Low-Dose Acitretin for Secondary Prevention of Keratinocyte Carcinomas in Solid-Organ Transplant Recipients.

BACKGROUND: Keratinocyte carcinomas, particularly squamous cell carcinoma (SCC), occur more frequently and aggressively in solid-organ transplant recipients (SOTRs) than in the general population. Systemic retinoids are effective in secondary prevention of keratinocyte carcinomas in this population, but their use is limited by adverse effects including a rebound effect in cases of treatment discontinuation. OBJECTIVE: Our aim was to determine whether low-dose acitretin is efficient in the secondary prevention of keratinocyte carcinomas in SOTRs. METHODS: This retrospective case-crossover study was conducted at a specialized dermatology clinic for SOTRs in a large transplantation center in 2010-2017. Patients with at least 1 previous keratinocyte carcinoma who were treated with acitretin 10 mg/day for 2 years were included. The main outcome was the difference in the number of new keratinocyte carcinomas diagnosed during treatment compared to during the 2-year pretreatment period. RESULTS: The cohort included 34 SOTRs. A significant reduction in the mean number of new keratinocyte carcinomas during treatment relative to the pretreatment period was observed (1.7 vs. 3.6, -53% p = 0.002). Similar results were noted on analysis by tumor type, for both SCC and basal cell carcinoma. CONCLUSION: This study of SOTRs demonstrated positive results for low-dose acitretin as a chemoprevention of keratinocyte carcinomas in this population.

Acitretin for Secondary Prevention of Keratinocyte Cancers in a Veteran Population: A Retrospective Cohort Study.

Acitretin, a vitamin A derivative used for psoriasis, can prevent keratinocyte carcinoma (KC). It induced regression of keratoacanthomas (KA) in animal models, presumably by activating retinoic acid and retinoid X receptors that regulate gene expression for growth and proliferation.1,2.

Acitretin-induced periungual pyogenic granulomas and review.

Periungual pyogenic granulomas are benign vascular tumors that present as painful, round, spontaneously bleeding lesions composed of rapidly proliferating capillaries and excess tissue. The vast majority of pyogenic granulomas are caused by physical trauma or infectious agents and they may resolve spontaneously. Herein, we highlight a very rare case of periungual pyogenic granulomas induced by the regularly prescribed oral retinoid acitretin during treatment for congenital palmoplantar keratoderma. This unique case showed that it is feasible to continue acitretin therapy in the presence of pyogenic granuloma development if proper dose reduction and topical therapies are utilized. The patient's lesions resolved within two weeks of this protocol's initiation and the pyogenic granulomas did not recur over the course of a six-month follow-up observation period. In addition, we performed a systematic review of the literature using PubMed databases for the clinical features and treatments in other reported acitretin-induced pyogenic granuloma cases; we compiled a comprehensive list of other prescription drugs known to cause pyogenic granulomas up-to-date.

Hypertrophic lichenoid dermatitis immune-related adverse event during combined immune checkpoint and exportin inhibitor therapy: A diagnostic pitfall for superficially invasive squamous cell carcinoma.

Immune checkpoint inhibitors (ICIs) for cancer treatment have revolutionized the field of medicine. However, an unintended but frequent consequence of ICI therapy is the development of cutaneous immune-related adverse events (irAEs), such as lichenoid dermatitis irAEs (LD-irAEs). The hypertrophic variant of LD-irAE may be a diagnostic challenge since it can mimic superficially invasive squamous cell carcinoma (SCC). A 79-year-old woman with metastatic melanoma who began treatment with an ICI-pembrolizumab-plus exportin-1 (XPO1) inhibitor presented after 1 month of therapy with symmetrical violaceous papules coalescing into plaques and with two nodules of the bilateral dorsal hands. Biopsy of the nodules revealed an actinic keratosis and atypical epidermal proliferation concerning for SCC. However, in the ensuing 3 weeks, the patient developed multiple new erythematous, violaceous, and scaly macules and papules, some coalescing into plaques on the extremities. Biopsies of these lesions revealed exuberant irregular epidermal hyperplasia with hypermaturation and lichenoid infiltrate concentrated at the base of the elongated, broadened rete ridges, consistent with hypertrophic LD-irAE. Treatment included topical fluocinonide ointment, intralesional triamcinolone injections and oral acitretin. Distinguishing hypertrophic LD-irAE and SCC can be challenging since both entities share histopathologic features; thus, correlation with clinical presentation is essential for diagnosis and optimal patient management.

