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Photodermatology, Photoimmunology &... Sep 2023
Topics: Humans; Alitretinoin; Retinoids; Tretinoin; Eczema; Photosensitivity Disorders; Chronic Disease
PubMed: 37199021
DOI: 10.1111/phpp.12888 -
The British Journal of Dermatology Sep 2023Effective treatment options for patients with chronic hand eczema (CHE) are scarce. Dupilumab is licensed for the treatment of moderate-to-severe atopic dermatitis and... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Adult; Humans; Alitretinoin; Antibodies, Monoclonal, Humanized; Eczema; Dermatitis, Atopic; Treatment Outcome; Double-Blind Method; Severity of Illness Index
PubMed: 37170922
DOI: 10.1093/bjd/ljad156 -
Journal of Inflammation Research 2023The incidence of pneumonia (PCP) in patients without human immunodeficiency virus (HIV) has been increasing. In this study, we aimed to investigate the metabolic...
PURPOSE
The incidence of pneumonia (PCP) in patients without human immunodeficiency virus (HIV) has been increasing. In this study, we aimed to investigate the metabolic changes in infection and the metabolic abnormalities in B-cell-activating factor receptor (BAFF-R)-deficient mice with infection.
METHODS
The important function of B cells during infection is increasingly recognized. In this study, a -infected mouse model was constructed in BAFF-R mice and wild-type (WT) mice. Lungs of uninfected WT C57BL/6, WT -infected, and BAFF-R -infected mice were used for metabolomic analyses to compare the metabolomic profiles among the groups, with the aim of exploring the metabolic influence of infection and the influence of mature B-cell deficiency during infection.
RESULTS
The results indicated that many metabolites, mainly lipids and lipid-like molecules, were dysregulated in infected WT mice compared with uninfected WT C57BL/6 mice. The data also demonstrated significant changes in tryptophan metabolism, and the expression levels of key enzymes of tryptophan metabolism, such as indoleamine 2,3-dioxygenase 1 (IDO1), were significantly upregulated. In addition, B-cell development and function might be associated with lipid metabolism. We found a lower level of alitretinoin and the abnormalities of fatty acid metabolism in BAFF-R -infected mice. The mRNA levels of enzymes associated with fatty acid metabolism in the lung were upregulated in BAFF-R -infected mice and positively correlated with the level of IL17A, thus suggesting that the abnormalities of fatty acid metabolism may be associated with greater inflammatory cell infiltration in the lung tissue of BAFF-R -infected mice compared with the WT -infected mice.
CONCLUSION
Our data revealed the variability of metabolites in -infected mice, suggesting that the metabolism plays a vital role in the immune response to infection.
PubMed: 37006807
DOI: 10.2147/JIR.S394608 -
Toxicology Mar 2023Cyanobacterial blooms are known sources of environmentally-occurring retinoid compounds, including all-trans and 9-cis retinoic acids (RAs). The developmental hazard for...
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 S100β 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.
Topics: Humans; Alitretinoin; Cell Differentiation; Neural Stem Cells; Receptors, Retinoic Acid; Retinoids; Tretinoin
PubMed: 36805303
DOI: 10.1016/j.tox.2023.153461 -
Biochemical and Biophysical Research... Jan 2023Retinoid 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...
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-LBD 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/β, LXRα/β, and THRα/β. 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.
Topics: Tretinoin; Ligands; Retinoid X Receptor alpha; Alitretinoin; Mutation
PubMed: 36563628
DOI: 10.1016/j.bbrc.2022.12.042 -
FASEB Journal : Official Publication of... Jan 2023Secondary lymphedema is a debilitating disease characterized by abnormal soft tissue swelling and caused by lymphatic system dysfunction. Despite a high prevalence of...
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.
Topics: Humans; Lymphangiogenesis; Alitretinoin; Endothelial Cells; Lymphedema; Lymphatic Vessels
PubMed: 36520015
DOI: 10.1096/fj.202200146RR -
Journal of Medical Virology Jan 2023Multiple treatment modalities for Kaposi sarcoma (KS) have been reported, including chemotherapy, radiation therapy, surgical excision, electrochemotherapy, and...
