Alitretinoin as a Treatment Modality for Ichthyosis in Women of Childbearing Age: A Case Series and Review of the Literature.

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.

Efficacy of alitretinoin in the treatment of Darier disease: a case report.

Darier disease is a rare autosomal dominant genodermatosis that initially first presents in adolescence with scaly reddish brown keratotic papules and plaques with a seborrheic and intertriginous distribution. The absence of specific targeted medications complicates the treatment process, and managing resistant cases can prove challenging due to recurrent exacerbations that may result in serious complications such as secondary bacterial and viral infections. Treatments of choice include antiseptics, topical corticosteroids, and systemic retinoids, mainly acitretin and isotretinoin. We report the case of a female patient with Darier disease that was unsuccessfully treated with acitretin and isotretinoin but showed significant improvement with alitretinoin. Previous reports on the efficacy of alitretinoin in Darier disease are reviewed.

Energy status regulates levels of the RAR/RXR ligand 9-cis-retinoic acid in mammalian tissues: Glucose reduces its synthesis in ß-cells.

9-cis-retinoic acid (9cRA) binds retinoic acid receptors (RAR) and retinoid X receptors (RXR) with nanomolar affinities, in contrast to all-trans-retinoic acid (atRA), which binds only RAR with nanomolar affinities. RXR heterodimerize with type II nuclear receptors, including RAR, to regulate a vast gene array. Despite much effort, 9cRA has not been identified as an endogenous retinoid, other than in pancreas. By revising tissue analysis methods, 9cRA quantification by liquid chromatography-tandem mass spectrometry becomes possible in all mouse tissues analyzed. 9cRA occurs in concentrations similar to or greater than atRA. Fasting increases 9cRA in white and brown adipose, brain and pancreas, while increasing atRA in white adipose, liver and pancreas. 9cRA supports FoxO1 actions in pancreas ß-cells and counteracts glucose actions that lead to glucotoxicity; in part by inducing Atg7 mRNA, which encodes the key enzyme essential for autophagy. Glucose suppresses 9cRA biosynthesis in the ß-cell lines 832/13 and MIN6. Glucose reduces 9cRA biosynthesis in 832/13 cells by inhibiting Rdh5 transcription, unconnected to insulin, through cAMP and Akt, and inhibiting FoxO1. Through adapting tissue specifically to fasting, 9cRA would act independent of atRA. Widespread occurrence of 9cRA in vivo, and its self-sufficient adaptation to energy status, provides new perspectives into regulation of energy balance, attenuation of insulin and glucose actions, regulation of type II nuclear receptors, and retinoid biology.

Kaposi Sarcoma Associated with Tofacitinib Use in a Patient with Rheumatoid Arthritis.

Kaposi sarcoma is a rare vascular malignancy associated with HHV-8 infection. Four variants of Kaposi sarcoma have been described: Classic, African, HIV-associated, and iatrogenic. Iatrogenic Kaposi sarcoma is typically associated with immunosuppression and organ transplantation. We present a case of iatrogenic Kaposi sarcoma associated with tofacitinib therapy. A 69-year-old woman with rheumatoid arthritis receiving tofacitinib presented with multiple firm, purple-red nodules and brown plaques on the left lower extremity and a single lesion on the right medial calf. Clinicopathologic correlation confirmed a diagnosis of Kaposi sarcoma. Tofacitinib was discontinued and she was started on Alitretinoin 0.1% gel bid. The purple-red Kaposi sarcoma nodules decreased 50% in size after 4 months and resolved at 1 year off the tofacitinib and initiation of alitretinoin gel. As the use of immunomodulators and biologics continues to expand, awareness of this association is important for prompt diagnosis and management.

Exploring the interactions of antihistamine with retinoic acid receptor beta (RARB) by molecular dynamics simulations and genome-wide meta-analysis.

