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ABSTRACT Trial Registration Palmoplantar pustular psoriasis (PPPP), or palmoplantar pustulosis (PPP), is a type of psoriasis that affects the skin on the palms and soles. It is characterised by dermatosis and small sterile pustules and is considered a significant burden on patients' quality of life, as there is currently no gold standard treatment or cure. This network meta‐analysis (NMA) compares the efficacy and safety of biologic and non‐biologic medications for PPPP and PPP. Medline, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched. The efficacy and safety of all medications were assessed through a frequentist NMA using a random‐effects model. Treatments were ranked using the net rank function, yielding P scores. Fourteen RCTs with 1056 participants were included. Guselkumab 100 mg was the most effective for improving PPPGA scores (p = 0.72, RR = 1.31, CI: 0.31–5.57). Guselkumab 100 mg was ranked the highest for achieving PPPASI‐75 (RR = 5.4, CI: 1.26–23.2, p = 0.023). Oral cyclosporine 1 mg/kg/day was ranked the highest for PPPASI‐50 (RR = 2.10, CI: 0.65–6.82). Etretinate 1 mg/kg/day had the highest rate of adverse events (RR = 1.78, CI: 0.92–3.44). Secukinumab 300 mg was associated with the highest rate of serious adverse events (RR = 1.58, CI: 0.21–12.02). Based on the P‐scores from our NMA, guselkumab 100 mg was the most effective for PPPGA improvement, guselkumab 100 mg for PPPASI‐75, oral cyclosporine 1 mg/kg/day for PPPASI‐50, etretinate 1 mg/kg/day had the most adverse events, and secukinumab 300 mg was associated with the highest rate of serious adverse events.PROSPERO registration number: CRD42023460842 [ABSTRACT FROM AUTHOR]