Dermatological manifestations in cardiofaciocutaneous syndrome: a prospective multicentric study of 45 mutation-positive patients.

BACKGROUND: Data on dermatological manifestations of cardiofaciocutaneous syndrome (CFCS) remain heterogeneous and almost without expert dermatological classification. OBJECTIVES: To describe the dermatological manifestations of CFCS; to compare them with the literature findings; to assess those discriminating CFCS from other RASopathies, including Noonan syndrome (NS) and Costello syndrome (CS); and to test for dermatological phenotype-genotype correlations. METHODS: We performed a 4-year, large, prospective, multicentric, collaborative dermatological and genetic study. RESULTS: Forty-five patients were enrolled. Hair abnormalities were ubiquitous, including scarcity or absence of eyebrows and wavy or curly hair in 73% and 69% of patients, respectively. Keratosis pilaris (KP), ulerythema ophryogenes (UO), palmoplantar hyperkeratosis (PPHK) and multiple melanocytic naevi (MMN; over 50 naevi) were noted in 82%, 44%, 27% and 29% of patients, respectively. Scarcity or absence of eyebrows, association of UO and PPHK, diffuse KP and MMN best differentiated CFCS from NS and CS. Oral acitretin may be highly beneficial for therapeutic management of PPHK, whereas treatment of UO by topical sirolimus 1% failed. No significant dermatological phenotype-genotype correlation was determined. CONCLUSIONS: A thorough knowledge of CFCS skin manifestations would help in making a positive diagnosis and differentiating CFCS from CS and NS.

Oxymatrine therapy inhibited epidermal cell proliferation and apoptosis in severe plaque psoriasis.

BACKGROUND: Psoriasis is a chronic skin disorder that manifests as epidermal keratinocyte hyperplasia. OBJECTIVES: We examined the effect of oxymatrine treatment on cell proliferation and apoptosis in skin lesions of psoriasis. PATIENTS AND METHODS: Patients with severe plaque psoriasis were treated with oxymatrine or with acitretin. The skin lesions were stained with proliferating cell nuclear antigen (PCNA), Ki-67 and Bcl-2, as well as examined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL). We performed correlations of the Psoriasis Area and Severity Index (PASI) and the proliferation and apoptosis index. RESULTS: Oxymatrine significantly reduced the psoriasis lesions as demonstrated by the reduced PASI score after treatment [6·91; 95% confidence interval (CI) 5·00-8·81, P < 0·001]. In the oxymatrine group, the mitotic index was 26·15 (95% CI 24·80-27·49) before oxymatrine treatment, decreasing to 14·52 (95% CI 13·82-15·25; P < 0·001) after treatment, but remained higher than the normal group (6·24; 95% CI 5·87-6·61, P < 0·001). Oxymatrine also inhibited the proliferation of epidermal cells in the skin lesion as indicated by the reduced proliferation index after treatment (P < 0·01). In addition, oxymatrine treatment reduced cellular apoptosis as shown by increased Bcl-2 expression and a decrease in TUNEL-positive cells. The PASI score was positively correlated with mitotic index, proliferation index and apoptotic index (TUNEL), but negatively correlated with Bcl-2 expression. CONCLUSIONS: Oxymatrine treatment reduced proliferation but inhibited apoptosis of cells in the skin lesion. The balance between cell proliferation and turnover may contribute to the significant alleviation of psoriasis by oxymatrine. What's already known about this topic? Psoriasis manifests as epidermal keratinocyte hyperplasia with proliferation, keratinocyte maturation and turnover rates. Current drugs for psoriasis may inhibit cell proliferation but could not adjust the balance of cell division, differentiation and apoptosis. What does this study add? We studied the efficacy of oxymatrine in the treatment of psoriasis and analysed the correlation of skin lesions, proliferation and apoptosis index before and after oxymatrine treatment. What is the translational message? Our study has demonstrated that oxymatrine is effective in the treatment of severe plaque psoriasis. It has comparable efficacy with acitretin. Because acitretin treatment was sometimes associated with metabolic abnormalities, our study suggests oxymatrine therapy as an alternative treatment for psoriasis in the context of acitretin allergy or adverse reactions.

