Adverse Pregnancy and Child Outcomes in Oral Retinoid-Exposed Pregnancies: A Nationwide Population-Based Study.

BACKGROUND: Oral retinoids are used to treat various dermatological conditions, and their use is increasing in women of childbearing age. However, there is limited knowledge on the incidence of adverse outcomes after retinoid exposure during pregnancy. We aimed to evaluate the risk of adverse outcomes associated with oral retinoid exposure during pregnancy. METHODS: We conducted a retrospective cohort study using the NHIS mother-child linked healthcare database in South Korea. We included all women who gave live birth from April 1, 2009 to December 31, 2020 and their children. The exposure was defined as having ≥ 1 prescription of isotretinoin, alitretinoin, and acitretin from one month before pregnancy to the delivery. The outcomes of interest were adverse child outcomes including major congenital malformations, low birth weight, and neurodevelopmental disorders (autism spectrum disorder and intellectual disorder), and adverse pregnancy outcomes including gestational diabetes mellitus, preeclampsia, and postpartum hemorrhage. Propensity score-based matching weights were used to control for various potential confounders. For congenital malformation, low birth weight, and adverse pregnancy outcomes, we calculated relative risk (RR) with 95% confidence interval (CI) using a generalized linear model and for neurodevelopmental disorders, we estimated hazard ratio (HR) with 95% CI using the Cox proportional hazard model. RESULTS: Of 3,894,184 pregnancies, we identified 720 pregnancies (0.02%) as the oral retinoid-exposed group. The incidence of major congenital malformation was 400.6 per 10,000 births for oral retinoid-exposed group and 357.9 per 10,000 births for unexposed group and the weighted RR was 1.10 (95% CI, 0.65-1.85) in oral retinoid-exposed group compared with unexposed group. The neurodevelopmental disorder showed a potential increased risk, with the weighted HR of 1.63 (95% CI, 0.60-4.41) for autism spectrum disorder and 1.71 (95% CI, 0.60-4.93) for the intellectual disorder, although it did not reach statistical significance. For low birth weight and adverse pregnancy outcomes, no association was observed with oral retinoid exposure during pregnancy. CONCLUSION: This study found no significantly increased risk of congenital malformations, autism spectrum disorders, and intellectual disability associated with oral retinoid exposure during pregnancy; however, given the limitations such as including only the live births and increased point estimate, potential risk cannot be fully excluded.

Acitretin induced primary hypothyroidism in Darier's disease: A rare case report.

ABSTRACT: Acitretin is a synthetic, second-generation retinoid mainly used for the treatment of Darier's disease (DD), which impacts biological processes by binding to a nuclear receptor from the corticosteroid/thyroid receptor superfamily, thereby altering gene expression. Our report outlines the case of a 41-year-old male patient who has received a clinical diagnosis of DD and does not exhibit any other coexisting comorbidities, who developed hypothyroidism posttreatment with acitretin, an unusual and rare side effect of the drug. His baseline routine investigations fell within normal limits before the initiation of acitretin. Acitretin-induced hypothyroidism was treated with thyroxine. Although a good therapeutic response was seen with acitretin, it could not be continued due to the development of side effects and was continued on topical therapy. This case emphasizes the likelihood of adverse effects linked to therapeutic levels of acitretin in patients without any prior history and signifies the critical importance of consistent blood monitoring throughout drug therapy.

Use of Acitretin Among Girls and Women of Childbearing Age and Occurrence of Acitretin-Exposed Pregnancies in Germany.

