Effectiveness and Persistence Of Acitretin, Ciclosporin, Fumaric Acid Esters and Methotrexate For Patients With Moderate-To-Severe Psoriasis

The real-world effectiveness and persistence of acitretin, ciclosporin, FAEs and methotrexate were generally low. Previous nonbiologic systemic therapies, male sex, comorbidities and alcohol consumption were risk factors associated with treatment ineffectiveness.

source: British Journal of Dermatology

Summary

A Cohort Study From

[Posted 17/May/2023]

AUDIENCE: Dermatology, Family Medicine

KEY FINDINGS: The real-world effectiveness and persistence of acitretin, ciclosporin, FAEs and methotrexate were generally low. Previous nonbiologic systemic therapies, male sex, comorbidities and alcohol consumption were risk factors associated with treatment ineffectiveness.

BACKGROUND: Real-world data evaluating effectiveness and persistence of systemic therapies for patients with psoriasis are limited. Purpose of the study is to determine the effectiveness and persistence of acitretin, ciclosporin, fumaric acid esters (FAEs) and methotrexate in patients with moderate-to-severe psoriasis.

DETAILS: Data from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR), a prospective, multicentre pharmacovigilance register of patients with moderate-to-severe psoriasis receiving biologic and/or conventional systemic therapies, were analysed. Eligible patients were >= 16 years of age receiving a first course of acitretin, ciclosporin, FAEs or methotrexate between 2007 and 2021 with >= 6 months' follow-up. Effectiveness was defined as achieving absolute Psoriasis Area and Severity Index (aPASI) <= 2 reported >= 4 weeks after treatment start date until date of cessation. To identify baseline clinical variables associated with treatment effectiveness, we used multivariable logistic regression models estimating the adjusted odds ratio (aOR) of achieving aPASI <= 2. To describe drug persistence associated with ineffectiveness, occurrence of adverse events or other reasons for discontinuation, survival estimates with 95% confidence intervals (CIs) were obtained using a flexible parametric model. Results were obtained using multiple imputed data. In total, 5430 patients were included in the analysis. Overall, 1023 (19%) patients were receiving acitretin, 1401 (26%) patients were on ciclosporin, 347 (6%) patients were on FAEs, and 2659 (49%) patients were receiving methotrexate at registration. The proportion of patients who achieved aPASI <= 2 was lower for those treated with acitretin [n = 118 (21%)] compared with those receiving ciclosporin [n = 233 (34%)], FAEs [n = 43 (29%)] and methotrexate [n = 372 (32%)]. Factors associated with ineffectiveness included prior experience to previous nonbiologic systemic therapies (acitretin) (aOR 0.64, 95% CI 0.42 -0.96), male sex (methotrexate) (aOR 0.58, 95% CI 0.46 -0.74), comorbidities (aOR 0.70, 95% CI 0.51 -0.97) and alcohol consumption (<= 14 units per week) (ciclosporin) (aOR 0.70, 95% CI 0.50 -0.98). Persistence associated with all reasons for discontinuation showed better survival for methotrexate compared with acitretin, ciclosporin and FAEs cohorts at 12 months [survival estimate 46.1 (95% CI 44.0 -48.3), 31.9 (95% CI 29.4 -34.7), 30.0 (95% CI 27.5 -32.4) and 35.0 (95% CI 29.9 -40.9), respectively].

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Copyright © British Association of Dermatologists. All rights reserved.

Source: Alabas, O. A., Mason, K. J., Yiu, Z. Z. N., et al. (2023). Effectiveness and Persistence Of Acitretin, Ciclosporin, Fumaric Acid Esters and Methotrexate For Patients With Moderate-To-Severe Psoriasis: A Cohort Study From BADBIR. British Journal of Dermatology. 2023; 188(5): 618-627. Published: May, 2023. DOI: 10.1093/bjd/ljad004.



Drug Survival of Methotrexate and Predictor Factors for Discontinuation in Psoriasis

MTX is a valuable, cost-effective option for long-term treatment of psoriasis although drug survival is not comparable with that of biological treatments.

source: Int J Dermatol

Summary

[Posted 20/May/2024]

AUDIENCE: Dermatology, Family Medicine

KEY FINDINGS: MTX is a valuable, cost-effective option for long-term treatment of psoriasis although drug survival is not comparable with that of biological treatments. Studies are needed to better understand the best dosing regimen to use, with the aim of achieving the best clinical outcomes and the lowest rate of side effects with this drug.

BACKGROUND: Methotrexate (MTX) is a systemic therapy largely used for moderate-severe psoriasis. There is a lack of data on its use in daily practice and particularly on its long-term effectiveness and survival in psoriasis.