Kaposi sarcoma (KS) is one of the most common AIDS-related malignant neoplasms, which can leave lesions on the skin among HIV patients. These lesions can be treated with 9-cis-retinoic acid (9-cis-RA), an endogenous ligand of retinoic acid receptors that has been FDA-approved for treatment of KS. However, topical application of 9-cis-RA can induce several unpleasant side effects, like headache, hyperlipidemia, and nausea. Hence, alternative therapeutics with less side effects are desirable. There are case reports associating over-the-counter antihistamine usage with regression of KS. Antihistamines competitively bind to H1 receptor and block the action of histamine, best known for being released in response to allergens. Furthermore, there are already dozens of antihistamines that are FDA-approved with less side effects than 9-cis-RA. This led our team to conduct a series of in-silico assays to determine whether antihistamines can activate retinoic acid receptors. First, we utilized high-throughput virtual screening and molecular dynamics simulations to model high-affinity interactions between antihistamines and retinoic acid receptor beta (RARß). We then performed systems genetics analysis to identify a genetic association between H1 receptor itself and molecular pathways involved in KS. Together, these findings advocate for exploration of antihistamines against KS, starting with our two promising hit compounds, bepotastine and hydroxyzine, for experimental validation study in the future.

The Endogenous Dual Retinoid Receptor Agonist Alitretinoin Exhibits Immunoregulatory Functions on Antigen-Presenting Cells.

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.

Efficacy and safety of dupilumab in patients with severe chronic hand eczema with inadequate response or intolerance to alitretinoin: a randomized, double-blind, placebo-controlled phase IIb proof-of-concept study.

BACKGROUND: Effective treatment options for patients with chronic hand eczema (CHE) are scarce. Dupilumab is licensed for the treatment of moderate-to-severe atopic dermatitis and has shown promising results for the treatment of hand eczema in other studies. OBJECTIVES: To evaluate the efficacy and safety of dupilumab in adult patients with severe CHE (subtypes recurrent vesicular hand eczema or chronic fissured hand eczema) who have an inadequate response/intolerance to alitretinoin, or when alitretinoin is medically inadvisable. METHODS: In this 16-week, randomized, double-blind, placebo-controlled proof-of-concept phase IIb trial, patients with severe CHE were randomized 2 : 1 to dupilumab 300 mg or placebo subcutaneously every 2 weeks. Patients visited the outpatient clinic at the initiation of the study drug, and every 4 weeks until 16 weeks of treatment. The primary endpoint was the proportion of patients achieving at least a 75% improvement on the Hand Eczema Severity Index score (HECSI-75) at week 16. Adverse events were monitored during each visit. The study was registered on ClinicalTrials.gov (identifier NCT04512339). RESULTS: In total, 30 patients were randomized, and 29 patients received the assigned study drug (dupilumab n = 20, placebo n = 9). At week 16, more patients achieved HECSI-75 in the dupilumab group than in the placebo group {95% [95% confidence interval (CI) 73.1-99.7] vs. 33% [95% CI 9.0-69.1]}. Dupilumab also showed greater least square mean percentage change from baseline to week 16 in peak pruritus Numerical Rating Scale compared with placebo [-66.5 ± 10.7 (95% CI -88.6 to -44.5) vs. -25.3 ± 17.0 (95% CI -60.1-9.4)]. Adverse events were similar for the dupilumab and placebo groups and were mostly mild. There were no serious adverse events, nor did any of the adverse events lead to discontinuation of the study drug. CONCLUSIONS: Dupilumab was efficacious and well tolerated. Larger studies of longer duration are needed to provide more evidence on the -efficacy of dupilumab in CHE. Moreover, larger studies could also enable comparisons between clinical subtypes or aetiological -diagnoses.

Effects of all-trans and 9-cis retinoic acid on differentiating human neural stem cells in vitro.