BACKGROUND AND OBJECTIVE: Acitretin has long-lasting teratogenic properties. Therefore, pregnancies must be avoided during and within 3 years after acitretin treatment. We aimed to describe (i) acitretin use in women of childbearing age in Germany, (ii) the occurrence of acitretin-exposed pregnancies, and (iii) malformations among children exposed in utero. METHODS: Using 2004-2019 data from the German Pharmacoepidemiological Research Database (GePaRD-claims data from ~ 20% of the German population), we determined annual age-standardized prevalence of acitretin use among girls and women aged 13-49 years. In longitudinal analyses, we estimated the number of exposed pregnancies by assessing whether the exposure window assigned to the last dispensation before pregnancy (days covered by dispensation plus 3 years) overlapped the onset of pregnancy or whether there was a dispensation in the first eight weeks of pregnancy. Data of live-born children with in utero exposure to acitretin were reviewed to assess the presence of congenital malformations. RESULTS: The age-standardized prevalence of acitretin use per 1000 girls and women was 0.04 in 2019. We identified 35 acitretin-exposed pregnancies; 94.3% of these pregnancies were classified as exposed because they occurred within 3 years after stopping acitretin treatment. Among 18 live-born children linked to their mother, four children (22.2%) had congenital malformations (three children with a major malformation). CONCLUSIONS: We observed 35 acitretin-exposed pregnancies mainly because treatment ended too late before pregnancy. Approximately one in five children born from these pregnancies had malformations, highlighting the importance of drawing more attention to the long-lasting teratogenicity of this drug.

Risk of Psychiatric Disorders in Patients with Psoriasis Prescribed Acitretin versus Disease-Modifying Antirheumatic Drugs: A Nationwide Matched Cohort Study.

BACKGROUND: Acitretin has been linked to the development of psychiatric disturbance. OBJECTIVES: The aim of this study was to assess the psychiatric hazards in patients with psoriasis prescribed acitretin compared with those prescribed disease-modifying antirheumatic drugs (DMARDs). METHODS: This is a nationwide matched cohort study. From Taiwan's National Health Insurance Research Database, adult patients with psoriasis between 1997 and 2013 were screened. Patients prescribed acitretin for at least 30 days per year on average (acitretin cohort) were matched 1:2 with those prescribed DMARDs for at least 30 days per year on average (reference cohort), by means of age, gender, and psoriasis duration. Patients prescribed medication of the corresponding cohort for more than 7 days during the observation period were excluded. Cumulative incidences of psychiatric disorders in both cohorts were plotted with the Kaplan-Meier method. The modified Cox regression models were constructed to estimate hazard ratios (HRs). RESULTS: In total, 1,152 and 2,304 patients in the acitretin and the reference cohorts, respectively, were included. The 4-year cumulative incidence of overall psychiatric disorders (19.62% vs. 12.06%; p < 0.001), mood disorders (12.81% vs. 7.67%; p < 0.001), and psychosis (7.21% vs. 4.63%; p < 0.001) in the acitretin cohort was significantly higher than that in the reference cohort. Acitretin was independently associated with psychiatric disorders (HR 1.51, 95% confidence interval [CI] 1.23-1.85). The risk is more accentuated in the subgroups of comorbid chronic liver disease (HR 2.60, 95% CI: 1.56-4.33) or psoriatic arthritis (HR 3.23, 95% CI: 1.75-5.97). Other independent risk factors included insomnia, acute coronary syndrome, females, and age. CONCLUSIONS: Compared with DMARDs, acitretin was associated with higher hazards of psychiatric disorders among psoriasis patients.

Effectiveness and persistence of acitretin, ciclosporin, fumaric acid esters and methotrexate for patients with moderate-to-severe psoriasis: a cohort study from BADBIR.

