Ultrasound Evaluation of the Effectiveness of the Use of Acitretin in the Treatment of Nail Psoriasis

The study aimed to evaluate the effect of retinoid treatment on the morphological changes in the nail apparatus in patients with nail psoriasis. Material and methods: 41 patients aged 32 to 64 with nail psoriasis, without clinical signs of psoriatic arthritis, started on acitretin 0.6 to 0.8 mg kg b.w./d, for six months and 28 people in the control group were included in the study. Both groups had ultrasound examination of fingernails and digital extensor tendon in the distal interphalangeal joints. In psoriatic patients, US examination was conducted before starting the treatment and after six months. A total of 685 nails were examined. Results: After six months of treatment, there was a reduction in the thickness of the nail bed and nail matrix (p = 0.046 and p = 0.031, respectively). The thickness of the nail plates decreased, although it was statistically insignificant (p = 0.059) and it was higher than in the control group (p = 0.034). The reduced severity of clinical nail changes after six months of retinoid treatment did not correlate with the reduction in extensor tendon thickness in any group of patients. Conclusions: In patients with nail psoriasis, acitretin treatment resulted in a rapid decrease in the thickness of the nail bed and matrix, but it did not affect the thickness of the nail plate after six months. There was no effect of acitretin on the digital extensor tendon thickness or the increased blood supply to the tendon area. The results of the study may indicate the usefulness of ultrasound nail examinations in patients with nail psoriasis not only to assess the advancement of morphological changes and response to treatment, but also to choose the potential treatment.

Retinoidy – mechanizm działania i zakres efektów niepożądanych po stosowaniu doustnym i aplikacji na skórę

Vitamin A derivatives are increasingly used in cosmetic procedures and pharmacological treatment. They can greatly affect the appearance of the skin, but like all other active substances – they can cause side effects (SEF). The aim of the study was to show the problems in which retinoids are used in dermatology and cosmetology, the way they work and the indication of possible side effects. Methods of minimizing side effects were analyzed and SEF differences after systemic and skin application were checked. Side effects caused by the use of retinoids are very common, dose-dependent, and the level of danger for the body varies from mild (dry skin) to very serious (teratogenicity, depression). The decision about taking retinoid treatment is made by the specialist after the interview. The appearance of SEF may require modification of the form or dose, sometimes it requires cessation of treatment.

A harlequin ichthyosis pig model with a novel ABCA12 mutation can be rescued by acitretin treatment

Harlequin ichthyosis (HI) is a severe genetic skin disorder and caused by mutation in the ATP-binding cassette A12 (ABCA12) gene. The retinoid administration has dramatically improved long-term survival of HI, but improvements are still needed. However, the ABCA12 null mice failed to respond to retinoid treatment, which impedes the development of novel cure strategies for HI. Here we generated an ethylnitrosourea mutagenic HI pig model (named Z9), which carries a novel deep intronic mutation IVS49-727 A>G in the ABCA12 gene, resulting in abnormal mRNA splicing and truncated protein production. Z9 pigs exhibit significant clinical symptom as human patients with HI. Most importantly, systemic retinoid treatment significantly prolonged the life span of the mutant pigs via improving epidermal maturation, decreasing epidermal apoptosis, and triggering the expression of ABCA6. Taken together, this pig model perfectly resembles the clinical symptom and molecular pathology of patients with HI and will be useful for understanding mechanistic insight and developing therapeutic strategies.

SY1425 (tamibarotene) Induces Profound Transcriptional Changes in AML Tumors with High Retinoic Acid Receptor Alpha

