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Mark Lebwohl

Publications and source records attributed to Mark Lebwohl.

At least 19 recordsLinked to original sources
PubMed2026

Deucravacitinib 5-Year Safety and Efficacy Results in Plaque Psoriasis: A Phase 3 Open-Label Extension of Randomized Clinical Trials.

BACKGROUND: Deucravacitinib, an oral, selective, tyrosine kinase 2 inhibitor, is approved for adults with moderate to severe plaque psoriasis who are candidates for systemic therapy and for adults with active psoriatic arthritis. OBJECTIVE: We evaluated deucravacitinib safety and efficacy over 5 years in the phase 3 POETYK PSO-1, PSO-2, and long-term extension (LTE) trials in patients with moderate to severe plaque psoriasis. METHODS: PSO-1 and PSO-2 (parent trials) randomized patients 1:2:1 to oral placebo, deucravacitinib 6 mg once daily, or apremilast 30 mg twice daily. At 52 weeks, patients enrolled in the LTE trial received open-label deucravacitinib. Safety was reported as exposure-adjusted incidence rates (EAIRs) per 100 person-years (PY). Clinician- and patient-reported outcomes were analyzed using modified nonresponder imputation in patients receiving continuous deucravacitinib from day 1 (PSO-1/PSO-2) through 5 years. RESULTS: Overall, 1519 patients received one or more deucravacitinib dose; total exposure was 5046.7 PY through data cutoff (September 2, 2024). EAIRs/100 PY were comparable or decreased from the 1-year to 5-year cumulative period for adverse events (AEs) (229.23, 127.40, respectively), serious AEs (5.68, 5.06), discontinuation due to AEs (4.38, 2.09), deaths (0.20, 0.22), serious infections excluding coronavirus disease 2019 (COVID-19) (1.53, 0.94), malignancies (1.02, 0.92), major adverse cardiovascular events (0.30, 0.34), and venous thromboembolism (0.20, 0.06). Clinical outcomes were well-maintained in patients receiving continuous deucravacitinib (n = 513) from 1 through 5 years, including achievement of a ≥ 75% reduction from baseline in the Psoriasis Area and Severity Index (1 year, 72.1% [95% CI 68.2-76.1]; 5 years, 67.3% [62.0-72.6]) and a static Physician Global Assessment score of 0 (clear) or 1 (almost clear) (1 year, 57.5% [53.1-61.9]; 5 years, 52.6% [47.0-58.1]). Dermatology Life Quality Index 0 or 1 was well-maintained from 1 year (52.5% [48.0-57.1]) through 5 years (45.4% [40.0-50.8]). CONCLUSIONS: These findings demonstrate a consistent safety profile with no new safety signals and durable clinical response through 5 years of treatment with deucravacitinib. CLINICAL TRIAL REGISTRATION: NCT03624127, NCT03611751, NCT04036435.

Humans↗
PubMed2006

Photoprotective effect of isoflavone genistein on ultraviolet B-induced pyrimidine dimer formation and PCNA expression in human reconstituted skin and its implications in dermatology and prevention of cutaneous carcinogenesis.

Genistein, the most abundant isoflavone of the soy derived phytoestrogen compounds, is a potent antioxidant and inhibitor of tyrosine kinase. We previously reported the antiphotocarcinogenic effects of genistein in SKH-1 murine skin, including its capacity for scavenging reactive oxygen species, inhibiting photodynamic DNA damage and downregulating UVB(ultra violet B)-induced signal transduction cascades in carcinogenesis. In this study we elucidate genistein's photoprotective efficacy within the context of full thickness human reconstituted skin relative to acute challenges with ultraviolet-B irradiation. Skin samples were pre-treated with three concentrations of genistein (10, 20 and 50 microM) 1 h prior to UVB radiation at 20 and 60 mJ/cm2. Proliferating cell nuclear antigen (PCNA) and pyrimidine dimer (PD) expression profiles were localized using immunohistochemical analysis on paraffin embedded samples 6 and 12 h post UVB exposure. Genistein dose dependently preserved cutaneous proliferation and repair mechanics at 20 and 60 mJ/cm2, as evidenced by the preservation of proliferating cell populations with increasing genistein concentrations and noticeable paucity in PCNA immunoreactivity in the absence of genistein. Genistein inhibited UV-induced DNA damage, evaluated with PD immunohistochemical expression profiles, demonstrated an inverse relationship with increasing topical genistein concentrations. Irradiation at 20 and 60 mJ/cm2 substantially induced PD formation in the absence of genistein, and a dose dependent inhibition of UVB-induced PD formation was observed relative to increasing genistein concentrations. Collectively all genistein pre-treated samples demonstrated appreciable histologic architectural preservation when compared with untreated specimens. These findings represent a critical link between our animal and cell culture studies with those of human skin and represent the first characterization of the dynamic alterations of UV-induced DNA damage and proliferating cell populations relative to pretreatment with genistein in human reconstituted skin. The implications of our findings serve as compelling validation to our conclusions that genistein may serve as a potent chemopreventive agent against photocarcinogenesis.