BACKGROUND: Real-world data evaluating effectiveness and persistence of systemic therapies for patients with psoriasis are limited. Objectives To determine the effectiveness and persistence of acitretin, ciclosporin, fumaric acid esters (FAEs) and methotrexate in patients with moderate-to-severe psoriasis. METHODS: Data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR), a prospective, multicentre pharmacovigilance register of patients with moderate-to-severe psoriasis receiving biologic and/or conventional systemic therapies, were analysed. Eligible patients were ≥ 16 years of age receiving a first course of acitretin, ciclosporin, FAEs or methotrexate between 2007 and 2021 with ≥ 6 months' follow-up. Effectiveness was defined as achieving absolute Psoriasis Area and Severity Index (aPASI) ≤ 2 reported ≥ 4 weeks after treatment start date until date of cessation. To identify baseline clinical variables associated with treatment effectiveness, we used multivariable logistic regression models estimating the adjusted odds ratio (aOR) of achieving aPASI ≤ 2. To describe drug persistence associated with ineffectiveness, occurrence of adverse events or other reasons for discontinuation, survival estimates with 95% confidence intervals (CIs) were obtained using a flexible parametric model. Results were obtained using multiple imputed data. RESULTS: In total, 5430 patients were included in the analysis. Overall, 1023 (19%) patients were receiving acitretin, 1401 (26%) patients were on ciclosporin, 347 (6%) patients were on FAEs, and 2659 (49%) patients were receiving methotrexate at registration. The proportion of patients who achieved aPASI ≤ 2 was lower for those treated with acitretin [n = 118 (21%)] compared with those receiving ciclosporin [n = 233 (34%)], FAEs [n = 43 (29%)] and methotrexate [n = 372 (32%)]. Factors associated with ineffectiveness included prior experience to previous nonbiologic systemic therapies (acitretin) (aOR 0.64, 95% CI 0.42-0.96), male sex (methotrexate) (aOR 0.58, 95% CI 0.46-0.74), comorbidities (aOR 0.70, 95% CI 0.51-0.97) and alcohol consumption (≤ 14 units per week) (ciclosporin) (aOR 0.70, 95% CI 0.50-0.98). Persistence associated with all reasons for discontinuation showed better survival for methotrexate compared with acitretin, ciclosporin and FAEs cohorts at 12 months [survival estimate 46.1 (95% CI 44.0-48.3), 31.9 (95% CI 29.4-34.7), 30.0 (95% CI 27.5-32.4) and 35.0 (95% CI 29.9-40.9), respectively]. CONCLUSIONS: The real-world effectiveness and persistence of acitretin, ciclosporin, FAEs and methotrexate were generally low. Previous nonbiologic systemic therapies, male sex, comorbidities and alcohol consumption were risk factors associated with treatment ineffectiveness.

Effectiveness and Safety of Acitretin for the Treatment of Hidradenitis Suppurativa, Predictors of Clinical Response: A Cohort Study.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the hair follicle which presents with painful nodules, abscesses, and fistulae in apocrine gland-bearing areas of the skin. Approved treatments include antibiotics and biologic drugs such as adalimumab. Despite these treatments, HS management is challenging. Acitretin is an oral retinoid used for its management as 3rd or 4th line therapy. There is little evidence regarding the effectiveness and safety of acitretin treatment for HS, and no reports have previously explored the potential clinical predictors associated with the response to the treatment. METHODS: Retrospective cohort study to assess the effectiveness and safety of acitretin treatment in HS patients who failed to respond to topical therapies. RESULTS: Sixty-two patients with moderate to severe HS were included. A significant decrease in the International HS Severity Scoring System (IHS4) score was found over time. Higher basal IHS4 score, family history of HS, follicular phenotype, and history of follicular plugging conditions were potential predictors of response. Most patients did not suffer any adverse events, and no severe side effects were observed. The main cause of discontinuation was lack of efficacy. CONCLUSION: Acitretin can be considered as a therapeutic option for patients with HS. The presence of follicular phenotype or a history of components of follicular occlusion syndrome is associated with better outcomes.

Real-world data on the use of secukinumab and acitretin in pediatric generalized pustular psoriasis.

To evaluate the outcomes of secukinumab and acitretin use in children with generalized pustular psoriasis (GPP), we compared the efficacy and adverse events of secukinumab in 20 children and acitretin in 16 children with GPP from January 1, 2019, to January 30, 2022. Among the 20 patients treated with secukinumab, the average time for pustules to fade, temperature to normalize, and C-reactive protein (CRP) to normalize was 3.83, 2.46, and 3.91 days, respectively. All patients recovered (Japanese Dermatological Association severity index score: 0/1) in 3 weeks. The adverse events were abnormal liver enzyme (10%), atopic dermatitis-like lesions (10%), herpes simplex (5%), and neutropenia (10%). For the patients treated with acitretin, the average time for pustules to fade, temperature to normalize, and CRP to normalize was 6, 6.14, and 8.73 days, respectively. The adverse events included mucocutaneous dryness (75%), dyslipidemia (37.5%), and abnormal liver enzyme (25%). These findings demonstrate that secukinumab has more favorable outcomes than acitretin, and secukinumab was well tolerated by the pediatric patients with GPP.

Biologics combined with conventional systemic agents for the treatment of children with severe psoriasis. Real-life data from the BiPe cohorts and a practice survey among French and Italian pediatric dermatologists.