Cyanobacterial blooms are known sources of environmentally-occurring retinoid compounds, including all-trans and 9-cis retinoic acids (RAs). The developmental hazard for aquatic organisms has been described, while the implications for human health hazard assessment are not yet sufficiently characterized. Here, we employ a human neural stem cell model that can differentiate in vitro into a mixed culture of neurons and glia. Cells were exposed to non-cytotoxic 8-1000 nM all-trans or 9-cis RA for 9-18 days (DIV13 and DIV22, respectively). Impact on biomarkers was analyzed on gene expression (RT-qPCR) and protein level (western blot and proteomics) at both time points; network patterning (immunofluorescence) on DIV22. RA exposure significantly concentration-dependently increased gene expression of retinoic acid receptors and the metabolizing enzyme CYP26A1, confirming the chemical-specific response of the model. Expression of thyroid hormone signaling-related genes remained mostly unchanged. Markers of neural progenitors/stem cells (PAX6, SOX1, SOX2, NESTIN) were decreased with increasing RA concentrations, though a basal population remained. Neural markers (DCX, TUJ1, MAP2, NeuN, SYP) remained unchanged or were decreased at high concentrations (200-1000 nM). Conversely, (astro-)glial marker S100ß was increased concentration-dependently on DIV22. Together, the biomarker analysis indicates an RA-dependent promotion of glial cell fates over neural differentiation, despite the increased abundance of neural protein biomarkers during differentiation. Interestingly, RA exposure induced substantial changes to the cell culture morphology: while low concentrations resulted in a network-like differentiation pattern, high concentrations (200-1000 nM RA) almost completely prevented such network patterning. After functional confirmation for implications in network function, such morphological features could present a proxy for network formation assessment, an apical key event in (neuro-)developmental Adverse Outcome Pathways. The described application of a human in vitro model for (developmental) neurotoxicity to emerging environmentally-relevant retinoids contributes to the evidence-base for the use of differentiating human in vitro models for human health hazard and risk assessment.

Structural characterization of 1,3-bis-tert-butyl monocyclic benzene derivatives with agonistic activity towards retinoid X receptor alpha.

Retinoid X receptor alpha (RXRα) plays pivotal roles in multiple biological processes, but limited information is available on the structural features of chemicals that show low affinity for RXRα, but nevertheless cause significant activation, though these may represent a human health hazard. We recently discovered that several industrial chemicals having 1,3-bis-tert-butylbenzene as a common chemical structure exhibit agonistic activity towards rat RXRα. In this study, we explored the structure-activity relationship of 1,3-bis-tert-butyl monocyclic benzene derivatives for RXRα activation by means of in vitro and in silico analyses. The results indicate that a bulky substituent at the 5-position is favorable for agonistic activity towards human RXRα. Since 1,3-bis-tert-butyl monocyclic benzene derivatives with bulky hydrophobic moieties differ structurally from known RXRα ligands such as 9-cis-retinoic acid and bexarotene, our findings may be helpful for the development of structural alerts in the safety evaluation of industrial chemicals for RXRα-based toxicity to living organisms.

Mutation of two residues converts the ligand-binding domain of RXRα into a uniform monomer without impairing the binding of retinoic acid and cofactors.

Retinoid X receptor (RXRα) is a nuclear receptor (NR) for retinoic acid (RA) and regulates various NR signaling pathways. Ligand-binding domain (LBD) of RXRα can bind with its ligand 9-cis-RA and cofactors, and mediate the forming of homodimer and homotetramer of RXRα and its heterodimer with other NRs, conferring RXRα the ability to play complicated roles in development and diseases. Due to the coexistence of monomer, dimer and tetramer, there are difficulties to study the structure and interaction of RXRα-LBD with its ligands and cofactors in solution and to distinguish the roles of different forms of RXRα in cell. Here, through analyzing available structures of RXRα-LBD, we selected two residues, D379 and L420, in the homodimer interface to design three mutants of RXRα-LBD. Recombinant proteins of the three mutants showed decreased proportions of dimer and tetramer but unchanged overall structure and binding affinities to 9-cis-RA, corepressor SMRT, and coactivator SRC2. Especially, the double-site mutant RXRα-LBDD379A-L420G existed as a uniform monomer. Furthermore, L420 was found to play a similar role in forming RXRα-LBD homodimer and its heterodimer with various NRs, while the role of D379 varies a lot, as it shows almost no interaction with RARα/ß, LXRα/ß, and THRα/ß. This study provides a new insight into the mechanism for forming RXRα-LBD homodimer and its heterodimer with other NRs, and will facilitate the studies on the structure and interaction of RXRα-LBD with ligands, cofactors and drugs in solution, and the broad physiological functions of RXRα cooperating with various NRs in cell.