Anticarcinogenic Agents↗
PubMed2006

Relapse, rebound, and psoriasis adverse events: an advisory group report.

Psoriasis is a chronic disease, the severity of which varies among patients and changes unpredictably over time in individual patients. Psoriasis can be exacerbated during treatment by infection, endocrine factors, hypocalcemia, medications, psychologic stress, skin trauma, or other factors. Patients who discontinue treatments may experience a return of disease--relapse--or worsening of disease--rebound. The National Psoriasis Foundation (NPF) proposed standardized definitions of relapse and rebound. Efalizumab, a recombinant humanized immunoglobulin G-1 monoclonal antibody, is approved for the management of psoriasis. During efalizumab clinical trials, a small percentage of patients experienced protocol-defined adverse events related to psoriasis. After publication of the NPF definition of rebound, post hoc exploratory analyses of the efalizumab clinical trial data were performed. The efalizumab clinical trial investigators discussed their observations, the analyses, and their individual approaches to the treatment of patients receiving or discontinuing efalizumab therapy, the conclusions of which are described herein.

Antibodies, Monoclonal↗
PubMed2006

Pseudoxanthoma elasticum is a recessive disease characterized by compound heterozygosity.

Pseudoxanthoma elasticum (PXE) is caused by mutations in the ABCC6 gene. Historically, PXE has been suggested to be inherited either in an autosomal dominant or autosomal recessive manner. To determine the exact mode of inheritance of PXE and to address the question of phenotypic expression in mutation carriers, we identified seven pedigrees with affected individuals in two different generations and sequenced the entire coding region of ABCC6 in affected individuals, presumed carriers with a limited phenotype and unaffected family members. Two allelic mutations were identified in each individual with unambiguous diagnosis of PXE, as well as in those with only minimal clinical signs suggestive of PXE but with positive skin biopsy. Missense mutations were frequently detected in the latter cases. In conclusion, PXE is inherited in an autosomal recessive manner and presence of disease in two generations is due to pseudodominance.

DNA Mutational Analysis↗
PubMed2006

Treatment of vitiligo using the 308-nm excimer laser.

OBJECTIVE: The aim of this study was to study the effectiveness of the 308-nm xenon chloride excimer laser in the treatment of vitiligo and to determine factors that favor a good response to treatment. BACKGROUND DATA: Targeted phototherapy using the 308-nm xenon chloride excimer laser represents an effective therapy for the management of vitiligo. However, studies on a large number of patients are few despite the increasing use of the excimer laser to treat patients with vitiligo. METHODS: A retrospective chart review of 97 patients with chronic stable vitiligo was done with a total of 221 vitiligo patches treated. RESULTS: Out of 221 vitiligo patches treated, 50.6% showed 75% pigmentation or more, 25.5% achieved 100% pigmentation of their patches, and 64.3% showed 50% pigmentation or more. Lesions on the face responded better than lesions elsewhere. CONCLUSION: The 308-nm xenon chloride excimer laser is an effective and safe modality for the treatment of vitiligo, with good results achieved in a relatively short duration of time.

Adolescent↗
PubMed2006

Chemoprevention of nonmelanoma skin cancer with systemic retinoids: practical dosing and management of adverse effects.

