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Linked Comment: B.F. Chong. Br J Dermatol 2021; 185:1084. [ABSTRACT FROM AUTHOR]

Background: Hydroxychloroquine (HCQ), a 4-aminoquinolone antimalarial, is regarded as the oral therapy of choice for cutaneous and systemic lupus erythematosus (SLE). It is also licensed for rheumatoid arthritis (RA). Studies of HCQ-treated patients with SLE or RA have demonstrated a positive correlation between whole-blood HCQ levels and clinical response. Such studies have involved measuring whole-blood concentrations at any given time point after HCQ ingestion assuming that steady-state concentrations would undergo limited fluctuation over a daily interval because HCQ has a long half-life. This approach might not sufficiently take into account the potential intra-patient variation in HCQ blood levels that can occur over a 24-hour period. Such variation, if significant, could affect the credibility of any concentration-response relationship provided from these previous studies. Objectives: The objectives of this report are to: (a) investigate the intra-patient variation in HCQ whole-blood levels and (b) suggest an optimum time for sampling patients for future studies. Methods: Six patients were recruited with cutaneous lupus erythematosus who had each been on HCQ 200 mg twice daily for at least six months, so that they were at steady-state. Each patient was fasted overnight and had standardized meals and dosing schedule. Whole blood was sampled at seven time points over 24 hours. Whole-blood HCQ levels were measured with high-performance liquid chromatography using gradient elution, fluorimetric detection and chloroquine as an internal standard. The assay had a mean inter- and intra-day coefficient of variation of 10% and 5% respectively and a limit of detection of 5ng/ml. Results: HCQ levels appeared to follow a biphasic pattern over the sampling period. Maximum levels were noted a median of four hours (range 2-6) after ingestion. Median intra-patient variation between trough and peak levels, 'Cmax' ((peak - trough)/trough x 100%), was 27% (range 8-150%). Conclusions: This study demonstrated that whole-blood HCQ levels vary 27% (median, range 8-150%) within an individual over a 12-hour period. Drug levels might differ between individuals because of multiple factors, including variable adherence to medication. Measuring HCQ levels for assessment of drug adherence could be valuable in the 'real-world' clinical setting. This could be assessed by taking a blood sample at any time following HCQ ingestion. If patients were found to have very low or undetectable levels of HCQ, non-adherence to HCQ should be suspected. [ABSTRACT FROM AUTHOR]

Background Polymorphic light eruption (PLE) is approximately four times more common in women than in men and often begins in young adult life. It is hypothesized that patients with PLE have an inherent resistance to UVL-induced immunosuppression, which is a physiological phenomenon in normal healthy individuals. Consequently, in PLE there is a delayed-type hypersensitivity reaction to a UVL-modified skin antigen, which results in an inflammatory reaction and a variable rash. The female hormone, 17β-oestradiol, has been shown to inhibit UVL-induced physiological suppression of contact hypersensitivity responses. This has been postulated to account for the female preponderance of PLE. If 17β-oestradiol plays a significant part in the disease, one might hypothesize that the severity of PLE might reduce in women after menopause. Objectives To compare the severity of PLE in pre-menopausal women with that in post-menopausal women. Methods Eighteen pre-menopausal and 18 post-menopausal women with PLE had their Polymorphic Light Eruption Severity Index (PLESI) scored by a single investigator. Results Pre-menopausal women (mean age 40 years; range 25-50) had a mean PLESI of 54.8 (range 0-86, SD 20.2). Post-menopausal women (mean age 63 years; range 53-78) had a mean PLESI of 36.8 (range 0-74, SD 18.2). A significant difference in mean PLESI values between pre- and post-menopausal women was noted (18.0; 95% CI 4.9-31.0; P = 0.008). At the time of the study, three subjects in the pre-menopausal group and one subject in the post-menopausal group were on oestrogen preparations. Even after excluding the four patients on oral oestrogens, there remained a statistically significant difference in the mean PLESI scores between the pre-menopausal and post-menopausal groups (55.10 vs. 36.64; difference of 18.46, 95% CI: 4.0-32.91; P = 0.014). Conclusions The severity of PLE was significantly less in post-menopausal women as compared with pre-menopausal women. [ABSTRACT FROM AUTHOR]

