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1.
Allergol Int ; 73(1): 137-142, 2024 Jan.
Article in English | MEDLINE | ID: mdl-37100717

ABSTRACT

BACKGROUND: Delgocitinib ointment, a topical Janus kinase inhibitor, is used as treatment of patients with atopic dermatitis (AD) aged ≥2 years in Japan. Although initiating appropriate and early treatment upon the onset of AD in childhood is important, the safety and efficacy of delgocitinib ointment in infants with AD have not been established. METHODS: This phase 3 study was conducted from October 2020 to June 2022 (number JapicCTI-205412). Eligible Japanese infants with AD aged 6 to <24 months received 0.25% or 0.5% of delgocitinib ointment twice daily for 52 weeks in an open-label uncontrolled manner. Topical corticosteroids were allowed to apply for worsening AD during the treatment period at the investigators' discretion. RESULTS: A total of 22 infants were enrolled. Adverse events (AEs) were reported in 21 (95.5%) infants and were mostly mild. No treatment-related AEs were reported. The Modified Eczema Area and Severity Index (mEASI) score continuously decreased until week 4, and the score reduction was maintained until week 52. The mean percent changes in the mEASI score from baseline were -73.5% at week 4, -81.7% at week 28, and -81.9% at week 52. Delgocitinib was not detected in the plasma of most infants (68.2%-95.2%). CONCLUSIONS: Delgocitinib ointment is well tolerated and effective for up to 52 weeks when applied to Japanese infants with AD.


Subject(s)
Dermatitis, Atopic , Infant , Humans , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/chemically induced , Ointments/therapeutic use , Treatment Outcome , Pyrroles/adverse effects , Double-Blind Method
2.
Exp Dermatol ; 32(2): 126-134, 2023 02.
Article in English | MEDLINE | ID: mdl-36222007

ABSTRACT

Melanoma is one of the most severe skin cancers, derived from melanocytes. Among various therapies for melanoma, adoptive immunotherapy using tumor-infiltrating lymphocytes/chimeric antigen receptor-T cells (TCs) is advanced in recent years; however, the efficacy is still limited, and major challenges remain in terms of safety and cell supply. To solve the issues of adoptive immunotherapy, we utilized induced pluripotent stem cells (iPSCs), which have an unlimited proliferative ability and various differentiation capability. First, we monoclonally isolated CD8+ TCs specifically reactive with NY-ESO-1, one of tumor antigens, from the melanoma patient's monocytes after stimulated with NY-ESO-1 peptide by manual procedure, and cultured NY-ESO-1-specific TCs until proliferated and formed colonies. iPSCs were consequently generated from colony-forming TCs by exogenous expression of reprogramming factors using Sendai virus vector. After the RAG2 gene in TC-derived iPSCs (T-iPSCs) was knocked out for preventing T-cell receptor (TCR) rearrangement, T-iPSCs were re-differentiated into rejuvenated cytotoxic TCs. We confirmed that TCR of T-iPSC-derived TC was maintained as the same of original TCs. In conclusion, T-iPSCs have a potential to be an unlimited cell source for providing cytotoxic TCs. Our study could be a "touchstone" to develop iPSC-based adoptive immunotherapy for the treatment of melanoma for the future clinical use.


Subject(s)
Induced Pluripotent Stem Cells , Melanoma , Humans , T-Lymphocytes, Cytotoxic/metabolism , Immunotherapy, Adoptive , Pilot Projects , Induced Pluripotent Stem Cells/metabolism , Melanoma/pathology , CD8-Positive T-Lymphocytes/metabolism , Receptors, Antigen, T-Cell/metabolism , Antigens, Neoplasm , Immunotherapy
3.
J Am Acad Dermatol ; 85(4): 854-862, 2021 10.
Article in English | MEDLINE | ID: mdl-34118298