Background Hand eczema is common and a cause of morbidity and occupational disability. When education, irritant/contact allergen avoidance, moisturisation and topical corticosteroids are insufficient to control chronic hand eczema, ultraviolet therapy or systemic immune-modifying drugs are used. There is no treatment pathway generally accepted by UK dermatologists. Primary objective Compare alitretinoin and ultraviolet therapy as first-line therapy in terms of disease activity at 12 weeks post planned start of treatment. Design Prospective, multicentre, open-label, two-arm parallel group, adaptive randomised controlled trial with one planned interim analysis, and an economic evaluation. Setting UK secondary care dermatology outpatient clinics. Participants Patients with severe chronic hand eczema unresponsive to at least 4 weeks of treatment with potent topical corticosteroids. Primary end point Natural logarithm of the Hand Eczema Severity Index + 1, 12 weeks post planned start of treatment. Randomisation Participants randomised 1 : 1 by minimisation to alitretinoin or ultraviolet therapy for 12 to 24 weeks. Blinding Blinded primary end-point assessor. Results Intention-to-treat population: 441 (100.0%) participants; 220 (49.9%) alitretinoin and 221 (50.1%) ultraviolet therapy. At least one dose was received by 212 (96.4%) alitretinoin and 196 (88.7%) ultraviolet therapy participants. Primary outcome The unadjusted median (interquartile range) relative change in hand eczema severity index at 12 weeks was 30% (10–70%) of that at baseline for alitretinoin compared with 50% (20–100%) for ultraviolet therapy. There was a statistically significant benefit of alitretinoin compared with ultraviolet therapy at 12 weeks, with an estimated fold change or relative difference (95% confidence interval) = 0.66 (0.52 to 0.82), p = 0.0003 at 12 weeks. There was no evidence of a difference at 24 or 52 weeks, with the estimated fold change (95% confidence interval) equal to 0.92 (0.798 to 1.08) and 1.27 (0.97 to 1.67), respectively. Primary analysis results were consistent for secondary end points Fifty-nine per cent allocated to alitretinoin and 61% allocated to ultraviolet therapy achieved a clear/almost clear assessment during the trial period. Differential treatment compliance observed: 145 (65.9%) alitretinoin and 53 (24.0%) ultraviolet therapy participants confirmed compliance (≥ 80% received, no treatment breaks > 7 days during first 12 weeks). High levels of missing data were observed. Safety One hundred and thirty-five reportable adverse events across 79 participants, 55 (25.0%) alitretinoin and 24 (10.9%) ultraviolet therapy. Four serious adverse events (two alitretinoin, two ultraviolet therapy). Four pregnancies reported (three alitretinoin, one ultraviolet therapy). No new safety signals were detected. Conclusion As a first-line therapy, alitretinoin showed more rapid improvement and superiority to ultraviolet therapy at week 12. This difference was not observed at later time points. Alitretinoin is cost-effective at weeks 12 and 52. Ultraviolet therapy is cost-effective after 10 years, with a high degree of uncertainty. Hand eczema severity index may be a useful primary outcome measure for hand eczema trials; ALPHA results will inform future trials. Limitations Treatment compliance was poor for ultraviolet therapy. Regular twice weekly treatment was not received by most patients. Assessment of long-term effects of randomised treatments was complicated by use of second-line treatments post treatment phase. Further work Further analysis of substudies and pilot data will provide valuable information for future studies. A clear need for better therapeutic approaches for severe chronic hand eczema remains. Future studies will need to further address long-term benefits of treatments given. Trial registration This trial is registered as ISRCTN80206075. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/186/01) and is published in full in Health Technology Assessment; Vol. 28, No. 59. See the NIHR Funding and Awards website for further award information. Plain language summary What was the question? The main question was which treatment was better at easing symptoms of severe hand eczema after 12 weeks. The two treatments compared were ones used most often by UK dermatologists. The first is a tablet called alitretinoin, which is taken once a day. The second is called ultraviolet therapy, where hands are soaked in a special liquid and placed under ultraviolet light twice a week at a hospital. What did we do? We treated 220 patients with alitretinoin and 221 patients with ultraviolet therapy. Patients received treatment for 12 to 24 weeks depending on how well their hand eczema responded. Patients could have different treatments afterwards, and we collected information on their hand eczema symptoms for up to 1 year. What did we find? After 12 weeks, severe hand eczema symptoms improved for both groups of patients but improved most for patients who took alitretinoin. However, 1 year after joining the trial, there was no evidence of a difference between alitretinoin and ultraviolet therapy as a first-line treatment. More patients stopped ultraviolet therapy early compared with patients who received alitretinoin. Different treatments may have been prescribed after the first treatment. What does this mean? Alitretinoin provides a convenient, instant relief or a ‘quick fix’ for patients with severe hand eczema. Alitretinoin is more convenient for lots of people, but it is important to have other options available for people who would prefer not to, or are unable to, take alitretinoin. For example, people who take alitretinoin can experience unwanted side effects, and people who are able to become pregnant must also use contraception. Long-term control of severe hand eczema is important. Individual discussions on the pros and cons of each treatment for hand eczema symptoms is needed. Providing flexible options to attend ultraviolet therapy appointments could be helpful (e.g. weekend/evenings). Scientific summary Background Hand eczema (HE) is common and an important cause of morbidity and occupational disability. One-year prevalence of HE is up to 10% in the general population, with 5–7% developing chronic hand eczema (CHE). Current evidence is not compelling enough to guide clinical practice. When patient education, irritant/contact allergen avoidance, moisturisation and topical corticosteroids are insufficient to control CHE, ultraviolet therapy (PUVA) or systemic immune-modifying drugs are used. There is no treatment pathway generally accepted among UK dermatologists. Most UK dermatology centres use phototherapy (mostly Immersion PUVA) or alitretinoin as first-line treatment for uncontrolled CHE. ALPHA is the first trial comparing alitretinoin with Immersion PUVA as a first-line therapy for patients with uncontrolled severe CHE. Objectives Primary objective Compare alitretinoin and Immersion PUVA as first-line therapy in terms of disease activity at 12 weeks post planned start of treatment. Secondary objectives Compare alitretinoin and Immersion PUVA in terms of disease activity over time (focusing on 24 and 52 weeks post planned start of treatment). Compare alitretinoin and Immersion PUVA in terms of time to relapse. Compare alitretinoin and Immersion PUVA in terms of quality of life (QoL) and patient benefit over 52 weeks post planned start of treatment. Determine cost-effectiveness of alitretinoin compared with Immersion PUVA over the short and longer term. Determine the educational need for patients. Compare alitretinoin and Immersion PUVA in terms of safety. Exploratory objectives included subgroup analyses to assess whether treatment response is affected by pre-specified baseline characteristics. Methods Design Prospective, multicentre, open-label, two-arm parallel group, adaptive randomised controlled trial with one planned interim analysis and an economic evaluation. Participants Patients with severe CHE unresponsive to at least 4 weeks of treatment with potent topical corticosteroids. Primary end point Natural logarithm of the Hand Eczema Severity Index (HECSI) + 1 at 12 weeks post planned start of treatment. Secondary end points Disease activity, measured by HECSI, modified Total Lesion Scoring System (mTLSS) and Physician’s Global Assessment (PGA) at 12, 24, 52 weeks post planned start of treatment. Time to relapse, defined as time between achieving clear/almost clear overall on the blinded assessor PGA and scoring 75% of their baseline HECSI, with sensitivity assessed by redefining relapse as 50% of their baseline HECSI. Dermatology Life Quality Index (DLQI) and Patient Benefit Index for Hand Eczema (PBI-HE) at 12, 24 and 52 weeks post planned start of treatment. Person-Centred Dermatology Self-Care Index (PeDeSi) at 12 and 52 (or 24) weeks post planned start of treatment. Reported adverse events (AEs) and serious adverse events (SAEs) over 52 weeks post planned start of treatment. Cost-effectiveness of alitretinoin compared with Immersion PUVA at week 12, 52 (short term) and over 10 years (long term). Randomisation Participants were randomised using minimisation 1 : 1 to alitretinoin 30 mg/day or Immersion PUVA for 12 weeks to 24 weeks. Randomisation factors were: randomising site, disease duration, clinical phenotype, atopy status, DLQI and skin type. Analysis Linear mixed models accounting for the longitudinal data structure were fitted to primary (HECSI) and secondary end points (mTLSS, DLQI) on the intention-to-treat (ITT) population, with adjustment for: smoking history, body mass index (BMI), foot involvement, baseline score, time since planned start of treatment and treatment group. Participant and participant–time interaction were fitted as random effects. An ordinal logistic mixed model was fitted to the PGA, and an ordinal logistic model without random effects was fitted to the PeDeSI at 12 weeks. Exploratory analyses explored differential treatment effects in pre-planned subgroups, correlation of scoring systems and second-line therapies, and safety data were summarised. Total cost and quality-adjusted life-years (QALYs) were estimated at weeks 12, 52, and 10 years after treatment initiation. The latter were combined to estimate short- and long-term cost-effectiveness. Short-term cost-effectiveness was estimated via a within-trial analysis at weeks 12 and 52 and via Markov model to estimate 10-year cost-effectiveness of both interventions. A resource use questionnaire was used to estimate short- and long-term cost of interventions and standard care, while EuroQol-5 Dimensions, three-level version (EQ-5D-3L) responses were used to estimate utility values and generate QALYs. This analysis followed the NHS and personal and social perspective (PSS). Cost-effectiveness was determined using National Institute for Health and Care Excellence (NICE) guidelines. Secondary analysis included societal perspective and QALYs determined by the DLQI. Data collection Data were collected at baseline, 4-weekly