Background: Palmoplantar pustulosis (PPP) is an inflammatory skin disorder that mostly affects smokers and manifests with painful pustular eruptions on the palms and soles. Although the disease can present with concurrent plaque psoriasis, TNF and IL-17/IL-23 inhibitors show limited efficacy. There is therefore a pressing need to uncover PPP disease drivers and therapeutic targets., Objectives: We sought to identify genetic determinants of PPP and investigate whether cigarette smoking contributes to disease pathogenesis., Methods: We performed a genome-wide association meta-analysis of 3 North-European cohorts (n = 1,456 PPP cases and 402,050 controls). We then used the scGWAS program to investigate the cell-type specificity of the association signals. We also undertook genetic correlation analyses to examine the similarities between PPP and other immune-mediated diseases. Finally, we applied Mendelian randomization to analyze the causal relationship between cigarette smoking and PPP., Results: We found that PPP is not associated with the main genetic determinants of plaque psoriasis. Conversely, we identified genome-wide significant associations with the FCGR3A/FCGR3B and CCHCR1 loci. We also observed 13 suggestive (P < 5 × 10 -6 ) susceptibility regions, including the IL4/IL13 interval. Accordingly, we demonstrated a significant genetic correlation between PPP and T H 2-mediated diseases such as atopic dermatitis and ulcerative colitis. We also found that genes mapping to PPP-associated intervals were preferentially expressed in dendritic cells and often implicated in T-cell activation pathways. Finally, we undertook a Mendelian randomization analysis, which supported a causal role of cigarette smoking in PPP., Conclusions: The first genome-wide association study of PPP points to a pathogenic role for deregulated T H 2 responses and cigarette smoking., Competing Interests: Disclosure statement This work was supported by NIHR BioResource Centre Maudsley, National Institute for Health Research Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London. We gratefully acknowledge capital equipment funding from the Maudsley Charity (grant no. 980) and Guy’s and St Thomas’s Charity (grant no. STR130505). The work was also supported by the NIHR Manchester Biomedical Research Centre (grant no. NIHR203308). The Trøndelag Health Study (HUNT) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The genotyping in HUNT was financed by the National Institutes of Health; University of Michigan; the Research Council of Norway; the Liaison Committee for Education, Research and Innovation in Central Norway; and the Joint Research Committee between St Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. The APRICOT trial was funded by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership (grant no. EME 13/50/17). This study was supported by Boehringer-Ingelheim and by the Psoriasis Association (grant nos. BSTOP50/5 and PhD studentship ST3/20 to A.H.C.). Z.Q.L. was supported by the Talent Development Fund of KK Women’s and Children’s Hospital, Singapore. N.J.R. is an NIHR Senior Investigator and is also supported by NIHR Newcastle Biomedical Research Centre, NIHR Newcastle In Vitro Diagnostics Co-operative, and NIHR Newcastle Patient Safety Research Collaboration. The views expressed are those of the author(s) and not necessarily those of the NHS, Department of Health, or King’s College London. None of the funders was involved in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Disclosure of potential conflict of interest: F. Capon has received grants and consultancy fees from Boehringer-Ingelheim. A. D. Burden has received consultancy fees from Boehringer-Ingelheim. C. E. M. Griffiths has received research grants and/or honoraria from AbbVie, Almirall, Anaptysbio, Boehringer-Ingelheim, Bristol Meyers Squibb, Evelo, GlaxoSmithKline, Inmagene, Janssen, Lilly, ONO Pharmaceuticals, Novartis, Pfizer, and UCB. P. Baum and S. Visvanathan are Boehringer-Ingelheim employees. S. Wahie has had nonfinancial support (sponsorship to attend dermatology conferences) from Janssen, AbbVie, Novartis, Almirall, and UCB. J. N. Barker declares paid activities as an advisor and speaker for AbbVie, Amgen, Boehringer-Ingelheim, Bristol Myers Squibb, Johnson & Johnson, Lilly, and Novartis. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Economic evidence for vitiligo treatments is absent., Objectives: To determine the cost-effectiveness of (i) handheld narrowband ultraviolet B (NB-UVB) and (ii) a combination of topical corticosteroid (TCS) and NB-UVB compared with TCS alone for localized vitiligo., Methods: Cost-effectiveness analysis alongside a pragmatic, three-arm, placebo-controlled randomized controlled trial with 9 months' treatment. In total 517 adults and children (aged ≥ 5 years) with active vitiligo affecting < 10% of skin were recruited from secondary care and the community and were randomized 1: 1: 1 to receive TCS, NB-UVB or both. Cost per successful treatment (measured on the Vitiligo Noticeability Scale) was estimated. Secondary cost-utility analyses measured quality-adjusted life-years using the EuroQol 5 Dimensions 5 Levels for those aged ≥ 11 years and the Child Health Utility 9D for those aged 5 to < 18 years. The trial was registered with number ISRCTN17160087 on 8 January 2015., Results: The mean ± SD cost per participant was £775 ± 83·7 for NB-UVB, £813 ± 111.4 for combination treatment and £600 ± 96·2 for TCS. In analyses adjusted for age and target patch location, the incremental difference in cost for combination treatment compared with TCS was £211 (95% confidence interval 188-235), corresponding to a risk difference of 10·9% (number needed to treat = 9). The incremental cost was £1932 per successful treatment. The incremental difference in cost for NB-UVB compared with TCS was £173 (95% confidence interval 151-196), with a risk difference of 5·2% (number needed to treat = 19). The incremental cost was £3336 per successful treatment., Conclusions: Combination treatment, compared with TCS alone, has a lower incremental cost per additional successful treatment