Lymphatic endothelial cell RXRα is critical for 9-cis-retinoic acid-mediated lymphangiogenesis and prevention of secondary lymphedema.

Secondary lymphedema is a debilitating disease characterized by abnormal soft tissue swelling and caused by lymphatic system dysfunction. Despite a high prevalence of secondary lymphedema after cancer treatments, current management is supportive and there are no approved therapeutic agents that can thwart disease progression. We have previously demonstrated that 9-cis-retinoic acid (9-cisRA) has the potential to be repurposed for lymphedema as it mitigates disease by promoting lymphangiogenesis at the site of lymphatic injury. Although the efficacy of 9-cisRA has been demonstrated in previous studies, the mechanism of action is not completely understood. In this study, we demonstrate that when RXRα is specifically deleted in lymphatic endothelial cells, 9-cisRA fails to induce lymphangiogenesis in vitro and prevent pathologic progression of postsurgical lymphedema in vivo. These findings demonstrate that downstream nuclear receptor RXRα plays a critical role in the therapeutic efficacy of 9-cisRA in postsurgical lymphedema.

Microsecond MD Simulations to Explore the Structural and Energetic Differences between the Human RXRα-PPARγ vs. RXRα-PPARγ-DNA.

The heterodimeric complex between retinoic X receptor alpha (RXRα) and peroxisome proliferator-activated receptor gamma (PPARγ) is one of the most important and predominant regulatory systems, controlling lipid metabolism by binding to specific DNA promoter regions. X-ray and molecular dynamics (MD) simulations have revealed the average conformation adopted by the RXRα-PPARγ heterodimer bound to DNA, providing information about how multiple domains communicate to regulate receptor properties. However, knowledge of the energetic basis of the protein-ligand and protein-protein interactions is still lacking. Here we explore the structural and energetic mechanism of RXRα-PPARγ heterodimer bound or unbound to DNA and forming complex with co-crystallized ligands (rosiglitazone and 9-cis-retinoic acid) through microsecond MD simulations, molecular mechanics generalized Born surface area binding free energy calculations, principal component analysis, the free energy landscape, and correlated motion analysis. Our results suggest that DNA binding alters correlated motions and conformational mobility within RXRα-PPARγ system that impact the dimerization and the binding affinity on both receptors. Intradomain correlated motions denotes a stronger correlation map for RXRα-PPARγ-DNA than RXRα-PPARγ, involving residues at the ligand binding site. In addition, our results also corroborated the greater role of PPARγ in regulation of the free and bound DNA state.

Use of GAL4 factor-based yeast assay to quantify the effects of xenobiotics on RXR homodimer and RXR/PPAR heterodimer in scallop Chlamys farreri.