Recommendations for the definition, evaluation, and treatment of nail psoriasis in adult patients with no or mild skin psoriasis: A dermatologist and nail expert group consensus.

Nail involvement in psoriasis is common, and the severity of it does not always parallel the intensity of cutaneous disease. We created a consensus group, of which the aim was to provide practical recommendations for the treatment of nail psoriasis in patients without skin psoriasis or with mild skin lesions with no indication for a systemic treatment. This collaborative process was conducted by an international panel of dermatologists with special expertise in nail disorders, using formal consensus methods. During this process, the panel strived to establish an agreement regarding the definition of nail psoriasis, the severity of nail psoriasis, and treatment response. Treatment recommendations are provided regarding nail psoriasis severity and matrix or bed involvement. Few-nail disease was considered as nail psoriasis affecting ≤3 nails. In the case of matrix involvement only, intralesional steroid injections were considered the treatment of choice. Topical steroids alone or in combination with topical vitamin D analogues were suggested for nail psoriasis limited to the nail bed. For the systemic treatment of nail psoriasis acitretin, methotrexate, cyclosporine, small molecules, and biologics may be employed.

Keratoacanthoma centrifugum marginatum after photodynamic therapy with good response to oral retinoids and topical 5-fluorouracil.

Keratoacanthoma centrifugum marginatum (KCM) is a rare variant of keratoacanthoma (KA), characterized by progressive peripheral growth, and usually devoid of deep invasion. Different systemic (oral retinoids) or topical treatments have been reported, but there is not a well-defined therapeutic protocol. We report the case of a KCM developing after photodynamic therapy (PDT) on the right leg of a 64-year-old woman. It was treated successfully with oral acitretin combined with topical 5-Fluorouracil + salicylic acid for 5 months. This is the first case of KCM developing after PDT and successfully treated with oral retinoid combined with topical treatment.

Acitretin combined with NB-UVB in the treatment of cutaneous CD30-positive anaplastic large cell lymphoma.

Cutaneous CD30+ lymphoproliferative disorders represent a spectrum of skin lymphatic reticular proliferative diseases, including lymphomatoid papulosis (LYP), primary cutaneous anaplastic large cell lymphoma (PC-ALCL), and borderline lesions between them. Although they all express CD30 as a phenotypic marker and share overlapping immunophenotypic features, they differ in clinical manifestations, pathological features, treatment, and prognosis. LYP is a kind of benign disease characterized by recurrent papules and nodules, and may spontaneously regress. PC-ALCL presents with solitary tumor or local grouped nodules characterized by large T-cells and may completely or partially resolve in fewer than half of cases. We reported a case of patient with clinical manifestation and pathologic features consistent with LYP in its early stages, which later turned into PC-ALCL. This patient was treated with acitretin combined with NB-UVB and had an obvious response.

Use of Topical and Systemic Retinoids in Solid Organ Transplant Recipients: Update and Review of the Current Literature.