to week 36 and 8-weekly to week 52. Sample size A minimum of 500 and maximum of 780 participants were required to detect a relative difference, or fold change, of 1.3 in HECSI score between treatment arms at 12 weeks post planned start of treatment (80% power; two-sided 5% significance level) assuming a coefficient of variation (CV) between 1.175 and 1.7 and 20% attrition. Note that a fold change of 1.3 is equivalent to a fold change of 0.77 if there was a benefit in the opposite direction. A sample size review was planned after 364 participants reached 12 weeks post planned start of treatment but was conducted early in August 2017. Following Data Monitoring and Ethics Committee (DMEC) review, a sample size of 514 participants was recommended based on a CV of 1.2. Results Screening and recruitment Thirty-one NHS hospitals in England, Scotland and Wales assessed 1557 patients for eligibility, registered 582 (37.4%) and randomised 441 (75.8%) participants between October 2015 and June 2021. Of 1557 patients screened, 642 (41.2%) were ineligible, with 347 (54.0%) not having a severe CHE diagnosis. Of 915 eligible patients, 582 (63.6%) were consented and registered. Of 333 patients who did not consent, 74 (22.2%) thought the Immersion PUVA schedule or travel was inconvenient, and 28 (8.4%) did not want alitretinoin. Of 141 patients not randomised, the main reasons were not meeting the eligibility criteria [n = 69 (48.9%)] or patient choice [n = 29 (20.6%)]. Of patients randomised, 220 (49.9%) were allocated to alitretinoin and 221 (50.1%) to Immersion PUVA. Of those allocated to alitretinoin, 201 (91.4%) started treatment within 7 days post randomisation compared with 165 (74.7%) of those allocated to Immersion PUVA. In total, 132 (29.9%) participants withdrew from, or were lost to, follow-up. The ITT population included 441 (100.0%) participants. Primary outcome Hand eczema severity index at 12 weeks In terms of relative change, the median [interquartile range (IQR)] score at 12 weeks was equal to 30% (10–70%) of that at baseline for the alitretinoin group compared with 50% (20–100%) in the Immersion PUVA group. There was a statistically significant benefit of alitretinoin compared with Immersion PUVA at 12 weeks, with an estimated fold change of 0.66 (0.52, 0.82), p = 0.0003 at 12 weeks. Secondary end points Hand eczema severity index over 52 weeks There was no evidence of a difference between alitretinoin and Immersion PUVA at 24 weeks or 52 weeks, with the estimated fold change [95% confidence interval (CI)] equal to 0.92 (0.798 to 1.08) and 1.27 (0.97 to 1.67), respectively. Modified total lesion symptom score over 52 weeks There was no evidence of a difference between treatment groups over 52 weeks, with the estimated difference (95% CI) equal to −0.37 (−1.23 to 0.48) at 12 weeks, −0.14 (−0.84 to 0.56) at 24 weeks and 0.41 (−0.59 to 1.40) at 52 weeks. Physician’s Global Assessment over 52 weeks At 12 weeks, the proportion of participants with available data achieving clear or almost clear (via blinded assessment) was 27.6% (47/170) for alitretinoin and 23.6% (35/148) for Immersion PUVA. Over 52 weeks, 59.4% (123/207) of alitretinoin participants with available data achieved at least one clear/almost clear assessment compared with 61.5% (118/192) of Immersion PUVA participants. There was no evidence of a difference between treatment groups over 52 weeks, with the estimated odds ratios (alitretinoin vs. Immersion PUVA) for achieving lower PGA scores and 95% CI equal to 1.22 (0.90 to 1.64) at 12 weeks, 1.18 (0.89 to 1.56) at 24 weeks and 1.10 (0.64 to 1.89) at 52 weeks. Dermatology quality of life index over 52 weeks There was a statistically significant benefit of alitretinoin compared with Immersion PUVA, with mean scores (95% CI) estimated to be 0.95 (0.09 to 1.82) lower at 12 weeks for the alitretinoin group compared with Immersion PUVA. There was no statistically significant treatment effect at 24 weeks [estimated difference in mean scores = −0.18 (−0.92 to 0.56)], but at 52 weeks, there was a statistically significant treatment effect with increased scores in the alitretinoin group compared with the Immersion PUVA group [estimated difference in mean scores = −1.62 (−2.62 to −0.62)]. The differences observed in the DLQI were not clinically significant. Person-Centred Dermatology Self-Care Index at 12 weeks At baseline, 16.1% (n = 71) were assessed as having sufficient knowledge, ability and confidence to self-manage their condition, with a similar distribution of education needs across treatment groups. At 12 weeks, the proportion of participants with available data who had sufficient knowledge and education was 26.2% (117/324), 28.0% (49/175) in the alitretinoin group and 24.2% (36/149) in the Immersion PUVA group. There was no evidence of a difference in terms of educational need between treatment groups, with an estimated odds ratio (alitretinoin vs. Immersion PUVA) of 0.65 (0.39 to 1.08). Patient Benefit Index – hand eczema over 52 weeks At 12 weeks, the median (IQR) score was equal to 2.3 (1.4–3.2) in the alitretinoin group and 1.9 (0.9–2.8) in the Immersion PUVA group. At 24 weeks, the median (IQR) score was unchanged at 2.3 (1.2–3.5) in the alitretinoin group but had increased to 2.8 (1.4–3.5) in the Immersion PUVA group. At 52 weeks, the median (IQR) score was 2.6 (1.6–3.3) in the alitretinoin group and 3.0 (1.7–3.6) in the Immersion PUVA group. Time to relapse At treatment phase completion, 34.1% (N = 75) of participants allocated to alitretinoin achieved a clear or almost clear response, compared with 25.8% (N = 57) allocated to Immersion PUVA. When relapse was defined as 75% of the baseline HECSI score, 20% (n = 15) of alitretinoin responders relapsed compared with 15.8% (n = 9) of Immersion PUVA responders. When relapse was defined as 50% of the baseline HECSI score, 37.3% (n = 28) of alitretinoin responders and 36.8% (n = 21) of Immersion PUVA responders relapsed. Health economic analysis Within-trial estimated costs indicate that Immersion PUVA is more costly than alitretinoin at weeks 12 and 52 (week 12: £3236 vs. £1904; week 52: £4424 vs. £3336, respectively). Treatment costs are the main drivers of Immersion PUVA costs (including therapy cost, medication and follow-up). Out-of-pocket expenditures are also higher for patients assigned to Immersion PUVA. These increase the cost difference at weeks 12 and 52 (from £1333 to £1650 at week 12 and from £1081 to £1841 at week 52). Immersion PUVA’s QALYs are higher at both time points (week 12: 0.165 vs. 0.159 and week 52: 0.798 vs. 0.761). When using DLQI, the estimated QALYs were slightly higher for alitretinoin compared with Immersion PUVA (week 12: 0.158 vs. 0.154; week 52: 0.784 vs. 0.782, respectively). When combined, the incremental cost-effectiveness ratios (ICERs) indicate alitretinoin is cost-effective at weeks 12 and 52 in all scenarios (primary analysis, societal perspective, and QALYs derived from DLQI). These results are robust, as the probability of cost-effectiveness is between 96% and 100%. Long-term cost-effectiveness The 10-year cost estimates indicate that patients allocated to alitretinoin are slightly more costly than Immersion PUVA (£5432 vs. £5361, respectively). In terms of QALYs, Immersion PUVA is slightly more effective (6.535 vs. 6.530, respectively). The latter suggests Immersion PUVA is the cost-effective strategy; however, results are uncertain, as only 50% of the probabilistic analysis iterations indicate this is the case. Safety data Seventy-nine participants had 135 reportable AEs, 25.0% (n = 55) participants allocated to alitretinoin and 10.9% (n = 24) participants allocated to Immersion PUVA. There were four serious AEs (SAEs; two alitretinoin, two Immersion PUVA); one suspected/expected to be related to treatment, and three related to underlying CHE. There were four pregnancies (three alitretinoin, one Immersion PUVA), including one alitretinoin patient in active treatment, who stopped treatment immediately. Treatment compliance In total, 212 (96.4%) participants randomised to alitretinoin and 196 (88.7%) randomised to Immersion PUVA received treatment. Full ‘trial’ compliance (≥ 80% received and no treatment breaks > 7 days during the first 12 weeks) was observed in 65.9% (N = 145) participants allocated to alitretinoin and 24.0% (N = 53) allocated to Immersion PUVA. Subgroup analysis No differential treatment effects were observed within subgroups defined by disease duration, clinical phenotype, disease severity, presence of atopy, filaggrin loss of function mutation, smoking history, BMI, foot involvement or biomarkers identified through tape stripping. Conclusion Alitretinoin and Immersion PUVA both led to reductions in symptoms. As a first-line therapy, alitretinoin showed a more rapid improvement and was superior to Immersion PUVA in terms of primary end point at 12 weeks. This difference was not observed at later time points. Alitretinoin was more cost-effective over the short term (12 and 52 weeks) with robust results. Long-term analysis indicates that Immersion PUVA is cost-effective in the long term; these results, however, are uncertain. These findings will inform clinical management of patients with severe CHE. Alitretinoin may be considered as the recommended first-line therapy; however, Immersion PUVA may also be considered for longer-term outcomes, particularly in patients where alitretinoin is not an appropriate treatment. Recruitment was difficult, with perceived treatment pathway challenges. The trial implemented a self-referral service, through which 13.8% of randomised participants were recruited. The Immersion PUVA schedule was problematic, with more than 20% of participants declining participation citing this as their main reason. Immersion PUVA treatment compliance was poor, and regular twice-weekly treatment was not achieved by most patients. Hand eczema severity index (HECSI) was the chosen primary outcome measure because it incorporated more details about the condition compared with PGA, which had been used previously. Furthermore, HECSI is continuous rather than discrete, which meant a smaller sample size was required for a desired level of power. The results from ALPHA will help inform future CHE trial designs. Most participants had some educational need for how to manage their condition, and overall, there remains a need for better therapeutic approaches for severe CHE. Just 59% and 61% of patients allocated to alitretinoin and Immersion PUVA, respectively, were known to achieve a clear/almost clear assessment at any time point during the trial period. Further work includes deeper analysis of substudies and pilot data to inform future research, which is needed to understand the long-term effects of treatments. Trial registration This trial is registered as ISRCTN80206075. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/186/01) and is published in full in Health Technology Assessment; Vol. 28, No. 59. See the NIHR Funding and Awards website for further award information.

