Therapeutic Efficacy of Etretinate on Cutaneous-type Adult T-cell Leukemia-Lymphoma.

Cutaneous-type adult T-cell leukemia-lymphoma is treated with antiviral or skin-directed therapy. Medications that are used to treat skin lesions of cutaneous T-cell lymphomas are also used for the cutaneous-type adult T-cell leukemia-lymphoma. Etretinate, a synthetic retinoid, has been used for treating cutaneous T-cell lymphomas; however, its clinical effectiveness for the treatment of cutaneous-type adult T-cell leukemia-lymphoma has not been fully studied. We conducted a retrospective assessment of the efficacy and safety of etretinate in 9 patients with cutaneous-type adult T-cell leukemia-lymphoma. Complete and partial responses to etretinate were observed in 1 and 7 patients, respectively. Among the responders, remission was maintained for more than 6 years in 2 patients. These results suggest that etretinate is a promising treatment option for cutaneous-type adult T-cell leukemia-lymphoma.

Treatment patterns and drug survival for generalized pustular psoriasis: A patient journey study using a Japanese claims database.

Generalized pustular psoriasis (GPP) is a potentially life-threatening skin disease. Although several medications are approved for treating GPP in Japan, there are limited data on real-world treatment patterns or drug survival (the number of prescribed days of treatment). This retrospective cohort study describes drug survival and treatment patterns of patients with newly diagnosed GPP (International Classification of Diseases, 10th Revision code L40.1), and ≥1 year of follow-up, using de-identified claims data (Medical Data Vision Co., Ltd.) from January 2016 to August 2021. Most (97.0%) of the 434 Japanese patients received first-line therapy of etretinate (26.4%), topical medications (14.7%), or cyclosporin (14.3%); 80.0% and 60.1% of patients received a second and third line of therapy (LOT), respectively. Use of etretinate (12.6%) and cyclosporin (5.9%) decreased in second-line therapies, whereas use of biologics (interleukin [IL]-17, 14.3%; IL-23 inhibitors, 7.6%) and topical medications (22.1%) increased or remained consistent. Approximately 50% of biologics were prescribed in combination with systemic medications or systemic corticosteroids. Median (range) time to next therapy (TTNT) was 2.8 (0.03-48.07) months for first-line therapy and 3.3 (0.03-52.97) months for all other LOTs. TTNT was longer for combination therapies (up to 16.5 months) compared with monotherapies (up to 7.5 months). Biologics exhibited longer drug survival with fewer treatment episodes compared with non-biologic systemic medications. Among frequently used therapies, the median (95% confidence interval) drug survival was 8.8 (5.8-11.8) months for etretinate, 4.3 (2.2-6.9) months for systemic corticosteroids, and 19.6 (16.1-26.7) months for secukinumab. Treatment patterns varied considerably, highlighting the need for treatment algorithms and effective, well-tolerated medications to support patients to help them remain on long-term therapy.

Acitretin prescribing patterns in women of childbearing potential.

BACKGROUND: Acitretin is indicated for severe psoriasis, but it is also a potent teratogen whose use should be avoided in women of childbearing potential. Topical medications, phototherapy, cyclosporine A, and new biologic agents provide safer alternatives for women of childbearing age with moderate to severe psoriasis. PURPOSE: To determine the demographics of acitretin prescribing patterns as an assessment of acitretin use in women of child-bearing potential. METHODS: We examined National Ambulatory Medical Care Survey (NAMCS) data from the years 1990-2009 to determine demographic data on patients who were prescribed etretinate or acitretin. We used age under 50 as a proxy for childbearing potential. RESULTS: From 1996-2009, there were an estimated 29 million office visits for psoriasis. Females accounted for 14.3 million of these visits, and 6.5 million (45.6%) of them were under the age of 50. The NAMCS contained only one record of a female patient under the age of 50 being prescribed acitretin from 1996-2009, the years during which acitretin had been available in the United States. This corresponds to an estimated 2.3% of all psoriasis patients prescribed acitretin during this time (20,000 out of 890,000). LIMITATIONS: The NAMCS estimates national trends based on a large nationwide database. While the use of acitretin in women under 50 is low, the precision of the estimate is limited by the small sample size provided by this database. CONCLUSIONS: There are now many alternative treatments besides acitretin for women of childbearing potential with moderate to severe psoriasis. Acitretin is used at most infrequently in this population. In females of reproductive potential, acitretin should be reserved for non-pregnant patients who are unresponsive to other therapies or whose clinical condition contraindicates the use of other treatments.