DETAILS: Authors performed a single-centered, retrospective, observational study to evaluate the drug survival of MTX in patients with psoriasis, treated in monotherapy with MTX between March 2015 and March 2022. Clinical and demographic characteristics were extracted from files of the patients. The drug survival was analyzed using Kaplan-Meier survival curves, considering separately overall discontinuation, discontinuation due to MTX ineffectiveness, and discontinuation due to adverse events. Multivariable Cox regression analyses were carried out including clinically meaningful variables. A total of 199 patients were included; 148 (74.4%) suspended MTX during the observation period. The reasons for discontinuation were adverse events (39.2%), ineffectiveness (38.5%), remission of psoriasis (12.2%), and other reasons (10.1%). Average duration of therapy was 10.1 months. Patients who remained on therapy after 1, 2, and 5 years of treatment were respectively 46.9, 35.6, and 29.3%. Positive predictive factors for therapy continuation were increasing age and the use of > 15 mg of MTX for a period > 3 months; the only negative predictive factor was the clinical variant of palmoplantar pustular.

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Source: Caldarola, G., De Luca, E., Mariani, M., et al. (2024). Drug Survival of Methotrexate and Predictor Factors for Discontinuation in Psoriasis. Int J Dermatol. 2024; 62(5): 649-656. Published: May, 2024. DOI: 10.1111/ijd.16652.



Metastasis Of Skin Squamous Cell Carcinoma In Kidney Transplant Recipients

Both groups, KTRs and ICs, exhibited similar primary tumor grades and metastasis evolution, but KTRs had a higher prevalence of lymphovascular invasion. Metastasis of cSCC was more common in males with low skin phototype, in KTRs, particularly on the head and neck. The study suggests a possible link between lymphovascular invasion and metastasis development in KTRs.

source: Int J Dermatol

Summary

[Posted 8/May/2024]

AUDIENCE: Dermatology, Oncology, Family Medicine

KEY FINDINGS: Both groups, KTRs and ICs, exhibited similar primary tumor grades and metastasis evolution, but KTRs had a higher prevalence of lymphovascular invasion. Metastasis of cSCC was more common in males with low skin phototype, in KTRs, particularly on the head and neck. The study suggests a possible link between lymphovascular invasion and metastasis development in KTRs.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the most common skin malignancy in kidney transplant recipients (KTRs) as a result of immunosuppression.

DETAILS: A worldwide increase in kidney transplantation justifies the determination of prognostic biomarkers by collecting detailed patient data on metastasis development. This study aims to characterize the clinical, epidemiological, and histopathological profiles of KTRs who developed metastasis of cSCC. Authors conducted a retrospective single-center study on 18 KTRs and 21 immunocompetent patients (ICs) with metastatic cSCC, using data from 2004 to 2021. ICs were older (median age 70.5 years) than KTRs (median age: 59.5 years). Both groups were predominantly male with Fitzpatrick skin phototype I/II. The primary tumor appeared around 83.5 ; months post-transplant, usually in sun-exposed areas (61.1%), though some non-exposed areas in ICs (23.8%) contradicted literature findings. KTRs took longer to develop metastasis (median: 11.0 months) compared to ICs (median: 5.5 months). The mean size of the primary tumor was smaller in KTRs (2.50 cm2) compared to ICs (4.55 cm2). The main lymph node chain affected by metastasis was parotid lymph nodes in KTRs (27.8%) and cervical/axillar lymph nodes in ICs (both 19.0%).

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Source: Alves, F. F. C., de Jesus, L. C. B., Cristelli, M. P., et al. (2024). Metastasis Of Skin Squamous Cell Carcinoma In Kidney Transplant Recipients. Int J Dermatol. 2024; 63(5): 560-564. Published: March, 2024. DOI: 10.1111/ijd.17029.



Rapidly Evolving Pre- and Post-surgical Systemic Treatment of Melanoma

Melanoma therapeutics continues to advance with combination adjuvant approaches now investigating anti-PD1 with lymphocyte activation gene 3 (LAG3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and individualized neoantigen therapies. How this progress will be integrated into the management of a unique patient to reduce recurrence, limit toxicity, and avoid over-treatment will dominate clinical research and patient care over the next decade.

source: Am J Clin Dermatol

Summary

[Posted 25/Mar/2024]

AUDIENCE: Dermatology, Family Medicine

KEY FINDINGS: Melanoma therapeutics continues to advance with combination adjuvant approaches now investigating anti-PD1 with lymphocyte activation gene 3 (LAG3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and individualized neoantigen therapies. How this progress will be integrated into the management of a unique patient to reduce recurrence, limit toxicity, and avoid over-treatment will dominate clinical research and patient care over the next decade.

BACKGROUND: With the development of effective BRAF-targeted and immune-checkpoint immunotherapies for metastatic melanoma, clinical trials are moving these treatments into earlier adjuvant and perioperative settings. BRAF-targeted therapy is a standard of care in resected stage III-IV melanoma, while anti-programmed death-1 (PD1) immunotherapy is now a standard of care option in resected stage IIB through IV disease.

