Tyrosine kinase 2 (TYK2) signaling pathways, which mediate cytokine signaling, are implicated in the pathophysiology of psoriasis. Selective inhibitors of TYK2 may be effective in treating psoriasis.
...We conducted a phase 2, double-blind trial of a TYK2 inhibitor, BMS-986165, in adults with moderate-to-severe psoriasis, excluding patients with a previous lack of response to agents targeting cytokine signaling through the same tyrosine kinase pathway. Patients were randomly assigned to receive the drug orally at a dose of 3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, or 12 mg daily or to receive placebo. The primary end point was a 75% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12 (higher scores indicate greater severity of psoriasis).
A total of 267 patients received at least one dose in an intervention group of the trial. At week 12, the percentage of patients with a 75% or greater reduction in the PASI score was 7% (3 of 45 patients) with placebo, 9% (4 of 44 patients) with 3 mg of BMS-986165 every other day (P=0.49 vs. placebo), 39% (17 of 44 patients) with 3 mg daily (P<0.001 vs. placebo), 69% (31 of 45 patients) with 3 mg twice daily (P<0.001 vs. placebo), 67% (30 of 45 patients) with 6 mg twice daily (P<0.001 vs. placebo), and 75% (33 of 44 patients) with 12 mg daily (P<0.001 vs. placebo). There were three serious adverse events in patients receiving the active drug, as well as one case of malignant melanoma 96 days after the start of treatment.
Selective inhibition of TYK2 with the oral agent BMS-986165 at doses of 3 mg daily and higher resulted in greater clearing of psoriasis than did placebo over a period of 12 weeks. Larger and longer-duration trials of this drug are required to determine its safety and durability of effect in patients with psoriasis. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT02931838 .).
Summary Smoking tobacco is the most preventable cause of morbidity and is responsible for more than three million deaths a year worldwide. In addition to a strong association with a number of ...systemic diseases, smoking is also associated with many dermatological conditions, including poor wound healing, premature skin aging, squamous cell carcinoma, melanoma, oral cancer, acne, psoriasis, and hair loss. This review focuses on the effects of smoking on premature skin aging. It has been long established that smoking has deleterious effects on skin. Epidemiological studies indicate that smoking is an important environmental factor in premature skin aging. In vitro studies indicate that tobacco smoke extract impairs the production of collagen and increases the production of tropoelastin and matrix metalloproteinases (MMP), which degrade matrix proteins, and also causes an abnormal production of elastosis material. Smoking increases MMP levels, which leads to the degradation of collagen, elastic fibers, and proteoglycans, suggesting an imbalance between biosynthesis and degradation in dermal connective tissue metabolism. Reactive oxygen species are also involved in tobacco smoke-induced premature skin aging. Scavengers of reactive oxygen species ameliorate the induction of MMP. Tobacco smoke extract also impacts dermal connective tissue in nude mice. Thus, in vitro and in vivo evidence indicates that smoking tobacco leads to accelerated aging of the skin. These findings might be useful to motivate those patients who are more concerned about their appearance than the potential internal damage associated with smoking to stop smoking.
•COVID-19 is associated with specific skin manifestations and drug eruption.•This case shows COVID-19–related drug eruption and specific clinical features.•Drug eruption preceding COVID-19 symptoms ...may facilitate early diagnosis.
Detailed analysis of the cells that infiltrate lesional skin cannot be performed in skin biopsy specimens using immunohistochemistry or cell separation techniques because enzyme treatments applied ...during the isolation step can destroy small amounts of protein and minor cell populations in the biopsy specimen. Here, we describe a method for isolating T cells from drops of whole blood obtained from lesions during skin biopsy in patients with cutaneous T-cell lymphoma. Lesional blood is assumed to contain lesional resident cells, cells from capillary vessels, and blood overflowing from capillary vessels into the lesion area. The lesional blood showed substantial increases in distinct cell populations, chemokines, and the expression of various genes. The proportion of CD8
CD45RO
T cells in the lesional blood negatively correlated with the modified severity-weighted assessment tool scores. CD4
CD45RO
T cells in the lesional blood expressed genes associated with the development of cancer and progression of cutaneous T-cell lymphoma. In addition, CD8
CD45RO
T cells in lesional blood had unique T-cell receptor repertoires in lesions of each stage. Assessment of lesional blood drops might provide new insight into the pathogenesis of mycosis fungoides and facilitate evaluation of the treatment efficacy for mycosis fungoides as well as other skin inflammatory diseases.