Oral erosive lichen planus associated with thymoma treated with etretinate.

A 68-year-old Japanese woman was referred to our hospital with a 1-year history of multiple erosions on the oral mucosa and a few pruritic, bean-sized, reddish-blue plaques on the body. Based on physical examination, pathological findings, and immunofluorescence findings, a diagnosis of lichen planus (LP) was made. Computed tomography scan revealed a thymoma. After thymectomy, cutaneous LP lesions subsided spontaneously. Oral lesions responded well to oral etretinate therapy. We speculate that direct tissue injury by CD8(+) T cells, activated by abnormal regulation of lymphocytes within the thymus, may cause LP.

Trends in prescriptions of oral medications for psoriasis: A single-center retrospective study.

The systemic treatment of psoriasis has changed markedly with the introduction of many novel drugs. However, clinicians have had limited opportunities to evaluate these new therapies. One of the new drugs, apremilast (a phosphodiesterase-4 inhibitor), was approved in 2017 in Japan. We previously reported oral treatment for psoriasis before the introduction of apremilast. In this study, we investigated the impact of apremilast on oral medication for psoriasis by comparing data obtained before and after apremilast became available. This retrospective study enrolled patients who visited the Department of Dermatology, Fukuoka University Hospital, who were diagnosed with psoriasis and treated with anti-psoriatic oral medications. Patients were divided into two groups: Group 1, who first visited our clinic between January 2010 and March 2016; and Group 2, who first visited our clinic between April 2016 and March 2022. The information collected included patient demographics, drug use (apremilast, cyclosporine, methotrexate, and etretinate), and treatment duration. In Group 1 (n = 149 patients), cyclosporine, methotrexate, and etretinate were prescribed to 59.1%, 16.6%, and 24.3% of the patients, respectively. In Group 2 (n = 129 patients), apremilast was prescribed to 52.5% of patients, while the number of prescriptions for cyclosporine and etretinate had decreased to 17.1% and 8.3%, respectively. The number of methotrexate prescriptions did not change significantly. Apremilast, methotrexate, and etretinate had longer continuation rates than cyclosporine in Group 2. In conclusion, apremilast replaced cyclosporine and etretinate mainly because of its better safety profile, whereas methotrexate remained in constant demand in both eras. New oral treatments for psoriasis, such as tyrosine kinase-2 inhibitors, are now in the pipeline, and our data will serve as a control for oral anti-psoriatic medicine before the coming era.

Epidemiological survey of patients with pustular psoriasis in the Japanese Society for Psoriasis Research from 2017 to 2020.

The Japanese Society for Psoriasis Research (JSPR) has been conducting annual epidemiological surveys of patients with pustular psoriasis in Japan since 2017. This study aimed to conduct a recent epidemiological analysis of patients with pustular psoriasis who were enrolled in the JSPR from 2017 to 2020. A total of 291 patients from 131 medical institutions were enrolled, of which 47.4% (138 cases) were males and 52.6% (153 cases) were females. The mean ± standard deviation (SD) age of the patients was 57.4 ± 20.3 years (males, 61.2 ± 17.3 years; females, 54.1 ± 22.1 years). The mean ± SD age of the patients at disease onset was 48.5 ± 22.5 years (males, 50.8 ± 20.6 years; females, 46.4 ± 24.0 years). The types of pustular psoriasis observed included the von Zumbusch type (59.8%), annular pustular psoriasis (8.2%), impetigo herpetiformis (6.5%), and acrodermatitis continua of Hallopeau (4.8%), of which, the majority of the patients with impetigo herpetiformis were female. Among the patients, 58.4% were treated with oral medications and 44.0% were treated with biologics. The most common oral medication prescribed was etretinate (52.4%), followed by corticosteroids (24.7%) and cyclosporin (22.9%). The most common biologics used were IL-17 inhibitors (ixekizumab [28.1%] and secukinumab [22.7%]), followed by tumor necrosis factor (TNF) inhibitors (infliximab [15.6%]) and IL-23 inhibitors (guselkumab [14.8%] and risankizumab [10.2%]). This survey thus provides new and significant information regarding the recent perspective of pustular psoriasis, such as patient characteristics and treatment trends, in Japan.