Retinoic acid receptor alpha (RARα) regulates myeloid differentiation and proliferation through the regulation of specific sets of genes. When unbound by a ligand, RARα is a repressive transcription factor while in its ligand-bound state it functions as a transcriptional activator. Previously, blast cells from a subset of individuals with non-APL AML were found to have a super-enhancer (SE), as revealed by H3K27 acetyl ChIP-Seq, associated with the RARA locus (hereafter called RARA-high), suggesting that tumor cell proliferation may have a dependency on RARA that can be exploited for therapeutic benefit. SEs are exceptionally large, highly active chromatin regions that are densely occupied by transcription factors and have been implicated in oncogene expression. Indeed, RARA-high non-APL AML cell lines showed >1000-fold increased sensitivity compared to RARA-low cells to the potent and selective RARα agonist SY-1425 (tamibarotene) as well as efficacy in non-APL AML patient derived xenograft models with a dependency on RARA. Since RARα is a transcription factor and the direct target of SY-1425, we investigated the change SY-1425 had on the transcriptional program of non-APL AML cell lines and the mechanism underlying those changes. Expression profiling on a panel of AML cell lines revealed that RARA-high AML cell lines had profound transcriptional changes in response to SY-1425, with 437 genes significantly changed, while RARA-low cell lines did not show significant gene expression changes. Gene set enrichment analysis (GSEA) of three RARA-high AML cell lines revealed that the genes upregulated by SY-1425 in the RARA-high cells are associated with immune signaling, interferon induction, protein secretion, and pathways associated with complement, MHC and integrin functions, all pathways indicative of more differentiated blood cells. Signatures downregulated by SY-1425 include MYC target genes. These findings are consistent with SY-1425 increasing the expression of genes involved in differentiation and decreasing those involved in proliferation. Genome-wide ChIP-Seq analysis revealed an increase in H3K27 acetylation at loci found to have strong RARα peaks as well as increased expression of those genes upon treatment with SY-1425. Together, these data support a model in which RARα binding nucleates functional enhancers in response to SY-1425 thereby upregulating proximal target gene expression and promotion of differentiation. The gene expression and epigenomic responses of RARA-high AML cell lines to SY-1425 were found to be similar to the responses of an APL cell line (NB-4) to retinoids or SY-1425. Gene sets identified in response to either retinoid treatment or genetic perturbation, such as forced expression or RAR-fusions or knockdown, matched the gene sets identified in RARA-high AML cell lines. Furthermore, the quantitative response of both NB-4 and RARA-high AML cell lines to SY-1425 was found to be similar. Across the genome, RARα binding was highly conserved between NB-4 and RARA-high AML cell lines with less overlap with the RARA-low cell lines. For example, the transcriptional and H3K27 acetylation alterations at the known PML-RARα target gene TGM2 following retinoid treatment was similar in NB-4 and the RARA- high cell lines. This locus also had a strong RARα binding site that is conserved among the cell lines and co-localized with a strong H3K27 acetylation peak. Consistent with the pattern of occupancy of RARα on the genome, the transcriptional response of the RARA enhancer-high cell lines to SY-1425 treatment was similar to the response of APL ex-vivo patient samples to retinoic acid treatment. These data support a model of a common biological response to retinoids between cells with the RARA-PML translocation in APL and cells with the RARA SE in AML. The mechanistic studies described here support the therapeutic potential of SY-1425 in myeloid leukemia patients who have a SE associated with RARA. A biomarker directed clinical trial of SY-1425, a potent and selective RARα agonist, in a subset of AML and MDS patients with an altered RARA locus (clinicaltrials.gov, NCT02807558) is supported by these data. Disclosures Fiore: Syros Pharmaceuticals: Employment, Equity Ownership. McKeown:Syros Pharmaceuticals: Employment, Equity Ownership. Lee:Syros Pharmaceuticals: Employment, Equity Ownership. Eaton:Syros Pharmaceuticals: Employment, Equity Ownership. Fritz:Syros Pharmaceuticals: Employment, Equity Ownership.

Side effects of retinoid therapy on the quality of vision

Retinoids are compounds chemically related to vitamin A, which are frequently used in dermatological practice (1). They are characterized by numerous mechanisms of action leading to normalization of keratinocyte proliferation and maturation. They have anti-seborrhoeic, immunomodulatory and anti-inflammatory effects (1, 2). A number of side effects to retinoid treatment have been recorded; one group of such side effects relates to eyes and vision. Dry eye syndrome and blepharoconjunctivitis are the most common side effects, appearing in 20-50 % of patients treated with retinoids. They often contribute to the occurrence of other side-effects such as eye discomfort and contact lens intolerance. Due to the widespread use in clinical practice, the adverse effects, including ocular side effects, should be studied. To confirm the variety of adverse effects of retinoids, several case reports of rare side-effects are presented.