Abstract Hidradenitis suppurativa (HS) is a debilitating chronic skin disorder characterized by painful inflammatory nodules, abscesses and sinus tracts involving intertriginous areas and has an adverse impact on patient quality of life. Over the past decade, the therapeutic options of HS have increased significantly to comprise multiple modalities, including topical medication, systemic therapies (mainly antibiotics, retinoids, and biologics), surgical approaches, and lifestyle modifications. Biologics alone or in combination with surgery remain the treatment of choice for moderate to severe disease. However, non-biologic therapies (including retinoids) may be used as monotherapy for mild disease and in combination with biologics and surgical treatment in moderate to severe disease. Retinoids, specifically isotretinoin, acitretin, and alitretinoin, are historically used in the management of HS, supported by anecdotal evidence and with variable treatment response. Although the current American and European guidelines offer different recommendations on the use of retinoids in HS, retinoids remain a valuable ally in HS management. This review provides a comprehensive analysis of the current scientific literature on retinoid therapy (topical and systemic) in HS, highlighting disparities in mechanisms of action, efficacy, and safety to clarify their role in HS treatment.

Hidradenitis suppurativa (HS) is a debilitating chronic skin disorder characterized by painful inflammatory nodules, abscesses and sinus tracts involving intertriginous areas and has an adverse impact on patient quality of life. Over the past decade, the therapeutic options of HS have increased significantly to comprise multiple modalities, including topical medication, systemic therapies (mainly antibiotics, retinoids, and biologics), surgical approaches, and lifestyle modifications. Biologics alone or in combination with surgery remain the treatment of choice for moderate to severe disease. However, non-biologic therapies (including retinoids) may be used as monotherapy for mild disease and in combination with biologics and surgical treatment in moderate to severe disease. Retinoids, specifically isotretinoin, acitretin, and alitretinoin, are historically used in the management of HS, supported by anecdotal evidence and with variable treatment response. Although the current American and European guidelines offer different recommendations on the use of retinoids in HS, retinoids remain a valuable ally in HS management. This review provides a comprehensive analysis of the current scientific literature on retinoid therapy (topical and systemic) in HS, highlighting disparities in mechanisms of action, efficacy, and safety to clarify their role in HS treatment. [ABSTRACT FROM AUTHOR]

