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Efficacy and Safety of Upadacitinib in Patients With Moderate-to-Severe Atopic Dermatitis: Phase 3 Randomized Clinical Trial Results Through 140 Weeks
No full textBACKGROUND: Upadacitinib is an oral selective Janus kinase inhibitor approved to treat moderate-to-severe atopic dermatitis (AD) in adults and adolescents; long-term efficacy and safety data beyond 1 year are needed.
OBJECTIVE: The aim was to evaluate the long-term efficacy and safety of upadacitinib treatment through 140 weeks in patients with moderate-to-severe AD.
METHODS: Measure Up 1 (MeUp1; NCT03569293), Measure Up 2 (MeUp2; NCT03607422), and AD Up (NCT03568318) are ongoing, phase 3, randomized clinical trials evaluating upadacitinib 15 mg (UPA15) and 30 mg (UPA30) in adults and adolescents with moderate-to-severe AD. This interim analysis evaluated efficacy and safety through week 140. At baseline, patients were randomized 1:1:1 to receive once-daily UPA15, UPA30, or placebo alone (MeUp1/2) or with concomitant topical corticosteroids (AD Up). At week 16, patients initially randomized to placebo were rerandomized 1:1 to UPA15 or UPA30. Skin and itch efficacy assessments included achievement of ≥ 75%/≥ 90%/100% improvement from baseline in Eczema Area and Severity Index (EASI 75/90/100), validated Investigator Global Assessment for AD score of clear/almost clear (vIGA-AD 0/1), and ≥ 4-point improvement from baseline in Worst Pruritus Numerical Rating Scale (∆WP-NRS≥4). Safety assessments included incidence of treatment-emergent adverse events.
RESULTS: A total of 2782 patients were randomized in MeUp1/2 or AD Up. Efficacy response rates, including optimal outcomes such as EASI 90 and WP-NRS score of 0/1, were sustained through week 140 in all three studies. At week 140, EASI 75 was achieved by 85.5%/90.5% (UPA15/UPA30; integrated MeUp1/2) and 81.5%/90.0% (UPA15/UPA30; AD Up) of patients, and vIGA-AD 0/1 was achieved by 56.6%/64.4% (UPA15/UPA30; integrated MeUp1/2) and 52.0%/56.8% (UPA15/UPA30; AD Up) of patients. Over 60% of patients across all three studies achieved ∆WP-NRS≥4 at week 140. Pooled safety data across all three studies demonstrated safety profiles consistent with 16-week and 52-week analyses.
CONCLUSIONS: UPA15 and UPA30 with and without topical corticosteroids demonstrated robust, durable efficacy and a favorable safety profile through 140 weeks in adults and adolescents with moderate-to-severe AD.
TRIAL REGISTRATION: Measure Up 1 (NCT03569293; https://clinicaltrials.gov/study/NCT03569293 ), Measure Up 2 (NCT03607422; https://clinicaltrials.gov/study/NCT03607422 ), and AD Up (NCT03568318; https://clinicaltrials.gov/study/NCT03568318 )
Efficacy and safety of ruxolitinib cream for the treatment of moderate to severe chronic hand eczema: Results from a 16-week, multicenter, randomized, double-blind study
No full textBACKGROUND: Chronic hand eczema (CHE) is a well-recognized inflammatory disorder.
OBJECTIVE: To evaluate the efficacy and safety of 1.5% ruxolitinib cream in adults with moderate to severe CHE.
METHODS: This phase 2 study enrolled adults with CHE from North America and Europe, an Investigator\u27s Global Assessment-CHE score of 3/4, ≥1 prior CHE therapy, and no current or recent history (≤5 y) of atopic dermatitis. Patients were randomized 1:1 to twice-daily 1.5% ruxolitinib cream or vehicle cream for 16 weeks.
RESULTS: Among 186 randomized patients, most who applied ruxolitinib cream achieved a score of 0 (clear) or 1 (almost clear) on the Investigator\u27s Global Assessment-CHE scale with a 2-grade improvement from baseline at Week 16 (53.2% vs 10.9% [vehicle]; P \u3c .0001; primary endpoint). Itch improvements (≥4-point improvement in numerical rating scale) were reported on Day 2 (9.1% vs 2.4%) and reached statistical significance on Day 7 (27.4% vs 9.0%; P = .0024). Improvements in skin pain and quality of life were reported during the study. Ruxolitinib cream was well tolerated, with no new safety signals and few (3.2%) application site reactions.