ABSTRACT

BACKGROUND: Delgocitinib 0.5% ointment, a topical Janus kinase inhibitor, has been approved in Japan for adult patients with atopic dermatitis (AD). OBJECTIVE: To evaluate the efficacy and safety of delgocitinib ointment in pediatric patients with AD. METHODS: Part 1 of this study was a 4-week double-blind period in which Japanese patients aged 2 through 15 years were randomized in a 1:1 ratio to delgocitinib 0.25% ointment or vehicle ointment. Part 2 was a 52-week extension period. Eligible patients entered part 2 to receive 0.25% or 0.5% delgocitinib ointment. RESULTS: At the initiation of the study, approximately half of the patients had moderate AD. At the end of treatment in part 1, the least-squares mean percent change from baseline in modified Eczema Area and Severity Index score, the primary efficacy endpoint, was significantly greater for delgocitinib ointment than for vehicle (-39.3% vs +10.9%, P < .001). In part 2, improvements in AD were also seen through week 56. Most adverse events were mild and unrelated to delgocitinib across the study periods. LIMITATIONS: Only Japanese patients were included. In part 2, no control group was included and rescue therapy was allowed. CONCLUSION: Delgocitinib ointment was effective and well tolerated when applied to Japanese pediatric patients with AD for up to 56 weeks.


Subject(s)
Dermatitis, Atopic , Eczema , Adult , Child , Dermatitis, Atopic/diagnosis , Dermatitis, Atopic/drug therapy , Double-Blind Method , Emollients , Humans , Ointments , Pyrroles , Treatment Outcome
4.
J Am Acad Dermatol ; 82(4): 823-831, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32029304

ABSTRACT

BACKGROUND: Previous studies showed the potential effectiveness of delgocitinib ointment, a novel topical Janus kinase inhibitor, in atopic dermatitis (AD). OBJECTIVE: This study aimed to evaluate the efficacy and safety of delgocitinib 0.5% ointment. METHODS: In part 1, a 4-week double-blind period, Japanese patients aged 16 years or older with moderate or severe AD were randomly assigned in a 2:1 ratio to delgocitinib 0.5% ointment or vehicle ointment. Eligible patients entered part 2, a 24-week extension period, to receive delgocitinib 0.5% ointment. RESULTS: At the end of treatment in part 1, the least-squares mean percent changes from baseline in the modified Eczema Area and Severity Index score, the primary efficacy endpoint, were significantly greater in the delgocitinib group than in the vehicle group (-44.3% vs 1.7%, P < .001). The improvement in modified Eczema Area and Severity Index score was maintained in part 2. Most adverse events were mild and unrelated to delgocitinib across the study periods. LIMITATIONS: Only Japanese patients were included. The vehicle-controlled period lasted only 4 weeks. In part 2, topical corticosteroids were allowed for the treatment of worsening of AD. CONCLUSION: Delgocitinib ointment was effective and well tolerated in Japanese adult patients with moderate to severe AD for up to 28 weeks.


Subject(s)
Dermatitis, Atopic/drug therapy , Dermatologic Agents/therapeutic use , Janus Kinase Inhibitors/therapeutic use , Pyrroles/therapeutic use , Adult , Dermatologic Agents/administration & dosage , Dermatologic Agents/adverse effects , Dermatologic Agents/pharmacokinetics , Double-Blind Method , Female , Humans , Janus Kinase Inhibitors/administration & dosage , Janus Kinase Inhibitors/adverse effects , Janus Kinase Inhibitors/pharmacokinetics , Male , Ointments , Pyrroles/administration & dosage , Pyrroles/adverse effects , Pyrroles/pharmacokinetics , Treatment Outcome , Young Adult
5.
J Allergy Clin Immunol ; 144(6): 1575-1583, 2019 12.
Article in English | MEDLINE | ID: mdl-31425780