Background: Acitretin, a synthetic vitamin A derivative, is the most studied and widely used oral retinoid for ichthyoses. Its major disadvantage is the need for contraceptive measures during 3 years after discontinuation. An alternative is needed for women of childbearing age. With alitretinoin, another retinoid, pregnancy is considered safe 1 month after discontinuation. Objectives: The aim of this study was to provide evidence for alitretinoin as an alternative for acitretin for ichthyosis in women of childbearing age. Our experience is shared in a case series combined with an overview of the current literature. Methods: Nine women of childbearing age (19–31 years, median 21) with different subtypes of ichthyosis (autosomal recessive congenital ichthyosis, (superficial) epidermolytic ichthyosis, erythrokeratoderma variabilis, and epidermolytic epidermal nevi, a mosaic form of epidermolytic ichthyosis) were included and treated with 30 mg alitretinoin during 2–28 months. Severity was measured by Ichthyosis Area Severity Index (IASI) and Investigator Global Assessment (IGA). A literature search in Pubmed using the Mesh terms "alitretinoin," "skin diseases, genetic" and "ichthyosis" was performed. Results: Significant reduction in the mean scores of IGA, IASI-erythema, IASI-scaling, and IASI-total was seen. Seven patients are still being treated, 1 patient stopped to become pregnant, 1 patient discontinued due to financial reasons. Observed side effects were reversible headache (n = 6), asteatotic eczema (n = 1), "not feeling well" temporarily (n = 1), and easier blistering of the feet (n = 1). The literature search resulted in six case reports and case series about alitretinoin in ichthyosis and ichthyosis syndromes with in total 29 patients. The vast majority of articles (21/29) reported significant improvement or even complete remission of skin symptoms. However, validated outcome measures to support these results were lacking. Side effects (n = 16) were relatively mild, except for benign intracranial hypertension (n = 1) and autoimmune hypothyroidism (n = 1). Conclusion: Our study shows, with validated outcome measures, that alitretinoin is effective to mitigate the symptoms of ichthyosis in women of childbearing age and a suitable alternative to acitretin. [ABSTRACT FROM AUTHOR]