LIMITATIONS: Relatively small sample size.
CONCLUSION: Ruxolitinib cream represents an effective treatment option for nonatopic CHE subtypes that are not controlled with standard therapies
A recurrent de novo damaging variant in EMP2 causes progressive symmetric erythrokeratoderma
No full textGenetic investigation in Mendelian skin disorders featuring generalized or localized skin scaling and redness, known as the ichthyoses, has revealed novel pathways relevant to epidermal integrity, barrier function, and desquamation. Here, we show that a recurrent de novo missense variant in EMP2 (epithelial membrane protein 2), which encodes a cell surface tetraspan protein in the growth-arrest specific 3 (GAS3)/peripheral myelin protein 22 (PMP22) family, is associated with a Mendelian skin disorder in the progressive symmetric erythrokeratoderma spectrum. The disorder features severely thickened, red, and scaly skin at sites of wound healing or repetitive movement including on the face, genitals, flexural areas, and the palms and soles. EMP2 has previously been shown to directly associate with focal adhesion kinase, which links cell junction forces to signaling pathways relevant to proliferation, migration, and wound healing. Using single-cell spatial transcriptomics in affected tissue, we found ectopic suprabasal activation of signaling pathways downstream of receptor tyrosine kinases including epidermal growth factor receptor (EGFR), which we confirmed with western blotting in affected cells, supporting a gain-of-function mechanism for mutant EMP2. Remarkably, treatment with erlotinib, an EGFR inhibitor, led to marked clinical improvement underscoring the key role of EMP2 in epidermal differentiation and proliferation
Improving Documentation and Follow-Up of Elevated Blood Pressure in a Family Clinic: A Quality Improvement Project
No full textIntroduction: Hypertension is a common and clinically significant condition frequently encountered in primary care. However, challenges such as poor documentation and inconsistent follow-up planning in many outpatient settings can result in suboptimal outcomes, increasing the risk of missed care opportunities. This quality improvement project aimed at improving documentation and follow-up planning for patients with elevated blood pressure (BP) (\u3e140/90 mmHg) at a family clinic in Michigan.
Objective: This quality improvement project is aimed at improving documentation and follow-up planning for elevated BP readings in adult patients seen during outpatient visits from 33% to 70% over a three-week period in a family medicine clinic.
Methods: The project was conducted at an outpatient family medicine clinic over a three-week period from June 9 to June 27. Adult patients aged 18 years and older with elevated BP were included, and a total of 60 patient charts were reviewed during the intervention period. The intervention consisted of a daily review of patient charts to identify elevated BP, ensuring that follow-up plans such as home BP monitoring, repeat BP checks, and lifestyle modification advice were documented in the electronic health record (EHR). Patients with elevated readings also received verbal counseling, and brief end-of-day team huddles were conducted to review documentation, and early in the cycle, brief staff education sessions were held to review the documentation standards. Data were collected through both EHR review and manual chart audits. A Plan-Do-Study-Act (PDSA) cycle was used to implement and evaluate the intervention.
Results: At baseline, only 33% (20 out of 60) of the patients with elevated BP had appropriate documentation and follow-up plan in the EHR. Following the three-week intervention, this increased to 80% (48 out of 60), surpassing the initial target of 70%. The documentation improvement was achieved using the iterative PDSA cycle approach, with adjustments made weekly to reinforce chart review, counselling, and end-of-day team huddles.