Multiple treatment modalities for Kaposi sarcoma (KS) have been reported, including chemotherapy, radiation therapy, surgical excision, electrochemotherapy, and cryotherapy. Common topical treatments include timolol, imiquimod, and alitretinoin. We searched our institutional database for patients with ICD-9 or 10 codes for KS seen by a dermatologist with experience in KS management from July 1, 2004 to January 1, 2022. We screened patient charts to include patients who received combination therapy of cryotherapy followed by topical imiquimod three times a week for 2 months (n = 9). Patients were followed in the clinic every 3 months. Time to resolution was assessed by photographic evidence of resolution as determined by a dermatologist and corroborated with clinical documentation in patient charts. Median age (IQR) at KS diagnosis was 58 (27.5) years. All patients were male (n = 9, 100%). Majority were white (n = 7, 78%) and non-Hispanic (n = 8, 89%). Five (56%) had classic KS, one (11%) had HIV-associated KS, and three (33%) were HIV-negative men who have sex with men. Median time to resolution was 30.5 weeks, with a median of two treatments. In our study, 93% (n = 42/45) of lesions and 89% (n = 8/9) of patients experienced complete resolution during a median (range) duration of follow-up of 58 (13-209) weeks. Side effects were limited to pain during cryotherapy, occasional blister formation after cryotherapy, and mild inflammation due to imiquimod. No infections were observed. Combination therapy of cryotherapy and topical imiquimod may be an efficacious and comparatively low-risk treatment for limited, cutaneous KS.
Topics: Humans; Male; Middle Aged; Female; Imiquimod; Sarcoma, Kaposi; Homosexuality, Male; Sexual and Gender Minorities; Cryotherapy; Skin Neoplasms; Immunotherapy; HIV Infections
PubMed: 36504005
DOI: 10.1002/jmv.28396 -
Annals of Dermatology Dec 2022
PubMed: 36478433
DOI: 10.5021/ad.20.293 -
AACE Clinical Case Reports 2022Although retinoid-associated central hypothyroidism has been reported on several occasions, there are very few studies on retinoid-associated central adrenal...
BACKGROUND/OBJECTIVE
Although retinoid-associated central hypothyroidism has been reported on several occasions, there are very few studies on retinoid-associated central adrenal insufficiency. Here, we present the case of a patient with alitretinoin-induced central hypothyroidism and adrenal insufficiency.
CASE REPORT
An 86-year-old man with a diagnosis of cutaneous T-cell lymphoma, treated with oral alitretinoin 30 mg po daily, topical steroids, and ultraviolet light therapy presented to the emergency department with generalized weakness, decreased energy, orthostasis, and unexplained falls. Thyroid-stimulating hormone (TSH) was 0.31 mIU/L (normal range: 0.4-4.4) from 1.93 before alitretinoin therapy, whereas free thyroxine was 5.7 pmol/L (normal range: 8-18) and the AM cortisol was 40 nmol/L (normal range: 120-535); these values were suggestive of central hypothyroidism and adrenal insufficiency. Adrenocorticotropic hormone (ACTH) was not measured because of a laboratory error. Alitretinoin was stopped, and one dose of hydrocortisone 100mg IV was initiated, followed by maintenance doses of oral hydrocortisone 20mg qam and 10mg qpm. Levothyroxine (50μg ) daily was started 24 hours later. After stopping hydrocortisone for 24 hours, the AM cortisol and ACTH levels were 406 nmol/L and 2.18 pmol/L (normal range:1.6-13.9), respectively. He was discharged on thyroid hormone replacement therapy and glucocorticoids. Repeat thyroid function tests 6 weeks later showed a TSH of 0.4 mIU/L, and free thyroxine of 9.7 pmol/L.
DISCUSSION
Alitretinoin activates nuclear receptors called retinoic acid receptors and retinoid X-receptors. Retinoic acid receptors and retinoid X-receptors are widely expressed in the anterior pituitary gland. RXR-selective ligands such as retinoids can suppress TSH secretion, resulting in central hypothyroidism. Retinoids have also been shown to decrease ACTH secretion, which can result in central adrenal insufficiency.
CONCLUSION
Although central adrenal insufficiency and hypothyroidism have not been commonly reported in patients taking retinoids, they should always be considered when caring for these patients.
PubMed: 36447824
DOI: 10.1016/j.aace.2022.08.004 -
Toxicology Letters Jan 2023Retinoid X receptor alpha (RXRα) plays pivotal roles in multiple biological processes, but limited information is available on the structural features of chemicals that...
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.
Topics: Humans; Rats; Animals; Retinoid X Receptor alpha; Alitretinoin; Protein Binding; Benzene Derivatives; Retinoid X Receptors
PubMed: 36368620
DOI: 10.1016/j.toxlet.2022.11.003