Retinoids are a frequently used class of drugs in the treatment of inflammatory as well as malignant skin diseases. Retinoids have differential affinity for the retinoic acid receptor (RAR) and/or the retinoid X receptor (RXR). The endogenous dual RAR and RXR agonist alitretinoin (9-cis retinoic acid) demonstrated remarkable efficacy in the treatment of chronic hand eczema (CHE) patients; however, detailed information on the mechanisms of action remains elusive. Here, we used CHE as a model disease to unravel immunomodulatory pathways following retinoid receptor signaling. Transcriptome analyses of skin specimens from alitretinoin-responder CHE patients identified 231 significantly regulated genes. Bioinformatic analyses indicated keratinocytes as well as antigen presenting cells as cellular targets of alitretinoin. In keratinocytes, alitretinoin interfered with inflammation-associated barrier gene dysregulation as well as antimicrobial peptide induction while markedly inducing hyaluronan synthases without affecting hyaluronidase expression. In monocyte-derived dendritic cells, alitretinoin induced distinct morphological and phenotypic characteristics with low co-stimulatory molecule expression (CD80 and CD86), the increased secretion of IL-10 and the upregulation of the ecto-5′-nucleotidase CD73 mimicking immunomodulatory or tolerogenic dendritic cells. Indeed, alitretinoin-treated dendritic cells demonstrated a significantly reduced capacity to activate T cells in mixed leukocyte reactions. In a direct comparison, alitretinoin-mediated effects were significantly stronger than those observed for the RAR agonist acitretin. Moreover, longitudinal monitoring of alitretinoin-responder CHE patients could confirm in vitro findings. Taken together, we demonstrate that the dual RAR and RXR agonist alitretinoin targets epidermal dysregulation and demonstrates strong immunomodulatory effects on antigen presenting cell functions. [ABSTRACT FROM AUTHOR]

Occupational allergic contact dermatitis is an occupational skin condition which is characterized by a delayed cell-mediated hypersensitivity reaction triggered by one or more work-related substances. In this article, we describe a hairdresser who presented with occupational allergic contact dermatitis and was treated with alitretinoin. It is important to emphasize the value of early diagnosis and treatment of occupational contact dermatitis as this allows us to tackle the physical, psychosocial and cost-related burdens that this disorder brings.

Background: Chronic hand dermatitis (CHD) is difficult to treat and has high individual and societal burdens. Phototherapy and oral alitretinoin are safe monotherapies for CHD, but their combination has not been assessed. Objective: To assess the effectiveness and safety of low dose oral alitretinoin combined with phototherapy versus high dose oral alitretinoin for CHD refractory to topical corticosteroids. Methods: This retrospective study of adult patients with CHD refractory to topical corticosteroid therapy compared low dose oral alitretinoin (10 mg three times weekly) combined with narrowband ultraviolet B therapy (three times weekly; LDA-UVB) to high dose oral alitretinoin (30 mg daily; HDA) for 16 weeks. Outcomes were improvement in disease severity measured by the Physician's Global Assessment and quality of life measured with the Dermatology Life Quality Index. Results: The mean age of the study population (n = 64) was 41.25 years and 57.8% were male. Both cohorts experienced improvements in disease severity and quality of life after 16 weeks, however, significantly more participants who received LDA-UVB (n = 21/33, 63.6%) achieved "clear" or "almost clear" assessments compared to those who received HDA (n = 12/31, 38.7%; P <.05). Adverse effects were significantly more prevalent in the HDA group (P <.0001) and included headache, elevated cholesterol, and dry lips. Conclusions: The combination of low dose oral alitretinoin with narrowband-UVB therapy was more effective and had fewer adverse effects compared to high dose oral alitretinoin for participants with CHD refractory to topical corticosteroid therapy. [ABSTRACT FROM AUTHOR]

Background: Patients taking part in a tertiary individual prevention program (TIP) for work‐related skin diseases frequently have chronic hand eczema (HE) for which alitretinoin is a treatment option. Objective: To investigate treatment with alitretinoin before and during the TIP and related factors. Methods: Data of 1614 patients taking part in the TIP between January 2015 and December 2019 were analyzed retrospectively. Results: Three hundred forty‐eight patients (21.6%) reported treatment with alitretinoin prior to the TIP showing an increase over time, particularly in men. In 45 patients (2.8%), alitretinoin treatment was initiated during the TIP. Treatment with alitretinoin was significantly less common among female than male patients, both prior to (P <.001) and during the TIP (P =.015). Female patients who had received alitretinoin in the past were significantly older than the other female patients (P <.001). Among patients treated with alitretinoin prior to the TIP, women had a significantly higher disease severity at admission than men (P =.007). Conclusions: About twenty percent of patients reported treatment with alitretinoin prior to the TIP. The data indicate that treatment of female TIP patients with alitretinoin is less frequent than among male patients and depends on age and disease severity. [ABSTRACT FROM AUTHOR]