BACKGROUND: In patients with nonmelanoma skin cancer that is high risk or characterized by numerous tumors, chemoprevention with systemic retinoids may effectively decrease the number of new tumors whereas the chemosuppressive effects may reduce the risk of recurrence or disease progression. A patient's intolerance of the mucocutaneous effects of retinoid therapy or abnormal laboratory findings may hamper continuous therapy. OBJECTIVE: To present a method for optimizing tolerance of systemic retinoids for chemoprevention and for monitoring and managing adverse events. METHODS: After reviewing the data on the use of systemic retinoids for chemoprevention, we developed a simplified approach for administering oral retinoids for chemoprevention of nonmelanoma skin cancer as well as basic guidelines for the prevention and management of adverse effects and appropriate laboratory monitoring. RESULTS: Chemoprevention with systemic retinoids in patients with a history of numerous tumors or high-risk skin cancer can be optimized with graduated dose escalation and preventive strategies for the most common adverse effects. Routine laboratory monitoring may assist in detecting adverse effects, which can be managed in most cases. CONCLUSION: In our experience, the effective use of systemic retinoids for chemoprevention of nonmelanoma skin cancer in high-risk patients can be optimized through a standardized, proactive approach.

Acitretin↗
PubMed2006

New roles for systemic retinoids.

Acitretin, the only oral retinoid indicated for the treatment of psoriasis, has shown activity when used in combination, rotational, and sequential therapy regimens with other therapies. When used with phototherapy, significantly greater activity has been observed at lower doses than with either approach as monotherapy. While initial anecdotal evidence is promising, clinical trials are needed to evaluate whether sequential or rotational use of biologic agents with acitretin may yield improved efficacy and an acceptable safety profile with decreased risk of immunosuppression. Acitretin and other retinoids also work as chemopreventative agents in psoriasis patients with extensive exposure to psoralen ultraviolet A (PUVA) and in solid-organ transplant patients where a number of studies have reported decreased numbers of squamous cell cancers when treated with acitretin.

Acitretin↗
PubMed2006

Calcinosis cutis in a patient with eosinophilia-myalgia syndrome: case report.

Eosinophilia-myalgia syndrome (EMS) often is a disabling disorder caused by the consumption of contaminated L-tryptophan. Affected patients present with an array of symptoms, including cutaneous manifestations, peripheral eosinophilia, myalgias, and long-term neurocognitive disability. This article is the first reported case of a patient with EMS who developed calcinosis cutis. While many long-term sequelae of EMS are reported in the literature, there are no reports of the development of dystrophic calcification in these patients. The calcinosis cutis in this patient with EMS may represent a new manifestation of EMS that has not been documented to date. If more patients with EMS develop calcinosis cutis, it will present a therapeutic challenge to the physicians managing these patients.

Aged↗
PubMed2005

Benzo[a]pyrene and its metabolites combined with ultraviolet A synergistically induce 8-hydroxy-2'-deoxyguanosine via reactive oxygen species.

We previously reported that benzo[a]pyrene (BaP) and UVA radiation synergistically induced oxidative DNA damage via 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation in vitro. The present study shows that microsomal BaP metabolites and UVA radiation potently enhance 8-OHdG formation in calf thymus DNA about 3-fold over the parent compound BaP. Utilization of various reactive oxygen species scavengers revealed that singlet oxygen and superoxide radical anion were involved in the 8-OHdG formation induced by microsomal BaP metabolites and UVA. Two specific BaP metabolites, benzo[a]pyrene-r-7,t-8-dihydrodiol-t-9,10-epoxide (+/-) (anti) (BPDE) and BaP-7,8-dione, were further tested for synergism with UVA. BaP-7,8-dione showed an effect on 8-OHdG formation induced by UVA radiation that was similar to that of the parent BaP, whereas BPDE exhibited significantly higher induction of 8-OHdG than BaP. At as low as 0.5 microM, BPDE plus UVA radiation substantially increased 8-OHdG levels about 25-fold over the parent BaP. BPDE increased the formation of 8-OHdG levels in both BPDE concentration- and UVA dose-dependent manners. Additionally, singlet oxygen was found to play a major role in 8-OHdG induction by BPDE and UVA. These results suggest that BaP metabolites such as BPDE synergize with UVA radiation to produce ROS, which in turn induce DNA damage.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2005

Combined subcarcinogenic benzo[a]pyrene and UVA synergistically caused high tumor incidence and mutations in H-ras gene, but not p53, in SKH-1 hairless mouse skin.

