge's g = -0.28) and photoprotection (adjusted difference = -0.23, Hedge's g = 0.45) after receiving XPAND (June 2019 assessment). XPAND was associated with lower treatment costs [-£2642; 95% confidence interval (CI) -£8715 to £3873] and fewer QALYs (-0.0141; 95% CI -0.0369 to 0.0028).

Conclusions: XPAND was associated with a lower UVR dose to face in patients with XP and was cost-effective.

Background: No currently approved treatment for paediatric plaque psoriasis selectively targets interleukin (IL)-23. In adults, guselkumab (a selective IL-23 inhibitor that targets the p19 subunit) demonstrated substantial efficacy with a favourable safety profile in treating moderate-to-severe plaque psoriasis.

Objectives: To evaluate the efficacy and safety of guselkumab in paediatric patients with moderate-to-severe plaque psoriasis (PROTOSTAR; NCT03451851).

Methods: This phase III randomized placebo-controlled study enrolled patients aged ≥ 6 to < 18 years with moderate-to-severe plaque psoriasis. In part 1 [week (W)0-W16], patients were randomized to receive guselkumab, placebo or open-label etanercept (active reference arm). At W16, part 1 patients entered a guselkumab withdrawal/retreatment period or continued/crossed over to receive guselkumab (W16-W52). Co-primary endpoints were Investigator Global Assessment (IGA) 0/1 and ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) [or U.S. Food and Drug Administration-required ≥ 90% improvement in PASI (PASI 90) co-primary endpoint] responses at W16 of part 1. Part 2 evaluated continuous open-label guselkumab treatment (W0-W52).

Results: Of 92 and 28 patients enrolled in parts 1 and 2, respectively, 86% and 96% continued treatment through W52. In part 1, at W16, significantly higher proportions of guselkumab-treated compared with placebo-treated patients achieved IGA 0/1 (66% vs. 16%; P < 0.001), PASI 75 (76% vs. 20%; P < 0.001) and PASI 90 (56% vs. 16%; P < 0.01). More than one-third of guselkumab-treated patients achieved clear skin [IGA 0: 39% vs. 4% placebo; 100% improvement in PASI (PASI 100): 34% vs. 0% placebo; both P < 0.01]. In part 2, at W52, 86%, 93% and 82% of guselkumab-treated patients achieved IGA 0/1, PASI 75 and PASI 90, respectively. Through W16 of part 1, 42%, 68% and 58% of guselkumab-, placebo- and etanercept-treated patients, respectively, experienced adverse events (AEs). Rates of AEs with guselkumab were similar through W52 in parts 1 and 2; common AEs included nasopharyngitis, upper respiratory tract infection and COVID-19. No serious or opportunistic infections occurred.

Conclusions: Guselkumab demonstrated significant and clinically meaningful responses in paediatric patients with moderate-to-severe plaque psoriasis, and all co-primary and major secondary endpoints were met. Safety outcomes for guselkumab in paediatric patients were similar to placebo and consistent with the established profile in adults, with no new safety signals identified. These findings support the use of guselkumab to treat paediatric patients with moderate-to-severe plaque psoriasis.

Background: Generalized pustular psoriasis (GPP) is a chronic, systemic, neutrophilic inflammatory disease. A previous Delphi panel established areas of consensus on GPP, although patient perspectives were not included and aspects of treatment goals remained unclear.

Objectives: To identify and achieve consensus on refined, specific treatment goals for GPP treatment via a Delphi panel with patient participation.

Methods: Statements were generated based on a systematic literature review and revised by a Steering Committee. Statements were categorized into overarching principles, and short- and long-term treatment goals. A global panel of 30 dermatologists and 3 patient representatives voted in agreement or disagreement with each statement. Consensus was defined as ≥ 80% approval by the panellists.

Results: Consensus was reached in the first round of voting and ≥ 90% agreement was reached for 23 of 26 statements. In summary, GPP requires a timely, tailored treatment plan, co-developed by patients and physicians, that involves a multidisciplinary approach and addresses the complexity, heterogeneity and chronicity of the disease. Short-term treatment goals should include pustule clearance within 7 days and prevention of pustule recurrence, reduction of cutaneous symptom burden (-4 or more points on the Itch and Skin Pain Numeric Rating Scale), improvement in systemic symptoms (e.g. resolution of fever within 3 days of treatment initiation and reduced fatigue), prevention of life-threatening complications and progressive improvement of inflammatory biomarkers. In patients with comorbid psoriatic diseases, treatment decisions should prioritize GPP. Long-term treatment goals should include minimizing disease activity through flare prevention and symptom control between flares, sustained disease control, management of comorbidities and improvement in quality of life (QoL). Small differences in perception between patients and physicians regarding the importance of certain treatment goals (e.g. avoiding hair and/or nail loss to improve QoL), reflect the complexity of assessing treatment goals and emphasize the need for a patient-centred approach.

Conclusions: In the first global Delphi panel in GPP to include patient perspectives, consensus between dermatologists and patients was achieved on overarching principles of treatment, and short- and long-term treatment goals for GPP. These findings provide valuable insights for developing guidelines that consider the perspectives of patients and physicians in the treatment of GPP.