ABSTRACT

BACKGROUND: Topical delgocitinib (JTE-052), a novel Janus kinase inhibitor, had been shown to be clinically effective in adults with atopic dermatitis (AD). However, the efficacy of topical delgocitinib in pediatric patients with AD remained unclear. OBJECTIVE: We sought to evaluate the efficacy and safety of delgocitinib ointment in pediatric patients with AD. METHODS: In this phase 2 clinical study (JapicCTI-173553) Japanese patients aged 2 through 15 years with AD were randomized in a 1:1:1 ratio to receive 0.25% or 0.5% delgocitinib ointment or vehicle ointment twice daily for 4 weeks. The primary efficacy end point was the percentage change from baseline in the modified Eczema Area and Severity Index score at the end of treatment (EOT). RESULTS: At EOT, modified Eczema Area and Severity Index scores in both delgocitinib groups were significantly reduced compared with that in the vehicle group. The least-squares mean percentage change from baseline was -54.2% in the 0.25% group and -61.8% in the 0.5% group versus -4.8% in the vehicle group (P < .001 for both comparisons). Similarly, all other efficacy parameters, including Investigator's Global Assessment and pruritus scores, in both delgocitinib groups were significantly improved compared with those in the vehicle group at EOT. Adverse events in both delgocitinib groups were mild in severity, and no serious adverse events were reported. CONCLUSIONS: Delgocitinib ointment improved clinical signs and symptoms in pediatric patients with AD and was well tolerated. These study results indicate that delgocitinib ointment can be a promising therapeutic option for pediatric patients with AD.


Subject(s)
Dermatitis, Atopic/drug therapy , Pyrroles/administration & dosage , Adolescent , Child , Child, Preschool , Dermatitis, Atopic/immunology , Dermatitis, Atopic/pathology , Double-Blind Method , Female , Humans , Male , Ointments , Pyrroles/adverse effects
6.
Exp Dermatol ; 28(7): 836-844, 2019 07.
Article in English | MEDLINE | ID: mdl-31070806

ABSTRACT

BACKGROUND: Type 1 interferons (IFNs), including IFN-ß, are widely used in adjuvant therapy for patients who undergo surgery for malignant melanoma to inhibit recurrence and in-transit metastasis. The precise mechanisms underlying the tumor-suppressive effects of IFN-ß on melanoma are not yet completely understood. OBJECTIVE: The purpose was to reveal the mechanisms underlying the tumor-suppressive effects of IFN-ß via interleukin (IL)-24. METHODS: Genome-wide oligonucleotide microarray, quantitative real-time reverse transcription-polymerase chain reaction (PCR), enzyme-linked immunosorbent assay and western blotting assay were performed using four melanoma cell lines (A375, RPMI-7951, SK-MEL-5 and SK-MEL-1) treated with natural-type IFN-ß to assess the expression of IL-24. Proliferation assay was performed using these melanoma cells and IL-24 knock-down melanoma cells. RESULTS: Genome-wide microarray analysis detected candidate genes upregulated in IFN-ß-sensitive cells after treatment with IFN-ß. We focused on IL-24 among the candidate genes encoding secretory proteins. Peak IL-24 mRNA expression completely correlated with the order of sensitivity of melanoma cells to IFN-ß. IFN-ß treatment induced extracellular IL-24 protein in IFN-ß-sensitive cells, but did not induce intracellular IL-24 protein. Knock-down of IL-24 changed melanoma cells into IFN-ß-resistant cells. The expression ratio of IL-22R1, one of the IL-24 receptors, correlated with the order of sensitivity of melanoma cells to IFN-ß. Treatment with recombinant human IL-24 did not have any effects on all the melanoma cell lines. CONCLUSION: Our data suggest that IFN-ß suppresses the proliferation of melanoma cells through extracellular IL-24 protein derived from melanoma cells.


Subject(s)
Interferon-beta/administration & dosage , Interleukins/administration & dosage , Melanoma/drug therapy , Apoptosis , Cell Line, Tumor , Cell Proliferation , Chemotherapy, Adjuvant , Genome-Wide Association Study , Humans , Oligonucleotide Array Sequence Analysis , Receptors, Interleukin/metabolism , Recombinant Proteins/administration & dosage
7.
N Engl J Med ; 371(4): 326-38, 2014 Jul 24.
Article in English | MEDLINE | ID: mdl-25007392