BACKGROUND: Solid organ transplant recipients (SOTRs) are at an increased risk of epithelial malignancies, mainly squamous cell carcinoma, and its precursor lesions such as actinic keratoses, warts, and porokeratosis, which may respond to retinoid therapy. OBJECTIVE: To review the published evidence on the efficacy and safety of topical and systemic retinoids for the treatment and prophylaxis of malignant and premalignant conditions that mostly afflict SOTRs. MATERIALS AND METHODS: Systematic review of the literature to summarize the level of evidence and grade of recommendation for retinoid therapy with emphasis in the SOTR population. RESULTS: Acitretin has the highest strength of recommendation (Grade A) for prophylaxis of nonmelanoma skin cancer (NMSC) and treatment and prophylaxis of actinic keratoses in SOTR. In nonimmunosuppressed patients, acitretin and isotretinoin have a Grade B recommendation for treatment of recalcitrant warts. Topical retinoids have not shown efficacy in preventing NMSC in immunocompetent patients. CONCLUSION: Retinoids constitute a highly efficacious alternative for the management of the most common conditions that affect SOTRs. Acitretin has the most robust evidence for chemoprophylaxis in SOTRs. Knowledge about the specific indications and expected side effects of topical and systemic retinoids may help optimize their therapeutic potential.

Variable response to low-dose naltrexone in patients with Darier disease: a case series.

BACKGROUND: Darier disease is a rare autosomal-dominant genodermatosis with a loss of function of a Ca2+ -ATPase pump (SERCA2-pump). Clinically, the disease is characterized by red-brown keratotic papules mainly in seborrhoeic areas and has only limited and unsatisfactory treatment options. Previously, low-dose naltrexone was described as a successful treatment option in Hailey-Hailey disease, a genodermatosis with a genetic mutation coding for a similar loss of function of a Ca2+ -ATPase pump (hSPCA1-pump). OBJECTIVE: To assess the efficacy of low-dose naltrexone as a treatment option in Darier disease. METHODS: Six patients with biopsy-proven Darier disease (four had severe, one had moderate and one mild clinical manifestations). The patients received off-label therapy with naltrexone [5 mg per os (p.o.)] and magnesium [200 mg p.o.]. Patients were followed up every 4 weeks for minimally 12 weeks. Upon clinical presentation, the disease severity and subjective pain and itch scores were assessed, and standardized photographs were obtained. RESULTS: The clinical response to naltrexone varied after 12 weeks. The four patients with severe Darier disease showed worsening after initial improvement during the first 4 weeks, whereas the two patients with a mild to moderate clinical manifestation clearly improved, showing almost full remission after 12 weeks with complete flattening of the keratotic papules. CONCLUSION: Low-dose naltrexone did not have an effect on severe Darier disease compared to Hailey-Hailey disease, but it was beneficial in mild to moderate forms of the disease. Further studies are needed to confirm these observations of variable responses.

Calcipotriol plus betamethasone dipropionate aerosol foam vs. apremilast, methotrexate, acitretin or fumaric acid esters for the treatment of plaque psoriasis: a matching-adjusted indirect comparison.

BACKGROUND: Plaque psoriasis has significant impact on patients' quality of life. Topical therapy is considered the treatment mainstay for mild-to-moderate disease according to guidelines. Calcipotriol/betamethasone dipropionate (Cal/BD) [0.005%/0.05%] aerosol foam is indicated for psoriasis vulgaris treatment in adults. Cal/BD foam trials demonstrated improved efficacy and similar safety in this population. Psoriasis treatment is complicated by the broad range of disease presentation, variability and therapeutic options; particularly decisions on transition from topical to non-biologic systemic treatment are difficult. Assessing comparative effectiveness of treatment options provides meaningful value to treatment decisions. OBJECTIVE: To compare efficacy of Cal/BD foam individual patient data from pooled trials with efficacy of non-biologic systemic treatments based on aggregated patient characteristics and treatment outcomes. METHODS: Individual data from four Cal/BD foam trials in 749 psoriasis patients were pooled to conduct matching-adjusted indirect comparisons. Literature review identified non-biologic systemic treatment trials where methods, populations and outcomes align with Cal/BD foam trials. Of 3090 screened publications, four studies of apremilast, methotrexate, acitretin or fumaric acid esters (FAE) were included. RESULTS: After baseline matching, patients treated with 4 weeks of Cal/BD foam had greater Physician's Global Assessment 0/1 response compared to those treated with 16 weeks of apremilast (52.7% vs. 30.4%; P < 0.001). Patients treated with Cal/BD foam had significantly greater Psoriasis Area and Severity Index (PASI) 75 response at Week 4 compared to 16 weeks of apremilast treatment (51.1% vs. 21.6%; P < 0.001). Cal/BD foam patients demonstrated significantly greater PASI 75 response improvements at Week 4 vs. 12 weeks of methotrexate (50.8% vs. 33.5%; P < 0.001) or acitretin (50.9% vs. 31.7%; P = 0.009), and comparable response to FAE (42.4% vs. 47.0%; P = 0.451). CONCLUSIONS: Despite recent treatment advances, unmet needs for psoriasis patients remain. Cal/BD foam offers improved efficacy in baseline matched psoriasis patients compared to apremilast, methotrexate or acitretin, and comparable efficacy to FAE.