Conclusion: This quality improvement cycle led to a significant improvement in the documentation and follow-up plans, highlighting its importance in better management of hypertension. The intervention has been sustained in the daily clinic practice, with minor adjustments made to support long-term sustainability. This may also serve as a model for similar clinic-based quality improvement efforts
Reducing alcohol-associated liver disease burden in the general population
No full textThe prevalence of alcohol use disorder (AUD) and alcohol-associated liver disease (ALD) is rising. The National Institute on Alcohol Abuse and Alcoholism organised a multistakeholder workshop focused on reducing the burden of ALD. Decreasing ALD morbidity and mortality requires a multipronged approach, including increased population-based screening for AUD, early recognition of ALD, and multidisciplinary treatment. Recommended screening tools for alcohol use include the alcohol use disorders identification test for consumption (AUDIT-C). In patients with elevated AUDIT-C scores (AUDIT-C score of ≥3 points in women, ≥4 points in men), screening for fibrosis is recommended using non-invasive blood-based tests, such as the Fibrosis-4 index. Sequential testing using blood-based and imaging-based non-invasive liver disease assessment is preferred to blood-based tests alone to increase the positive predictive value of referral pathways. Screening, brief intervention, and referral to treatment are effective for reducing unhealthy alcohol use among adults who are not alcohol dependent. Integrated care models that incorporate mental health treatment into general medical settings are crucial for AUD and ALD. Emerging care models, such as multidisciplinary ALD clinics and substance use navigators, can improve patient engagement and outcomes. Markers of success include a reduction in per capita alcohol consumption, declines in morbidity and mortality related to AUD and ALD, and a decrease in health-care costs
New diagnostic methods for Escherichia marmotae and the first report of its identification in clinical isolates in North America
No full textBACKGROUND: Genomic sequences of E. marmotae and E. coli differ by 10%. Discovered as an environmental cryptic clade of Escherichia, E. marmotae also occurs in human infections. Microbiological and MALDI-TOF-MS methods frequently misidentify E. marmotae as E.coli. Our goal was to develop methods that reliably distinguish E. marmotae from E. coli to improve therapeutic decisions and treatments.
METHODS: A Taqman PCR method was developed to distinguish E. marmotae from E. coli based on genomic sequences of uidA, uidB, and a positive control targeting adk in E. marmotae and E. coli. MALDI-TOF-MS spectra were obtained for environmental and clinical isolates using a bioMérieux VITEK MALDI-TOF-MS system.
RESULTS: UidA- and uidB species-specific PCR amplified DNA from E. marmotae with 100% specificity, and not from E. coli or other Escherichia species. The Biomérieux VITEK MALDI-TOF-MS consistently misidentified E. marmotae as E. coli, with median IVD confidence scores for both E. marmotae and E. coli of 99.9%; however, RUO scores for E. marmotae (median 0%) were significantly lower (P \u3c 0.0001) than for E. coli (median = 87.4%). The spectral peak between m/z 7,250 to 7,280 consistently occurred between 7,260 and 7,268 in E. marmotae and only between 7,268 and 7,280 in E. coli, with no overlap (p \u3c 0.001). Application of these spectral criteria to 176 clinical isolates revealed the first identification of a E. marmotae isolate from a human infection in North America. The isolate had originally been diagnosed as E. coli based on a 99.1% IVD confidence score. This first North American clinical isolate was confirmed as E. marmotae by Taqman-PCR and whole genome sequencing. This isolate had numerous antibiotic resistance gene markers and unlike most clinical E. coli, this E. marmotae isolate lacked motility at 37°C.
CONCLUSION: Clinical tests based on these methods of differentiating E. marmotae and E. coli may assist in determining the prevalence of this emerging pathogen and making therapeutic decisions
Endoscopic management of esophageal perforations: a multi-center study
No full textBACKGROUND: Esophageal perforation (EP) is a rare but life-threatening condition with an incidence of approximately 3.1 per million annually. While iatrogenic injury during endoscopy is the leading cause, other etiologies include spontaneous rupture, trauma, and malignancy. EP can present with nonspecific symptoms, most commonly chest pain or dysphagia, and diagnostic delays are associated with worse outcomes. Multiple non-operative strategies exist, including primary closure, stenting (bypass), combination therapy, and conservative management. However, data guiding the optimal approach remain limited. The aim of this study was to evaluate outcomes of different non-operative management strategies for EP and identify predictors of successful repair.
METHODS: We retrospectively analyzed adult patients with EP across three Mayo Clinic sites between 2007 and 2023. Patients were categorized into four groups based on treatment modality. Demographics, clinical features, imaging, endoscopic intervention, and outcomes were recorded. The primary outcome was clinical success, defined as avoidance of surgical intervention. Logistic regression was used to identify predictors of success.