Retinoid X receptor (RXR) and peroxisome proliferators-activated receptors (PPAR) have been shown as important targets of endocrine disrupting effects caused by organotin compounds (OTCs). In vitro methods for non-model species are instrumental in revealing not only mechanism of toxicity but also basic biology. In the present study, we constructed the GAL4 factor-based recombinant yeast systems of RXRα/RXRα (RR), RXRα/PPARα (RPα) and RXRα/PPARγ (RPγ) of the scallop Chlamys farreri to investigate their transcriptional activity under the induction of OTCs (tributyltin chloride, triphenyltin chloride, tripropyltin chloride and bis(tributyltin)oxide), their spiked sediments and five other non­tin compounds (Wy14643, rosiglitazone, benzyl butyl phthalate, dicyclohexyl phthalate and bis(2-ethylhexyl) phthalate). The results showed that the natural ligand of RXR, 9-cis-retinoic acid (9cRA), induces transcriptional activity in all three systems, while four OTCs induced the transcriptional activity of the RR and RPα systems. None of the five potential non­tin endocrine disruptors induced effects on the RPα and RPγ systems. The spiked sediment experiment demonstrated the feasibility of the recombinant yeast systems constructed in this study for environmental sample detection. These results suggest that OTCs pose a threat to affect function of RXRα and PPARα of bivalve mollusks. The newly developed GAL4 factor-based yeast two-hybrid system can be used as a valuable tool for identification and quantification of compounds active in disturbing RXR and PPAR of bivalves.

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.

Clinical phenotypes of adult atopic dermatitis and related therapies.

PURPOSE OF REVIEW: To report current knowledge on the different clinical phenotypes of adult atopic dermatitis. Possible therapeutic intervention in relation to phenotype is also evaluated. RECENT FINDINGS: Atopic dermatitis is a chronic inflammatory disease affecting up to 10% of adults. It can manifest with different clinical phenotypes, causing diagnostic difficulties. Long-term is often required and systemic drugs are needed for moderate-to-severe forms. However, few drugs are registered for atopic dermatitis in many countries. Furthermore, limited data exist regarding the treatment in relation to individual clinical phenotypes. SUMMARY: Currently, the most relevant data are those for cyclosporine, alitretinoin, and dupilumab. Cyclosporine and dupilumab showed to be effective in the treatment of atopic dermatitis, although in trials and real-life experiences the different phenotypes treated are usually not reported. However, cyclosporine appears to be effective in prurigo nodularis. Alitretinoin is reported to be particularly efficacious for atopic dermatitis of the hands, while it is ineffective for other locations of the disease. Dupilumab demonstrated its efficacy in prurigo nodularis and nummular eczema phenotypes of atopic dermatitis; moreover, especially in elderly patients, its effectiveness seems to be faster if the folds of the limbs are involved.

Treatments for AIDS/HIV-related Kaposi sarcoma: A systematic review of the literature.

BACKGROUND: Treatment guidelines are not well established in AIDS-related Kaposi sarcoma (KS). OBJECTIVE: We aim to review the evidence on efficacy of treatments for AIDS-related Kaposi sarcoma. METHODS: We searched the Cochrane Library, PubMed, and Embase Database from date of database inception till July 2020. Randomized controlled trials reporting intervention consisting of any type of treatment compared to control/placebo to a different treatment modality or different combination of treatment/treatment doses with a diagnosis of AIDS-related KS are selected. MAIN OUTCOMES AND MEASURES: Primary outcomes were response rates defined as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Secondary outcomes were cosmesis and adverse outcomes such as pain and erythema. RESULTS: Thirteen out of 536 articles met our eligibility criteria. Three studies reported the efficacy of chemotherapy, two studies looked at different doses of radiotherapy regimes, and three studies compared different antiretroviral therapy (ART) and chemotherapy regimens. Other studies reported topical therapies such as alitretinoin gel, IM862, and bHCG injection which showed varied efficacies. LIMITATIONS: Lack of standardization classification of disease activity and clinical outcomes and treatment modalities precluded meaningful comparison of studies. CONCLUSION: The evidence of efficacy of any particular intervention is overall varied and there was insufficient evidence to recommend any particular intervention. We have provided an overview of treatments for KS but larger studies need to be carried out to verify the efficacy of treatment options reported in the literature.