Keywords: alitretinoin; azathioprine; chronic; clinical trial; hand eczema EN alitretinoin azathioprine chronic clinical trial hand eczema 366 368 3 09/08/22 20221001 NES 221001 Alitretinoin is the only registered systemic treatment of severe chronic hand eczema (HE), but it is most effective in hyperkeratotic HE.1 It has never been compared in head-to-head studies to other immunomodulating systemic drugs, for example, azathioprine, that can be used (off-label) for severe HE. In one daily practice case series, patients showed moderate-to-good improvement of their HE after treatment with azathioprine.2 Based on this case series, in which only one patient with hyperkeratotic HE was included, combined with observations in clinical practice, azathioprine could prove superior to alitretinoin in HE subtypes other than hyperkeratotic HE. [Extracted from the article]

Retinol (ROL) and its biologically active metabolite, all-trans retinoic acid (ATRA), are essential for a number of reproductive processes. However, there is a paucity of information regarding their roles in ovarian folliculogenesis, oocyte maturation, and early embryogenesis. The objectives of this study were to quantify and compare peripheral plasma (PP) and follicular fluid (FF) retinoid levels, including ATRA in women undergoing in vitro fertilization (IVF) and to investigate the relationship between retinoid levels and embryo quality. Retinoid levels were evaluated in PP and FF from 79 women undergoing IVF at the time of oocyte retrieval and corresponding embryo quality assessed on a daily basis after retrieval for 3 days until uterine transfer. Analysis compared the retinoid levels with day 3 embryo grades and between endometriosis versus control patients. Results demonstrated distinctive levels of retinoid metabolites and isomers in FF versus PP. There was a significantly larger percentage of high-quality grade I embryos derived from the largest versus smallest follicles. An increase in follicle size also correlated with a >50% increase in FF ROL and ATRA concentrations. Independent of follicle size, FF yielding grade I versus nongrade I embryos showed higher mean levels of ATRA but not ROL. In a nested case-control analysis, control participants had 50% higher mean levels of ATRA in their FF and PP than women with endometriosis. These findings strongly support the proposition that ATRA plays a fundamental role in oocyte development and quality, and that reduced ATRA synthesis may contribute to decreased fecundity of participants with endometriosis.

Alitretinoin is the only systemic agent approved to treat moderate‐severe chronic hand eczema (CHE) unresponsive to potent topical corticosteroids. No nationwide Italian data regarding real‐life efficacy, safety, and tolerability of treatment are available. The DECISA project (DErmatology Clinics in Italy: Survey on Alitretinoin) retrospectively examined data from a registry including 15 Dermatology Clinics authorized to prescription of alitretinoin for CHE patients. Disease severity was assessed at baseline, and after 3 and 6 months of treatment, using the 5‐point Physician Global Assessment (PGA) and the modified Total Lesion‐Symptoms‐Severity (mTLSS) scores. Between November 2010 and July 2018, data of 248 male and 190 female patients (mean age 49.71 ± 13.20 years) treated with alitretinoin were collected. Of them, 43.2% had irritant contact dermatitis, 22.2% allergic contact dermatitis, 18.0% atopic dermatitis, 16.7% mixed (irritant/allergic) type of eczema. At 3 months, the 420 re‐evaluated patients showed significantly reduced mTLSS and PGA (P <.0000001 vs baseline for both); PGA was clear/almost clear in 35.6% of cases. At 6 months, the 341 re‐evaluated patients showed significant (P <.0000001) improvement of mTLSS and PGA vs baseline and 3 months (PGA clear/almost clear: 41.4%). Relapses occurred in 125 patients; 58 underwent an additional course of alitretinoin, with similarly good results. No relevant safety issues were reported; 86 patients experienced adverse effects, which forced 40 to prematurely stop treatment. The DECISA project results confirm the real‐life efficacy, safety and tolerability of alitretinoin in the treatment of moderate to severe CHE refractory to standard topical therapies. [ABSTRACT FROM AUTHOR]

Background: Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma (CTCL). There is currently no cure for CTCL, and treatment is aimed at limiting disease progression. This study evaluated the efficacy and tolerability of alitretinoin in CTCL management. Methods: A retrospective, multicenter study was conducted on CTCL patients treated with alitretinoin as a primary agent or in combination with standard therapies. Results: Forty-eight patients with MF (n = 40) and SS (n = 8) with a median age of 59.7 years (±14.3) were eligible for study inclusion. Treatment response data were evaluated in 40 patients and safety in 42 patients. 40.0% of the patients had early-stage, 43.8% had advanced-stage CTCL, and in 16.7% of patients there was insufficient information for staging. 40.0% (16/40) of the patients achieved a complete or partial response, whereas 47.5% (19/40) achieved stable disease, 12.5% (5/40) had progressive disease, and there were no cases of disease relapses in responders. Both early and advanced stages of CTCL were responsive to alitretinoin as a primary or combined modality. Alitretinoin was well tolerated, and 64.3% (27/42) of patients did not report any side effects. The most commonly observed side effect was hypertriglyceridemia. Conclusions: This retrospective analysis supports the efficacy and safety of alitretinoin in clearing skin disease and preventing disease progression in CTCL as a monotherapy or in combination with standard therapies. [ABSTRACT FROM AUTHOR]