ABSTRACT

BACKGROUND: Interleukin-17A is considered to be central to the pathogenesis of psoriasis. We evaluated secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe plaque psoriasis. METHODS: In two phase 3, double-blind, 52-week trials, ERASURE (Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis) and FIXTURE (Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis), we randomly assigned 738 patients (in the ERASURE study) and 1306 patients (in the FIXTURE study) to subcutaneous secukinumab at a dose of 300 mg or 150 mg (administered once weekly for 5 weeks, then every 4 weeks), placebo, or (in the FIXTURE study only) etanercept at a dose of 50 mg (administered twice weekly for 12 weeks, then once weekly). The objective of each study was to show the superiority of secukinumab over placebo at week 12 with respect to the proportion of patients who had a reduction of 75% or more from baseline in the psoriasis area-and-severity index score (PASI 75) and a score of 0 (clear) or 1 (almost clear) on a 5-point modified investigator's global assessment (coprimary end points). RESULTS: The proportion of patients who met the criterion for PASI 75 at week 12 was higher with each secukinumab dose than with placebo or etanercept: in the ERASURE study, the rates were 81.6% with 300 mg of secukinumab, 71.6% with 150 mg of secukinumab, and 4.5% with placebo; in the FIXTURE study, the rates were 77.1% with 300 mg of secukinumab, 67.0% with 150 mg of secukinumab, 44.0% with etanercept, and 4.9% with placebo (P<0.001 for each secukinumab dose vs. comparators). The proportion of patients with a response of 0 or 1 on the modified investigator's global assessment at week 12 was higher with each secukinumab dose than with placebo or etanercept: in the ERASURE study, the rates were 65.3% with 300 mg of secukinumab, 51.2% with 150 mg of secukinumab, and 2.4% with placebo; in the FIXTURE study, the rates were 62.5% with 300 mg of secukinumab, 51.1% with 150 mg of secukinumab, 27.2% with etanercept, and 2.8% with placebo (P<0.001 for each secukinumab dose vs. comparators). The rates of infection were higher with secukinumab than with placebo in both studies and were similar to those with etanercept. CONCLUSIONS: Secukinumab was effective for psoriasis in two randomized trials, validating interleukin-17A as a therapeutic target. (Funded by Novartis Pharmaceuticals; ERASURE and FIXTURE ClinicalTrials.gov numbers, NCT01365455 and NCT01358578, respectively.).


Subject(s)
Antibodies, Monoclonal/therapeutic use , Interleukin-17/antagonists & inhibitors , Psoriasis/drug therapy , Adult , Antibodies/blood , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal, Humanized , Double-Blind Method , Etanercept , Female , Humans , Immunoglobulin A/blood , Immunoglobulin G/adverse effects , Immunoglobulin G/therapeutic use , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Infections/etiology , Injections, Subcutaneous , Interleukin-17/immunology , Male , Middle Aged , Psoriasis/immunology , Receptors, Tumor Necrosis Factor/therapeutic use
8.
Radiology ; 284(1): 134-142, 2017 07.
Article in English | MEDLINE | ID: mdl-28045646

ABSTRACT

Purpose To determine the feasibility of dual-energy (DE) computed tomography (CT) with an iodine overlay image (IOI) for evaluation of psoriatic arthritis in the hand. Materials and Methods Approval from the institutional ethics committee and written informed consent from all patients were obtained. This prospective study included 16 patients who had psoriasis with finger joint symptoms from January 2015 to January 2016. Contrast material-enhanced (CE) DE CT and 1.5-T CE magnetic resonance (MR) imaging were performed within 1 month of each other. DE CT was performed with a tube voltage of 80 kV and 140 kV with use of a 0.4-mm tin filter. Images acquired with both modalities were evaluated by two radiologists independently by using a semiquantitative scoring system. Interreader agreement was calculated for each modality: Weighted κ values were calculated for synovitis, flexor tenosynovitis, and extensor peritendonitis, and κ values were calculated for periarticular inflammation. With consensus scores and CE MR images as the reference, the sensitivity and specificity of IOI DE CT for inflammatory lesions were calculated. Statistical analysis of discordant readings was performed by using the McNemar test. Results Interreader agreement for inflammatory lesions was excellent or good (weighted κ = 0.83 and κ = 0.75 in IOI DE CT; weighted κ = 0.81 and κ = 0.87 in CE MR imaging). The sensitivity and specificity of IOI DE CT were 0.78 and 0.87, respectively. Total agreement was 86.3%; however, there were significantly more lesions detected with IOI DE CT than with CE MR imaging alone (134 vs 20 lesions in 1120 evaluated items; P < .001). Sixty-nine percent of the abnormalities detected with IOI DE CT alone were located in distal interphalangeal joints. Conclusion IOI DE CT is a new imaging modality that may be useful for evaluating psoriatic arthritis in the hand, particularly in the detection of inflammatory lesions in small joints, and may be more useful than CE MR imaging, within the limitation that there is no histopathologic reference. © RSNA, 2017.