Combined subcarcinogenic doses of benzo[a]pyrene (BaP) and UVA induced H-ras, but not p53, gene mutations 8 weeks before tumor emergence in SKH-1 mice. Neither UVA (40 kJ/m2) nor BaP (8 nmol) induced any tumors after mice were topically treated 3 times/week for 25 weeks. However, combined BaP-UVA treatment synergistically increased tumor incidence and multiplicity. All tumors induced by BaP-UVA were malignant. The epidermis was collected from mice treated for 2, 6 and 10 weeks. DNA from UVB- (0.3 kJ/m2) or BaP-UVA-(8 nmol and 40 kJ/m2-induced tumors was isolated and screened for H-ras and p53 mutations. Four types of point mutation, GGC-->GAC, GCC, GTC and CGC, occurred in UVB-induced tumors at H-ras codon 13; and one type of point mutation, GGA-->GAA, at codon 12. Treatment with either BaP alone or BaP-UVA for 10 weeks caused GGA-->GAA mutation at codon 12 or GGC-->GAC mutation at codon 13 in nontumor skin, respectively, as well as in tumors induced by BaP-UVA. All of the 10-week samples treated with either BaP or BaP-UVA showed detectable mutations at codons 12 and 13, but the genetic load was significantly higher in BaP-UVA-treated mice than in those exposed only to BaP. UVA alone induced mutations at codon 12 in only one-third of samples. G-->A mutations induced by BaP or BaP-UVA at position 38 of codon 13 have not been reported previously. C-->T transitions were detected in p53 hot spots of exon 8 in 2 of 19 BaP-UVA-induced tumors but were not found in nontumor skin.

Animals↗
PubMed2005

No evidence for increased risk of cutaneous squamous cell carcinoma in patients with rheumatoid arthritis receiving etanercept for up to 5 years.

OBJECTIVE: To determine the incidence of cutaneous squamous cell carcinoma (SCC) in patients with rheumatoid arthritis receiving etanercept, a tumor necrosis factor antagonist, for up to 5 years. DESIGN: An etanercept clinical trials' database and an etanercept postmarketing surveillance database were retrospectively analyzed for the incidence of SCC. SETTING: Patients enrolled in clinical trials of etanercept were from private and institutional practices. The postmarketing database comprised reports from postmarketing trials and solicited and spontaneous reports. Patients A total of 1442 patients with rheumatoid arthritis with 4257 patient-years of etanercept exposure (median exposure, 3.7 years) are included in the clinical trials' database. More than 125,000 patients with more than 250,000 patient-years of etanercept exposure are included in the etanercept postmarketing database. Interventions Most patients enrolled in clinical trials of etanercept received a dosage of 25 mg of etanercept subcutaneously twice weekly for most of the time they received etanercept therapy. RESULTS: Only 4 cases of SCC were observed in the etanercept clinical trials' database, an incidence that compares favorably with the expected incidences based on general population data from Arizona (13.1) and Minnesota (5.9). Similarly, few cases of SCC (1 per 10,000 patient-years) have been reported during postmarketing surveillance of etanercept therapy. CONCLUSION: In patients with rheumatoid arthritis, etanercept use of up to 5 years does not seem to be associated with an increase in the incidence of cutaneous SCC.

Adult↗
PubMed2005

Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6.

Pseudoxanthoma elasticum (PXE) is a systemic heritable disorder that affects the elastic tissue in the skin, eye, and cardiovascular system. Mutations in the ABCC6 gene cause PXE. We performed a mutation screen in ABCC6 using haplotype analysis in conjunction with direct sequencing to achieve a mutation detection rate of 97%. This screen consisted of 170 PXE chromosomes in 81 families, and detected 59 distinct mutations (32 missense, eight nonsense, and six likely splice-site point mutations; one small insertion; and seven small and five large deletions). Forty-three of these mutations are novel variants, which increases the total number of PXE mutations to 121. While most mutations are rare, three nonsense mutations, a splice donor site mutation, and the large deletion comprising exons 23-29 (c.2996_4208del) were identified as relatively frequent PXE mutations at 26%, 5%, 3.5%, 3%, and 11%, respectively. Chromosomal haplotyping with two proximal and two distal polymorphic markers flanking ABCC6 demonstrated that most chromosomes that carry these relatively frequent PXE mutations have related haplotypes specific for these mutations, which suggests that these chromosomes originate from single founder mutations. The types of mutations found support loss-of-function as the molecular mechanism for the PXE phenotype. In 76 of the 81 families, the affected individuals were either homozygous for the same mutation or compound heterozygous for two mutations. In the remaining five families with one uncovered mutation, affected showed allelic compound heterozygosity for the cosegregating PXE haplotype. This demonstrates pseudo-dominance as the relevant inheritance mechanism, since disease transmission to the next generation always requires one mutant allelic variant from each parent. In contrast to other previous clinical and molecular claims, our results show evidence only for recessive PXE. This has profound consequences for the genetic counseling of families with PXE.