Abstract Background Acitretin is the main retinoid used to treat severe inherited ichthyosis. Alternatives may be considered if it results ineffective or there are side-effects, or for women of childbearing age. Our objective is evaluation of the effects and tolerance of alitretinoin. An observational retrospective multicentric study was designed to analyse patients with inherited ichthyosis treated by alitretinoin. Results A total of 13 patients were included, 11 of whom were receiving acitretin at inclusion. The main reason for switching to alitretinoin was a desire for pregnancy, but also because of side-effects or unsatisfactory efficacy. Starting dose was 10 mg/day, increased to 20 or 30 mg/day. Alitretinoin seemed to be more effective than acitretin at reducing erythema, but was less effective at reducing scaling or hyperkeratosis. Global efficacy was considered low for two patients, moderate for nine, and high for two. Treatment was well-tolerated, except for one patient who presented with benign intracranial hypertension leading to discontinuation of treatment. Conclusions Alitretinoin may be suitable for hereditary ichthyosis with prominent erythema, especially for women of childbearing age.

Chronic hand/foot eczemas are common, but treatment is often challenging, with widespread dissatisfaction over current available options. Detailed history is important, particularly with regard to potential exposure to irritants and allergens. Patch testing should be regarded as a standard investigation. Individual treatment outcomes and targets, including systemic therapy, should be discussed early with patients, restoring function being the primary goal, with clearing the skin a secondary outcome. Each new treatment, where appropriate, should be considered additive or overlapping to any previous therapy. Management extends beyond mere pharmacological or physical treatment, and requires an encompassing approach including removal or avoidance of causative factors, behavioural changes and social support. To date, there is little evidence to guide sequences or combinations of therapies. Moderately symptomatic patients (e.g. DLQI ≥ 10) should be started on a potent/super‐potent topical corticosteroid applied once or twice per day for 4 weeks, with tapering to twice weekly application. If response is inadequate, consider phototherapy, and then a 12‐week trial of a retinoid (alitretinoin or acitretin). Second line systemic treatments include methotrexate, ciclosporin and azathioprine. For patients presenting with severe symptomatic disease (DLQI ≥ 15), consider predniso(lo)ne 0.5–1.0 mg/kg/day (or ciclosporin 3 – 5 mg/kg/day) for 4–6 weeks with tapering, and then treating as for moderate disease as above. In non‐responders, botulinum toxin and/or iontophoresis, if associated with hyperhidrosis, may sometimes help. Some patients only respond to long‐term systemic corticosteroids. The data on sequencing of newer agents, such as dupilumab or JAK inhibitors, are immature. [ABSTRACT FROM AUTHOR]

Lichen planus is a benign inflammatory disorder of unknown etiology that may affect the skin, mucosae, scalp, and nails. When the nails are affected, it may lead to permanent destruction with severe functional and psychosocial consequences. Therefore, prompt diagnosis and early treatment are essential, even in mild cases. There are currently no guidelines for the management of nail lichen planus and the published literature on treatment is limited. The aim of this review is to provide practical management recommendations for the classical form of nail lichen planus, especially when restricted to the nails. Topical treatment has poor short-term efficacy and may cause long-term side effects. Instead, intralesional and intramuscular triamcinolone acetonide should be considered first-line therapies. Oral retinoids are second-line choices, and immunosuppressive agents may also be considered. [ABSTRACT FROM AUTHOR]

The first pharmaceutical retinoids approved by the U.S. Food and Drug Administration were given black‐box warnings against their use in pregnancy due to potential teratogenic effects. These first‐ and second‐generation retinoids were initially formulated for oral dosing and are structurally very similar to vitamin A, which has beneficial effects on skin as well as plays a vital role in driving healthy embryogenesis. Some of these early retinoids have since been reformulated for topical application, which has resulted in their diminished potential for systemic exposures. Additionally, rational drug design has been applied to create today's third‐generation retinoids (adapalene, tazarotene, and bexarotene). These compounds include aromatic rings within their molecular cores to provide structural rigidity that contrasts with the flexible aliphatic backbone of vitamin A and the earlier generations of retinoids, and thus limits their off‐target activity. As a result of these design features, the teratogenic potential in animals of the third‐generation retinoids and those reformulated for topical use is generally less than seen with oral administration of earlier generations of retinoids. The available, but limited, epidemiologic data further show little‐to‐no teratogenic potential associated with real‐life use of these compounds in humans. Given the paucity of epidemiologic data available at this time, however, it is recommended that the use of topical retinoids during pregnancy be avoided. However, in circumstances when inadvertent exposure in pregnancy may occur, the available data provide some reassurance that adverse pregnancy outcomes are unlikely. [ABSTRACT FROM AUTHOR]