Subject(s)
Arthritis, Psoriatic/diagnostic imaging , Finger Joint/diagnostic imaging , Hand Dermatoses/diagnostic imaging , Magnetic Resonance Imaging/methods , Tomography, X-Ray Computed/methods , Arthritis, Psoriatic/pathology , Contrast Media , Female , Finger Joint/pathology , Hand Dermatoses/pathology , Humans , Image Interpretation, Computer-Assisted , Iohexol , Male , Middle Aged , Prospective Studies , Sensitivity and Specificity
9.
Exp Dermatol ; 26(11): 1068-1074, 2017 11.
Article in English | MEDLINE | ID: mdl-28482119

ABSTRACT

Analysis of psoriatic parakeratotic cells is helpful for understanding the pathogenesis of psoriasis. Methylation analysis can be performed on psoriatic scales, but it is unclear whether genes can be silenced by DNA methylation in psoriatic stratum corneum. The present study was conducted to detect genes silenced in psoriatic stratum corneum. Methylation array analysis with 485 577 probes, quantitative real-time methylation-specific PCR (RT-MSP) and bisulphite sequencing were performed for 30 psoriatic scale samples, 6 fully developed psoriatic skin samples and 12 normal skin samples. Immunohistochemical staining of HOXA5 was performed for 29 psoriatic epidermal samples and 13 normal epidermal samples. The genome-wide methylation array detected two CpG sites within CpG islands (CGIs) located in promoter regions of HOXA5 and LIAS that had methylation levels of >0.6 in at least one of the three psoriatic scale samples and of <0.2 in all three normal skin tissue samples (methylation rate range, 0.0-1.0). RT-MSP for HOXA5CGI, in which the primers were successfully developed, revealed that the average methylation level of 27 psoriasis scales (60.2%) is significantly higher than that of 9 normal skin samples (34.6%) (P=.013). Immunohistochemical staining revealed that HOXA5 protein was not expressed in the stratum corneum of fully developed psoriatic epidermis, but the protein was expressed in the stratum corneum of incompletely developed epidermis and normal epidermis. In conclusion, HOXA5 can be silenced in the stratum corneum of psoriasis. The silenced gene was identified by non-invasive methylation analysis of psoriatic scales.


Subject(s)
Epidermis/metabolism , Gene Silencing , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Psoriasis/genetics , Psoriasis/metabolism , CpG Islands/genetics , DNA Methylation , Genome-Wide Association Study , Humans , Promoter Regions, Genetic , Real-Time Polymerase Chain Reaction/methods , Sequence Analysis, DNA/methods , Sulfites , Transcription, Genetic
10.
Eur Radiol ; 27(12): 5034-5040, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28674965

ABSTRACT

Iodine mapping is an image-processing technique used with dual-energy computed tomography (DECT) to improve iodine contrast resolution. CT, because of its high spatial resolution and thin slice reconstruction, is well suited to the evaluation of the peripheral joints. Recent developments in the treatment of inflammatory arthritis that require early diagnosis and precise therapeutic assessment encourage radiological evaluation. To facilitate such assessment, we describe DECT iodine mapping as a novel modality for evaluating rheumatoid arthritis and psoriatic arthritis of the hands and feet. KEY POINTS: • Dual-energy CT iodine mapping can delineate inflammation of peripheral inflammatory arthritis. • DECT iodine mapping has high spatial resolution compared with MRI. • DECT iodine mapping has a high iodine contrast resolution. • DECT iodine mapping may reflect therapeutic effects.


Subject(s)
Arthritis, Rheumatoid/diagnostic imaging , Contrast Media , Iodine , Adult , Aged , Aged, 80 and over , Arthritis, Psoriatic/diagnostic imaging , Female , Humans , Image Processing, Computer-Assisted/methods , Lateral Ligament, Ankle/diagnostic imaging , Magnetic Resonance Imaging , Male , Middle Aged , Radiography, Dual-Energy Scanned Projection/methods , Retrospective Studies , Tomography, X-Ray Computed/methods
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