Generalized pustular psoriasis in a child: observation of long-term combination therapy with etretinate and calcipotriol for 16 years.

Generalized pustular psoriasis (GPP) is a rare condition in young children. It is difficult to treat and may require long-term systemic therapy. We report the long-term course of a 3-year-old boy whose onset of psoriasis dated to age 7 months. He was treated with etretinate and psoralen plus ultraviolet A therapy initially and then with etretinate alone, and at age 12, topical calcipotriol was added. At the age of 19, he had been taking oral retinoids for 16 years, with a mean dose of etretinate of 0.22 mg/kg per day, a total amount of approximately 37 g, without evidence of stunted growth, ligamentous calcification, hyperostosis, or hepatic toxicity.

Pityriasis rubra pilaris type 1 spontaneously resolving after 20 years.

Pityriasis rubra pilaris (PRP) is an uncommon, idiopathic, papulosquamous eruption. We report a longitudinal study of a patient with PRP type 1 who was treated with retinoid therapy for 9 years and whose symptoms resolved spontaneously after 20 years. There are no data in the literature on the disease course of PRP type 1 persisting beyond the usual 3 years. This case highlights both the extreme chronicity of PRP and the possibility of remission after many years of active disease.

Evaluation of the transfusion safety of blood products and determination of plasma concentrations of acitretin and etretinate in patients receiving transfusions.

BACKGROUND: Acitretin and etretinate are potentially teratogenic. Many people taking acitretin for psoriasis have donated blood during the deferral period in Korea. Therefore, many of the blood products from these donors treated with acitretin have been circulated in Korea. STUDY DESIGN AND METHODS: A high-performance liquid chromatography system (HP 1050, Agilent Technologies) was used to measure the drug concentrations in five blood products and in patients. Sixty patients taking acitretin were enrolled to determine their plasma drug levels. Forty-one female patients were recruited to investigate the residual plasma levels of acitretin and etretinate in relation to their teratogenicity. We calculated the elimination rate of acitretin and etretinate during the manufacturing process. RESULTS: Sixty individuals taking acitretin expressed variable acitretin (<2.0-206.8 ng/mL) and etretinate levels (<2.0-9.1 ng/mL). All patients that had a transfusion had concentrations of acitretin and etretinate lower than the lower limit of quantification (LLOQ; 2 ng/mL). The concentrations of acitretin and etretinate in five blood products were less than the LLOQ. Approximately 98.84 percent (log value, 1.94) of the acitretin and 99.93 percent (log value, 3.14) of the etretinate was eliminated during the manufacturing process of albumin. More than 99.99 percent (log values, 5.95-15.76) of acitretin and etretinate was eliminated during the manufacturing processing of immunoglobulin and blood coagulation factors. CONCLUSIONS: We confirmed the effective manufacturing processing of various blood products. We also demonstrated that individuals receiving transfusions with blood products originating from donors treated with acitretin were not at risk for significant exposure to the acitretin and etretinate.

Moving toward bioadjuvant approaches to head and neck cancer prevention.

Head and neck squamous cell carcinoma affects >45,000 Americans annually. Patients who are successfully treated for their primary tumor are at high risk of developing a second primary tumor, making effective preventive strategies highly desirable for this disease. Although a landmark study in 1990 suggested some benefit of high-dose retinoids in head and neck cancer prevention, subsequent trials using more tolerable doses have shown limited clinical success. Newer preventive strategies have included bioadjuvant therapy combining retinoids with interferon and alpha-tocopherol, combinations of molecularly targeted agents, and oncolytic viruses. Furthermore, considerable evidence has supported a cancer protective role for several nutrients, including green tea and curcumin analogs. Natural compounds such as these with favorable long-term safety profiles might be particularly suited to the cancer prevention setting, in which patients will usually tolerate only moderate risk and toxicity.

Case of harlequin ichthyosis with a favorable outcome: Early treatment and novel, differentially expressed, alternatively spliced transcripts of the ATP-binding cassette subfamily A member 12 gene.