Efficacy of oxymatrine for treatment and relapse suppression of severe plaque psoriasis: results from a single-blinded randomized controlled clinical trial.

BACKGROUND: Drugs that are currently used in the treatment of psoriasis are associated with drawbacks such as rapid recrudescence, high costs and unwanted side-effects. Oxymatrine has a long history of clinical use in the treatment of hepatitis and cancer in China. OBJECTIVES: To explore the efficacy and safety of intravenous oxymatrine in patients with severe plaque psoriasis. METHODS: A total of 67 patients were randomly allocated to receive oxymatrine injections (0.6 g per day for 8 weeks) or acitretin capsules (0.75 mg kg-1 per day from week 0 to week 2 and 20-30 mg per day from week 3 to week 8) and followed up for another 24 weeks. The primary end point was the percentage of patients with ≥ 50% reduction of Psoriasis Area and Severity Index (PASI 50) at week 32. The secondary end points included the skin classification grade and the Dermatology Quality of Life Index (DLQI) score. Side-effects were recorded throughout the whole study to assess the safety profile. RESULTS: Treatment with oxymatrine or acitretin for 8 weeks significantly decreased PASI score, skin classification grade and DLQI score (P < 0.001), with no significant differences between the oxymatrine and acitretin groups in terms of PASI 50. However, at week 32, the relapse rate in the oxymatrine group was significantly lower than that of the acitretin group (P < 0.001). Moreover, while there was an increase in the number of patients with metabolic abnormalities in the acitretin group, a significant reduction was observed in the oxymatrine group. Furthermore, rates of adverse reactions were significantly decreased in the oxymatrine group compared with that of the acitretin group (P < 0.001). CONCLUSIONS: Treatment with oxymatrine effectively ameliorated severe plaque psoriasis, and was accompanied by only minor adverse effects.

The acitretin and methotrexate combination therapy for psoriasis vulgaris achieves higher effectiveness and less liver fibrosis.

Both acitretin and methotrexate are effective in ameliorating psoriatic lesion. However, their combination has been seldom reported in the treatment of psoriasis because of the warning regarding the potential hepatotoxicity of the drug interactions. This study was designed to investigate the effectiveness of such combination therapy for psoriasis vulgaris, and the potential benefit as well as side effect during the treatment. Thirty-nine patients with psoriasis vulgaris were treated with acitretin, methotrexate or their combination or as control. Similarly, K14-VEGF transgenic psoriasis-like mice were treated with these drugs. Human primary keratinocytes and hepatic stellate cells were used for analyzing their effect in vitro. The results showed that the combination therapy exhibited higher effectiveness in remitting skin lesion, but did not significantly affect the liver function of both patients and mice. Moreover, the combination groups showed less elevation of profibrotic factors in sera when compared with methotrexate alone groups accordingly. Furthermore, primary keratinocytes expressed more involucrin as well as loricrin and proliferated more slowly on the combined stimulation. Interestingly, such combination treatment induced lower expression of profibrotic factors in hepatic stellate cells. In conclusion, the acitretin-methotrexate combination therapy for psoriasis vulgaris can achieve higher effectiveness and result in less liver fibrosis.

Optimizing acitretin use in patients with plaque psoriasis.