Amino Acid Sequence↗
PubMed2005

Clinical efficacy of efalizumab in patients with chronic plaque psoriasis: results from three randomized placebo-controlled Phase III trials: part I.

BACKGROUND: Effective psoriasis therapies are needed for long-term symptom control. OBJECTIVE: Assess efalizumab (Raptiva) efficacy in a large cohort of psoriasis patients. METHODS: Data from three Phase III, randomized, double-blind, parallel-group, placebo-controlled, multicenter studies were pooled. Patients (n = 1,651) with moderate to severe plaque psoriasis received 12 weeks of subcutaneous efalizumab 1 or 2 mg/kg/wk or placebo. RESULTS: All efficacy measures reached statistical significance within each of the individual studies (p < 0.001) and overall. More efalizumab-treated patients achieved > or = 75% and > or = 50% Psoriasis Area and Severity Index (PASI) improvement at week 12 than did placebo-treated patients (27.8% vs 3.8% [p < 0.001] and 56.1% vs 14.6% [p < 0.001], respectively). Significant PASI improvements occurred as early as week 2 (12.5% vs 7.9%, p =0.0001). Adverse events were generally mild to moderate. CONCLUSION: Efalizumab resulted in early and significant improvement for all efficacy endpoints and was well tolerated in patients with moderate to severe chronic plaque psoriasis.

Adolescent↗
PubMed2005

The use of systemic immune moderators in dermatology: an update.

In addition to corticosteroids, dermatologists have access to an array of immunomodulatory therapies. Azathioprine, cyclophosphamide, methotrexate, cyclosporine, and mycophenolate mofetil are the systemic immunosuppressive agents most commonly used by dermatologists. In addition, new developments in biotechnology have spurred the development of immunobiologic agents that are able to target the immunologic process of many inflammatory disorders at specific points along the inflammatory cascade. Alefacept, efalizumab, etanercept, and infliximab are the immunobiologic agents that are currently the most well known and most commonly used by dermatologists. This article reviews the pharmacology, mechanism of action, side effects, and clinical applications of these therapies.

Dermatologic Agents↗
PubMed2005

Oral phosphate binders in the treatment of pseudoxanthoma elasticum.

BACKGROUND: Pseudoxanthoma elasticum (PXE) is a systemic connective tissue disorder involving elastic fiber calcification and fragmentation with major clinical manifestations occurring in the cutaneous, ocular, and cardiovascular systems. Normalization of the serum calcium-phosphate product through hemodialysis in a previous patient with perforating periumbilical PXE and elevated serum phosphate resulted in regression of skin lesions. OBJECTIVE: We sought to study the effect of pharmacologically limiting the intestinal absorption of phosphate in patients with PXE. METHODS: Patients received baseline skin examinations, target skin lesion evaluation, and photography; renal function tests and serum calcium and phosphate levels; urine calcium, phosphate, and creatinine levels; skin biopsy; and eye examinations and indocyanine-green angiography. Patients were treated with aluminium hydroxide tablets or liquid and returned every 2 to 4 months for skin photography and lesion evaluation. Repeated skin biopsies were performed on clinically improved target sites. Ophthalmologic evaluation was obtained at yearly intervals. RESULTS: Of 6 patients, 3 showed significant clinical improvement of skin lesions and all 3 of these patients showed histopathologic regression of disease in their target lesions. No deterioration of eye disease was seen in any of the 6 patients at 1-year follow-up. CONCLUSION: Our results demonstrate that the calcification seen in PXE may be reversible in some patients. This could hold true for eye and vascular lesions and for skin. Further studies supporting these results could reveal the first real treatment option for PXE.

Adult↗