than NB-UVB only. Combination treatment would be considered cost-effective if decision makers are willing to pay £1932 per additional treatment success., (© 2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Evidence for the effectiveness of vitiligo treatments is limited., Objectives: To determine the effectiveness of (i) handheld narrowband UVB (NB-UVB) and (ii) a combination of potent topical corticosteroid (TCS) and NB-UVB, compared with TCS alone, for localized vitiligo., Methods: A pragmatic, three-arm, placebo-controlled randomized controlled trial (9-month treatment, 12-month follow-up). Adults and children, recruited from secondary care and the community, aged ≥ 5 years and with active vitiligo affecting < 10% of skin, were randomized 1 : 1 : 1 to receive TCS (mometasone furoate 0·1% ointment + dummy NB-UVB), NB-UVB (NB-UVB + placebo TCS) or a combination (TCS + NB-UVB). TCS was applied once daily on alternating weeks; NB-UVB was administered on alternate days in escalating doses, adjusted for erythema. The primary outcome was treatment success at 9 months at a target patch assessed using the participant-reported Vitiligo Noticeability Scale, with multiple imputation for missing data. The trial was registered with number ISRCTN17160087 on 8 January 2015., Results: In total 517 participants were randomized to TCS (n = 173), NB-UVB (n = 169) and combination (n = 175). Primary outcome data were available for 370 (72%) participants. The proportions with target patch treatment success were 17% (TCS), 22% (NB-UVB) and 27% (combination). Combination treatment was superior to TCS: adjusted between-group difference 10·9% (95% confidence interval 1·0%-20·9%; P = 0·032; number needed to treat = 10). NB-UVB alone was not superior to TCS: adjusted between-group difference 5·2% (95% CI - 4·4% to 14·9%; P = 0·29; number needed to treat = 19). Participants using interventions with ≥ 75% expected adherence were more likely to achieve treatment success, but the effects were lost once treatment stopped. Localized grade 3 or 4 erythema was reported in 62 (12%) participants (including three with dummy light). Skin thinning was reported in 13 (2·5%) participants (including one with placebo ointment)., Conclusions: Combination treatment with home-based handheld NB-UVB plus TCS is likely to be superior to TCS alone for treatment of localized vitiligo. Combination treatment was relatively safe and well tolerated but was successful in only around one-quarter of participants., (© 2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Importance: Although palmoplantar pustulosis (PPP) can significantly impact quality of life, the factors underlying disease severity have not been studied., Objective: To examine the factors associated with PPP severity., Design, Setting, and Participants: An observational, cross-sectional study of 2 cohorts was conducted. A UK data set including 203 patients was obtained through the Anakinra in Pustular Psoriasis, Response in a Controlled Trial (2016-2019) and its sister research study Pustular Psoriasis, Elucidating Underlying Mechanisms (2016-2020). A Northern European cohort including 193 patients was independently ascertained by the European Rare and Severe Psoriasis Expert Network (2014-2017). Patients had been recruited in secondary or tertiary dermatology referral centers. All patients were of European descent. The PPP diagnosis was established by dermatologists, based on clinical examination and/or published consensus criteria. The present study was conducted from October 1, 2014, to March 15, 2020., Main Outcomes and Measures: Demographic characteristics, comorbidities, smoking status, Palmoplantar Pustulosis Psoriasis Area Severity Index (PPPASI), measuring severity from 0 (no sign of disease) to 72 (very severe disease), or Physician Global Assessment (PGA), measuring severity as 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), and 4 (severe)., Results: Among the 203 UK patients (43 men [21%], 160 women [79%]; median age at onset, 48 [interquartile range (IQR), 38-59] years), the PPPASI was inversely correlated with age of onset (r = -0.18, P = .01). Similarly, in the 159 Northern European patients who were eligible for inclusion in this analysis (25 men [16%], 134 women [84%]; median age at onset, 45 [IQR, 34-53.3] years), the median age at onset was lower in individuals with a moderate to severe PGA score (41 years [IQR, 30.5-52 years]) compared with those with a clear to mild PGA score (46.5 years [IQR, 35-55 years]) (P = .04). In the UK sample, the median PPPASI score was higher in women (9.6 [IQR, 3.0-16.2]) vs men (4.0 [IQR, 1.0-11.7]) (P = .01). Likewise, moderate to severe PPP was more prevalent among Northern European women (57 of 134 [43%]) compared with men (5 of 25 [20%]) (P = .03). In the UK cohort, the median PPPASI score was increased in current smokers (10.7 [IQR, 4.2-17.5]) compared with former smokers (7 [IQR, 2.0-14.4]) and nonsmokers (2.2 [IQR, 1-6]) (P = .003). Comparable differences were observed in the Northern European data set, as the prevalence of moderate to severe PPP was higher in former and current smokers (51 of 130 [39%]) compared with nonsmokers (6 of 24 [25%]) (P = .14)., Conclusions and Relevance: The findings of this study suggest that PPP severity is associated with early-onset disease, female sex, and smoking status. Thus, smoking cessation intervention might be beneficial.