DETAILS: With both modalities, recurrence-free survival and distant-metastasis-free survival are improved by a relative 35-50%, yet no improvement in overall survival has been demonstrated. Neoadjuvant anti-PD1 therapy improves event-free survival by approximately an absolute 23%, although improvements in overall survival have yet to be demonstrated. Understanding which patients are most likely to recur and which are most likely to benefit from treatment is now the highest priority question in the field. Biomarker analyses, such as gene expression profiling of the primary lesion and circulating DNA, are preliminarily exciting as potential biomarkers, though each has drawbacks. As in the setting of metastatic disease, markers that inform positive outcomes include interferon-γ gene expression, PD-L1, and high tumor mutational burden, while negative predictors of outcome include circulating factors such as lactate dehydrogenase, interleukin-8, and C-reactive protein. Integrating and validating these markers into clinically relevant models is thus a high priority.

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Source: Augustin, R. C. and Luke, J. J. (2024). Rapidly Evolving Pre- and Post-surgical Systemic Treatment of Melanoma. American Journal of Clinical Dermatology. Published: March, 2024. DOI: 10.1007/s40257-024-00852-5.



Human Hair Graying Revisited

The temporary reversibility of graying is highlighted by several drugs and hormones that induce repigmentation, indicating potential target pathways. Authors advise caution in directly applying mouse model concepts, define major open questions, and discuss future human antigraying strategies.

source: JID

Summary

Principles, Misconceptions, and Key Research Frontiers

[Posted 6/Mar/2024]

AUDIENCE: Dermatology, Family Medicine

KEY FINDINGS: The temporary reversibility of graying is highlighted by several drugs and hormones that induce repigmentation, indicating potential target pathways. Authors advise caution in directly applying mouse model concepts, define major open questions, and discuss future human antigraying strategies.

BACKGROUND: Hair graying holds psychosocial importance and serves as an excellent model for studying human pigmentation and aging in an accessible miniorgan.

DETAILS: Current evidence suggests that graying results from an interindividually varying mixture of cumulative oxidative and DNA damage, excessive mTORC1 activity, melanocyte senescence, and inadequate production of pigmentation-promoting factors in the hair matrix. Various regulators modulate this process, including genetic factors (DNA repair defects and IRF4 sequence variation, peripheral clock genes, P-cadherin signaling, neuromediators, HGF, KIT ligand secretion, and autophagic flux. This leads to reduced MITF- and tyrosinase-controlled melanogenesis, defective melanosome transfer to precortical matrix keratinocytes, and eventual depletion of hair follicle (HF) pigmentary unit (HFPU) melanocytes and their local progenitors. Graying becomes irreversible only when bulge melanocyte stem cells are also depleted, occurring later in this process. Distinct pigmentary microenvironments are created as the HF cycles: early anagen is the most conducive phase for melanocytic reintegration and activation, and only during anagen can the phenotype of hair graying and repigmentation manifest, whereas the HFPU disassembles during catagen.

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Copyright © The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. All rights reserved.

Source: Paus, R., Sevilla, A., and Grichnik, J. M. (2024). Human Hair Graying Revisited: Principles, Misconceptions, and Key Research Frontiers. Journal of Investigative Dermatology. 2024; 144(3): 474-491. Published: March, 2024. DOI: 10.1016/j.jid.2023.09.276.



Plectin Deficiency in Fibroblasts Deranges Intermediate Filament and Organelle Morphology, Migration, and Adhesion

Plectin, a highly versatile and multifunctional cytolinker, has been implicated in several multisystemic disorders. Most sequence variations in the human plectin gene (PLEC) cause epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), an autosomal recessive skin-blistering disorder associated with progressive muscle weakness.

source: JID

Summary

[Posted 28/Feb/2024]

AUDIENCE: Dermatology, Family Medicine

KEY FINDINGS:

BACKGROUND: Plectin, a highly versatile and multifunctional cytolinker, has been implicated in several multisystemic disorders. Most sequence variations in the human plectin gene (PLEC) cause epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), an autosomal recessive skin-blistering disorder associated with progressive muscle weakness.

DETAILS: In this study, authors performed a comprehensive cell biological analysis of dermal fibroblasts from three different patients with EBS-MD, where PLEC expression analyses revealed preserved mRNA levels in all cases, whereas full-length plectin protein content was significantly reduced or completely absent. Downstream effects of pathogenic PLEC sequence alterations included massive bundling of vimentin intermediate filament networks, including the occurrence of ring-like nuclei-encasing filament bundles, elongated mitochondrial networks, and abnormal nuclear morphologies. We found that essential fibroblast functions such as wound healing, migration, or orientation upon cyclic stretch were significantly impaired in the cells of patients with EBS-MD. Finally, EBS-MD fibroblasts displayed reduced adhesion capacities, which could be attributed to smaller focal adhesion contacts. Our study not only emphasizes plectin's functional role in human skin fibroblasts, it also provides further insights into the understanding of EBS-MD–associated disease mechanisms.

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Copyright © The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology. All rights reserved.

Source: Zrelski, M. M., Hosele, S., Kustermann, M., et al. (2024). Plectin Deficiency in Fibroblasts Deranges Intermediate Filament and Organelle Morphology, Migration, and Adhesion. Journal of Investigative Dermatology. 2024; 144(3): 547-562.e9. Published: March, 2024. DOI: 10.1016/j.jid.2023.08.020.



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