Harlequin ichthyosis (HI) is the most severe form of autosomal recessive congenital ichthyosis, with a high mortality rate. Recent advances in neonatal care and the early administration of retinoids have improved the survival rate of HI. Here, we present a case of HI who was successfully treated with early administration of etretinate and showed good prognosis. Next-generation sequencing identified novel mutations of the ATP-binding cassette subfamily A member 12 gene (ABCA12), c.5884+4_+5delAA and c.7239G>A, which caused skipping of exons 39 and 48, respectively. Transcripts with exon 48 skipping, which cause a deletion in the second ATP-binding cassette of ABCA12, were dominantly expressed in the skin. Besides the early administration of etretinate, the differential expression of the mutant protein with limited segmental deletion of ABCA12 may be related to the favorable outcome of our patient.

Compound heterozygous mutations including a de novo missense mutation in ABCA12 led to a case of harlequin ichthyosis with moderate clinical severity.

Harlequin ichthyosis (HI) is one of the most devastating genodermatoses. Recently, ABCA12 mutations were identified as the cause of HI. A newborn Japanese male demonstrated the typical features of HI. The patient was treated with oral etretinate and his general condition has been good (now aged 1.5 years). This patient with moderate clinical severity was compound heterozygous for a novel de novo missense mutation 1160G > A (S387N) in exon 10 and a maternal deletion mutation 4158_4160delTAC (T1387del) in exon 28 of ABCA12. T1387del was a deletion of a highly conserved threonine residue within the first adenosine 5' triphosphate-binding domain and is thought to seriously affect the function of the ABCA12 protein. Conversely, the residue 387 is located outside the known active sites of ABCA12 and S387N is predicted not to lead to a serious functional deficiency in ABCA12. Electron microscopy revealed abnormal lamellar granules in the granular layer cells and a moderate number of lipid vacuoles in the cornified cells. Disturbed glucosylceramide transport was confirmed in the cultured keratinocytes from the patient. No de novo mutation in ABCA12 has yet been reported either in HI or lamellar ichthyosis. The present case suggested that a de novo ABCA12 mutation might underlie HI.

The treatment of psoriasis and psoriatic arthritis: an interdisciplinary approach.

Psoriatic arthritis is a common inflammatory arthritis associated with psoriasis, occurring in 5% to 40% of patients with cutaneous disease. Recently, there has been an increased appreciation of the need to use an integrated approach to these 2 diseases, considering both entities when determining therapeutic choices. In this review, the available therapeutic options for psoriatic arthritis are considered, along with the potential benefit that these medications may have for cutaneous psoriasis. Finally, a conceptual model for the therapy of psoriasis and psoriatic arthritis, the Four Quadrant Model, is presented as a simplified framework to use when considering treatment for psoriatic disease.

Etretinate blood levels in monitoring of compliance and contamination in a chemoprevention trial.

We measured serum etretinate to monitor compliance in an ongoing chemoprevention trial in which heavy smokers are randomized to either etretinate or placebo orally for 6 months. Blood is collected for determination of etretinate levels before treatment and then at 2, 4, 8, 16, and 24 weeks after randomization. The monitoring strategy was assessed by interim evaluation. There were 276 posttreatment samples available from 75 randomized subjects of whom 36 received etretinate and 39 placebo. The mean coefficient of variation for the internal standard retinyl acetate in serum was 4.16% for the high-pressure liquid chromatography method used. Among positive samples, the mean etretinate concentration was 25.7 ng/mL (SD, 23.4). Of the 131 samples obtained from subjects randomized to etretinate, 120 or 91.6% had detectable levels compared with 4 of 145 or 2.8% placebo samples. Among the 36 subjects given etretinate, at least one positive test occurred. In 27 of these 36 participants, etretinate was detected in every sample obtained. In the other nine, the absence of drug could be explained by pill counts or a history of discontinuation of treatment for six. Among the 39 subjects given placebo, the four positive samples were from four individuals, all of whom were negative on three other occasions. These data confirm the usefulness of the monitoring system we used and indicate that compliance and/or contamination will not be major problems in this trial.

Fibrodysplasia ossificans progressiva-like condition in a cat.

Fibrodysplasia ossificans progressiva (FOP)-like condition was diagnosed in a Japanese domestic cat with stiffness, marked atrophy of the muscles, and limited mobility of all joints in both the pelvic limbs. Etretinate, a retinoid, was used for medical management; however, no improvement in the clinical signs was observed. Inheritance of the disorder has not yet been demonstrated. Furthermore, the clinical signs and histopathological findings of feline FOP-like condition in the present case differed from those of the previously reported cases.