Background Secukinumab has demonstrated high, sustained efficacy in psoriasis to 52 weeks on a fixed-interval regimen. Objective We sought to compare a retreatment-as-needed versus a fixed-interval ...regimen. Methods In this double-blind study, adults with moderate to severe plaque psoriasis were randomized 1:1 to subcutaneous secukinumab at 300 mg (n = 484) or 150 mg (n = 482) weekly from baseline until week 4, and at week 8. At week 12, patients achieving 75% or more improvement from baseline Psoriasis Area and Severity Index score (PASI 75) were rerandomized to 2 dose levels of secukinumab retreatment as needed (n = 217, 300 mg; n = 206, 150 mg) or fixed interval (n = 217; n = 203). Primary end point was noninferiority of retreatment as needed versus fixed interval for maintaining PASI 75 to week 52. Results Secukinumab induced high responses by week 12 (84.4%-91.1% PASI 75 responders). From week 12 to week 52, more patients on fixed interval (78.2%, 300 mg; 62.1%, 150 mg) maintained PASI 75 versus retreatment as needed (67.7%; 52.4%); statistical noninferiority of retreatment as needed was not established. Overall safety, including very low incidences of treatment-emergent anti-drug antibodies (<0.5%), was similar between regimens. Limitations The primary end point was developed without any known precedent. Conclusion Secukinumab fixed interval showed clear benefit versus the study-specified retreatment-as-needed regimen for maintaining efficacy. Both regimens exhibited safety consistent with previous trials. The potential of retreatment as needed with secukinumab warrants further investigation.
Merkel cell carcinoma (MCC) is widely known as a highly malignant skin cancer. The pathogenesis of MCC, however, remains mysterious due to the extremely small number of cases and its prevalence in ...the elderly. Despite its high‐grade malignancy, spontaneous regression occurs with some frequency. The immune activity of the tumor underlies this peculiar behavior. In recent years, immune checkpoint blockade therapies, including the anti‐programmed death ligand 1 antibody, have provided successful results. These therapies, however, are ineffective in approximately half the patients with advanced MCC and few treatments are available for those patients. In this review, we summarize the increasing body of evidence relating to the immune activity of MCC and immunological biomarkers. The interesting and sometimes peculiar behavior of MCC, such as their spontaneous regression, is largely due to their high immunosensitivity. Understanding the tumor immunokinetics of MCC should provide critical insight for understanding cancer immunotherapy. Here, we introduce a new classification for MCC according to its immune activity. Combined application of programmed death ligand 1 (a prognostic factor and predictor of the efficacy of immune checkpoint inhibitors in various cancers) with glucose‐6‐phosphate dehydrogenase (a new promising biomarker for MCC) may enable classification of MCC based on its immune status. Whether the new classification can be used to predict the efficacy of immune checkpoint blockade therapies remains to be evaluated in future studies, but the classification may facilitate future treatment selection.
Little is known about the disease burden, health‐care resource utilization (HCRU), or treatment of patients with generalized pustular psoriasis (GPP) in Japan. This retrospective cohort study used ...data from the Japanese Medical Data Center database to compare the demographics, comorbidities, and medication use of patients with GPP and plaque psoriasis and estimate their all‐cause HCRU. The patient selection period was from January 1, 2015 to December 31, 2019, and patients must have had at least one confirmed inpatient claim or outpatient claim for GPP or plaque psoriasis. During the 12‐month follow‐up period, 110 patients with GPP and 20,254 patients with plaque psoriasis were identified. An age‐ and sex‐matched (4:1) comparator control cohort, including members of the general population without a diagnosis of psoriasis (but allowing for a diagnosis of psoriatic arthritis), GPP, or palmoplantar pustulosis, was used. The most prevalent comorbidities in patients with GPP included allergic rhinoconjunctivitis, hypertension, and peptic ulcer disease. Patients with GPP were more likely to experience more comorbidities than those with plaque psoriasis, including asthma, chronic obstructive pulmonary disease, interstitial pneumonia, hyperuricemia and gout, tonsillitis, psoriatic arthritis, other psoriasis, and osteoporosis. Patients with GPP were more likely to be treated with a combination therapy than those with plaque psoriasis (65.5% vs 21.7%, respectively) and less likely to be treated with a topical medication alone (20.9% vs 50.8%). Patients with GPP had more outpatient visits than patients in the plaque psoriasis or matched control cohorts (mean standard deviation, 14.8 8.3 vs 11.0 7.6 and 7.8 7.2, respectively). They were also more likely to require inpatient hospitalization (24.5% vs 6.4% and 5.0%, respectively). Despite study limitations, patients with GPP in Japan were found to have a higher disease burden, including presence of comorbidities and medication use, than those with plaque psoriasis.
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