RESULTS: A total of 72 patients were included (mean age 63.7 years, 65.3% male). The most common cause was iatrogenic injury (58.3%), and the distal esophagus was the most frequent site (67.6%). Non-operative success was 100% in the primary closure and combination groups, and 42.9% in the conservative group (p \u3c 0.001). On multivariate analysis, non-conservative therapy significantly predicted success (aOR 22.4, 95% CI [1.2-407.4], p = 0.036).
CONCLUSION: Primary closure and combination endoscopic approaches offer superior outcomes in managing EP. Early intervention with appropriate modality selection is critical to avoid surgical escalation and improve prognosis
Study of the NOTCH3 Gene Reveals the First CADASIL Cases in Crete and a Novel Pathogenic Variant
No full textBACKGROUND: NOTCH3 gene variants are associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). In this study we aimed to examine the presence of pathogenic NOTCH3 variants in individuals with suspected CADASIL on the Greek island of Crete. This represents the first report of CADASIL patients in Crete.
METHODS: We reviewed the medical records of the University Hospital of Heraklion and identified three patients with the clinical diagnosis of CADASIL. In these patients pathogenic NOTCH3 variants were identified through targeted or whole-exome sequencing (WES).
RESULTS: A novel heterozygous variant in exon 4 of the NOTCH3 gene (p.Cys206Trp; NM_000435.3:c.618C\u3eG) was found in a 67-year-old woman who suffered from recurrent ischemic strokes, cognitive impairment, depression, and headache, as well as her son, who presented with headache, anxiety disorder, and insomnia. Brain MRI for both patients revealed white matter disease, including the anterior temporal lobes. The characteristics of this variant (a Cys-related variant in the epidermal growth factor repeats area) support its pathogenicity. We also identified a 72-year-old patient affected by CADASIL and carrying a previously described p.Arg607Cys (NM_000435.3:c.1819C\u3eT) NOTCH3 variant.
CONCLUSIONS: This report extends the geographic and genotypic spectrum of pathogenic NOTCH3 variants and documents the first CADASIL cases on the island of Crete, Greece
Secondary Free Flap Reconstruction of the Maxilla Following Obturator Failure
No full textBACKGROUND: In patients with acquired maxillary defects, obturators are often effective, but some fail, necessitating further surgery, typically via free flap reconstruction. Long-term functional outcomes in these cases are underreported. This study examines the outcomes of secondary free flap reconstruction in patients who failed obturator use, focusing on enteral and tracheostomy tube dependence, dental implantation rates, and complications.
METHODS: This retrospective cohort study included patients who were initially planned for maxillary reconstruction with an obturator but were unable to retain it due to mechanical issues, not financial constraints.
RESULTS: Seventy-one patients were included. There were no flap losses. Postoperatively, 98.6% (70 patients) underwent tracheostomy decannulation, 90.1% (64 patients) tolerated an oral diet, and 49.3% (35 patients) received successful dental implants. Postoperative complications occurred in 11.3% (8 patients).
CONCLUSIONS: Secondary free flap reconstruction yields favorable outcomes in patients with failed obturators, improving tracheostomy dependence, diet tolerance, and dental implantation success. Financial considerations may influence flap choice
Spontaneous Mandible Regeneration After Segmental Resection in a Pediatric Patient With Ameloblastoma
No full textBACKGROUND: The purpose of this case report is to highlight the understated regenerative potential of the pediatric mandible, which favors early aggressive management and delayed secondary reconstruction of the mandible in the management of ameloblastoma, a well-known pathology.
METHODS: This is a case of an otherwise healthy 12-year-old girl presented with complaints of loose teeth and right facial swelling. An orthopantogram was obtained, which revealed a unilocular radiolucent lesion of the right mandible. The lesion was biopsied to be plexiform ameloblastoma, and the patient underwent segmental mandibulectomy and temporary reconstruction with custom reconstruction mandibular bar with future plans for microvascular reconstruction.
RESULTS: Patient was followed postoperatively with serial orthopantograms and 3-dimensional computed tomography at 17 months that revealed progressive mandibular regeneration avoiding need for further reconstruction.
CONCLUSIONS: Delayed reconstruction of the mandible in the pediatric population can be minimized with early aggressive management of a solid ameloblastoma. The ideal environment for regeneration of the mandible should be taken into consideration during treatment planning: the absence of infection, rigid fixation, patient age, and an intact periosteum