Acitretin is one of the systemic agents used for the treatment of psoriasis. Because different acitretin dosages resulted therapeutically successful, there is no general agreement on the optimal dose regimen. To report acitretin efficacy and safety in a real-life setting, wherein patient-tailored dose regimen is usually prescribed, a retrospective analysis evaluating charts of all plaque-type psoriasis patients treated with acitretin from the clinic database was performed. PASI score improvement, as well as PASI 50, 75, 90, and 100 responses were assessed throughout the observational period. Overall, 52% PASI score reduction and a satisfactory safety profile were detected. PASI 50, 75, 90, and 100 response was achieved by 53%, 48%, 28%, and 14%, respectively. Treatment consisted on a mean daily acitretin dose of 25.01 mg. The initial dose was increased (51.2% of cases) or decreased (48.8%) prescribing a mean daily dose of 29.8 mg and 20.02 mg, respectively. This study proposed a dose regimen customized on clinical response and patient's needs, to optimized acitretin benefit.

Efficacy of Isotretinoin and Acitretin in Treatment of Frontal Fibrosing Alopecia: Retrospective Analysis of 54 Cases.

This study aimed to assess the efficacy of systemic retinoids in treating frontal fibrosing alopecia (FFA). It was based on a retrospective analysis of 54 female patients with FFA treated with: oral isotretinoin at the daily dose of 20 mg (29/54) or acitretin at the daily dose of 20 mg (11/54) or with oral finasteride 5 mg/daily (14/54). The study was conducted between 2007 and 2017. The basic of the study is the measurement of distance between the frontal hairline and the glabellar crease prior to the commencement of treatment and after 6, 12, and 24 months. The treatment with systemic retinoids lasted between 12 and 16 months (the mean duration of treatment was 13.5 months). The primary treatment goal was defined as no further progression of disease after 12 months of treatment, while the secondary treatment goal was defined as no further progression of disease following the discontinuation of systemic retinoids. The primary treatment goal was achieved by 76% (23/29) of patients treated with isotretinoin, 73% (8/11) of patients treated with acitretin, and 43% (6/14) of patients treated with finasteride. The secondary treatment goal was achieved by 72% (21/29) of patients treated with isotretinoin, 73% (8/11) of patients treated with acitretin, and 43% (6/14) of patients treated with finasteride. Thus, the administration of systemic retinoids may be beneficial for the stabilization of frontal hairline in patients with FFA.

J Drugs Dermatol. 2017;16(10):988-992.

Hypertrophic lichen planus - successful treatment with acitretin.

Lichen planus classifies into different subtypes according to morphology and location. Hypertrophic LP (HLP) manifests a great challenge due to persistent itching, the risk to develop into squamous cell carcinoma and therapeutic resistance. We report two clinical cases exemplary for the successful treatment of dramatic-resistant HLP with acitretin.

Alitretinoin and acitretin in severe chronic hand eczema; results from a retrospective daily practice study.

Acitretin has been used off-label for years to treat chronic hand eczema, but acitretin is less often prescribed as alitretinoïne was approved. This study evaluates both retinoids in a daily practice cohort of patients with severe chronic hand eczema in terms of drug survival and reasons for discontinuation. Patients using alitretinoin or acitretin between 01-01-1994 and 01-08-2015 were included in this retrospective daily practice study and analyzed by Kaplan-Meier drug survival curves. Potential determinants were analyzed by Cox regression analyses. Ninety-five patients were treated with alitretinoin and 109 patients with acitretin. The main reasons for discontinuation were adverse events and cleared hand eczema, 29.5 and 27.4% in alitretinoin versus 43.1 and 23.9% in acitretin. Patients with hyperkeratotic hand eczema had most often a good effect of treatment: 68.3% in alitretinoin and 50.7% in acitretin treatment. The drug survival rates of alitretinoin and acitretin after 12, 24, 36, and 52 weeks were 69.3, 45.1, 19.6, 7.0% and 74.3, 45.5, 33.8, 23.2%, respectively. Alitretinoin and acitretin are effective treatment options for patients with hand eczema. However, both treatments were more effective in patients with hyperkeratotic hand eczema. Fewer patients discontinued alitretinoin compared with acitretin due to adverse events.