Combined therapies involve the use of multiple drugs to increase efficacy and reduce the toxicity of individual treatments. We evaluated the use of combinations of conventional systemic therapies and biologics in children with psoriasis in daily practice. This two-part study used data from the 170 children in the Franco-Italian BiPe cohorts to evaluate the use, efficacy, and safety of combined conventional systemic-biologic therapies, and from a survey carried out among French and Italian dermatologists to better understand the reasons for using or avoiding these combinations. In total, 33 children (19.4%) from 13 dermatology centers received 48 combined conventional systemic-biologic therapies (cumulative duration: 43.6 years), including three triple combination therapies (acitretin-methotrexate, with a TNF-alpha inhibitor). A total of 14 different combinations were used, most frequently etanercept-acitretin (n = 10), adalimumab-acitretin (n = 7), adalimumab-methotrexate (n = 5), and ustekinumab-methotrexate (n = 5). The combined therapies were started at biologic initiation in 41 cases (85.4%), and after a period of biologic monotherapy in the remaining 7 cases. Mean PGA and PASI scores decreased between baseline and M3 with all the combinations used. Four serious adverse events were reported, all with favorable outcomes. The survey was completed by 61 dermatologists: 39 (63.9%) had previously used or planned to use the combined therapies, most commonly TNF-alpha inhibitors with acitretin or methotrexate. The main reason for using these treatments was to improve the outcome of biologic therapies in cases of partial efficacy or loss of efficacy. Combined therapies have been used frequently in the treatment of childhood psoriasis, in a range of clinical situations and in variable drug combinations, without significant toxicity. Although the use of these combined therapies needs to be clarified in future management guidelines, these combined therapies should be considered for the treatment of children with severe psoriasis, psoriatic arthritis, and recalcitrant disease.

Retinoid-induced skeletal hyperostosis in disorders of keratinization.

For disorders of keratinization, topical treatment alone may be ineffective, and systemic retinoid therapy may be indicated. Treatment with systemic retinoids (acitretin, isotretinoin and alitretinoin) has been shown to be effective in reducing disease severity; however, potentially rare adverse effects (AEs) may occur, including hyperostotic skeletal changes. The true prevalence of this AE in adult patients administered life-long therapy is unknown. We identified 3 of 127 (2.4%) patients (with ichthyosis or Darier disease) who had been prescribed isotretinoin with or without acitretin, and who developed radiological signs and clinical symptoms of hyperostosis and ligamentous ossification. This clinical review highlights the significance of retinoid-induced skeletal hyperostosis in patients prescribed long-term, high-dose retinoid therapy for disorders of keratinization. Patients commencing systemic retinoid therapy, particularly women of childbearing age, should be counselled about this important and potentially serious AE, especially if long-term treatment is indicated.

Oral isotretinoin versus acitretin in male patients with multiple recalcitrant common warts: A randomized, double-blinded placebo-control study.

BACKGROUND: Management of multiple recalcitrant common warts represents a therapeutic challenge. Both oral isotretinoin and acitretin have shown a promising efficacy in the treatment of various types of warts. However, a comparative study of the two medicines in wart treatment has not yet been conducted. OBJECTIVE: The aim of this study was to assess the efficacy and adverse effects of oral isotretinoin versus acitretin in the treatment of multiple recalcitrant common warts. METHODS: This study was conducted on 75 adult male patients with recalcitrant multiple common warts. The patients were randomly assigned to three groups: group 1 (30 patients) received oral isotretinoin, group 2 (30 patients) received acitretin, and group 3 received oral placebo (15 patients). The treatment was given daily until complete clearance or for a maximum of 3 months. RESULTS: Complete clearance of the treated lesions was observed in 18 patients (60%) of the isotretinoin group, in 22 patients (73.3%) of the acitretin group, and in 0 patients (0%) of the placebo group. A statistically significant difference was observed in the therapeutic response between the treatment groups, and the placebo group was observed. Adverse effects of the used drugs were mild and transient. CONCLUSION: Oral isotretinoin and acitretin are promising effective modalities with minimal side effects for the treatment male patients with multiple recalcitrant common warts with a relative superiority of acitretin.