Background: Systematic reviews suggest that narrowband ultraviolet B light combined with treatments such as topical corticosteroids may be more effective than monotherapy for vitiligo., Objective: To explore the clinical effectiveness and cost-effectiveness of topical corticosteroid monotherapy compared with (1) hand-held narrowband ultraviolet B light monotherapy and (2) hand-held narrowband ultraviolet B light/topical corticosteroid combination treatment for localised vitiligo., Design: Pragmatic, three-arm, randomised controlled trial with 9 months of treatment and a 12-month follow-up., Setting: Sixteen UK hospitals - participants were recruited from primary and secondary care and the community., Participants: Adults and children (aged ≥ 5 years) with active non-segmental vitiligo affecting ≤ 10% of their body area., Interventions: Topical corticosteroids [mometasone furoate 0.1% (Elocon ® , Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA) plus dummy narrowband ultraviolet B light]; narrowband ultraviolet B light (narrowband ultraviolet B light plus placebo topical corticosteroids); or combination (topical corticosteroids plus narrowband ultraviolet B light). Topical corticosteroids were applied once daily on alternate weeks and narrowband ultraviolet B light was administered every other day in escalating doses, with a dose adjustment for erythema. All treatments were home based., Main Outcome Measures: The primary outcome was self-assessed treatment success for a chosen target patch after 9 months of treatment ('a lot less noticeable' or 'no longer noticeable' on the Vitiligo Noticeability Scale). Secondary outcomes included blinded assessment of primary outcome and percentage repigmentation, onset and maintenance of treatment response, quality of life, side effects, treatment burden and cost-effectiveness (cost per additional successful treatment)., Results: In total, 517 participants were randomised (adults, n  = 398; and children, n  =  119; 52% male; 57% paler skin types I-III, 43% darker skin types IV-VI). At the end of 9 months of treatment, 370 (72%) participants provided primary outcome data. The median percentage of narrowband ultraviolet B light treatment-days (actual/allocated) was 81% for topical corticosteroids, 77% for narrowband ultraviolet B light and 74% for combination groups; and for ointment was 79% for topical corticosteroids, 83% for narrowband ultraviolet B light and 77% for combination. Target patch location was head and neck (31%), hands and feet (32%), and rest of the body (37%). Target patch treatment 'success' was 20 out of 119 (17%) for topical corticosteroids, 27 out of 123 (22%) for narrowband ultraviolet B light and 34 out of 128 (27%) for combination. Combination treatment was superior to topical corticosteroids (adjusted risk difference 10.9%, 95% confidence interval 1.0% to 20.9%; p  = 0.032; number needed to treat = 10). Narrowband ultraviolet B light was not superior to topical corticosteroids (adjusted risk difference 5.2%, 95% confidence interval -4.4% to 14.9%; p  = 0.290; number needed to treat = 19). The secondary outcomes supported the primary analysis. Quality of life did not differ between the groups. Participants who adhered to the interventions for > 75% of the expected treatment protocol were more likely to achieve treatment success. Over 40% of participants had lost treatment response after 1 year with no treatment. Grade 3 or 4 erythema was experienced by 62 participants (12%) (three of whom were using the dummy) and transient skin thinning by 13 participants (2.5%) (two of whom were using the placebo). We observed no serious adverse treatment effects. For combination treatment compared with topical corticosteroids, the unadjusted incremental cost-effectiveness ratio was £2328.56 (adjusted £1932) per additional successful treatment (from an NHS perspective)., Limitations: Relatively high loss to follow-up limits the interpretation of the trial findings, especially during the post-intervention follow-up phase., Conclusion: Hand-held narrowband ultraviolet B light plus topical corticosteroid combination treatment is superior to topical corticosteroids alone for treatment of localised vitiligo. Combination treatment was relatively safe and well tolerated, but was effective in around one-quarter of participants only. Whether or not combination treatment is cost-effective depends on how much decision-makers are willing to pay for the benefits observed., Future Work: Development and testing of new vitiligo treatments with a greater treatment response and longer-lasting effects are needed., Trial Registration: Current Controlled Trials ISRCTN17160087., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 64. See the NIHR Journals Library website for further project information.