Vaccination recommendations for adults receiving biologics and oral therapies for psoriasis and psoriatic arthritis: Delphi consensus from the medical board of the National Psoriasis Foundation.

BACKGROUND: For psoriatic patients who need to receive nonlive or live vaccines, evidence-based recommendations are needed regarding whether to pause or continue systemic therapies for psoriasis and/or psoriatic arthritis. OBJECTIVE: To evaluate literature regarding vaccine efficacy and safety and to generate consensus-based recommendations for adults receiving systemic therapies for psoriasis and/or psoriatic arthritis receiving nonlive or live vaccines. METHODS: Using a modified Delphi process, 22 consensus statements were developed by the National Psoriasis Foundation Medical Board and COVID-19 Task Force, and infectious disease experts. RESULTS: Key recommendations include continuing most oral and biologic therapies without modification for patients receiving nonlive vaccines; consider interruption of methotrexate for nonlive vaccines. For patients receiving live vaccines, discontinue most oral and biologic medications before and after administration of live vaccine. Specific recommendations include discontinuing most biologic therapies, except for abatacept, for 2-3 half-lives before live vaccine administration and deferring next dose 2-4 weeks after live vaccination. LIMITATIONS: Studies regarding infection rates after vaccination are lacking. CONCLUSION: Interruption of antipsoriatic oral and biologic therapies is generally not necessary for patients receiving nonlive vaccines. Temporary interruption of oral and biologic therapies before and after administration of live vaccines is recommended in most cases.

National Psoriasis Foundation COVID-19 Task Force guidance for management of psoriatic disease during the pandemic: Version 2-Advances in psoriatic disease management, COVID-19 vaccines, and COVID-19 treatments.

OBJECTIVE: To update guidance regarding the management of psoriatic disease during the COVID-19 pandemic. STUDY DESIGN: The task force (TF) includes 18 physician voting members with expertise in dermatology, rheumatology, epidemiology, infectious diseases, and critical care. The TF was supplemented by nonvoting members, which included fellows and National Psoriasis Foundation staff. Clinical questions relevant to the psoriatic disease community were informed by inquiries received by the National Psoriasis Foundation. A Delphi process was conducted. RESULTS: The TF updated evidence for the original 22 statements and added 5 new recommendations. The average of the votes was within the category of agreement for all statements, 13 with high consensus and 14 with moderate consensus. LIMITATIONS: The evidence behind many guidance statements is variable in quality and/or quantity. CONCLUSIONS: These statements provide guidance for the treatment of patients with psoriatic disease on topics including how the disease and its treatments affect COVID-19 risk, how medical care can be optimized during the pandemic, what patients should do to lower their risk of getting infected with severe acute respiratory syndrome coronavirus 2 (including novel vaccination), and what they should do if they develop COVID-19. The guidance is a living document that is continuously updated by the TF as data emerge.

Aiming for Cure and Preventive Initiatives in Psoriatic Disease: Building Synergy at NPF, GRAPPA, and PPACMAN.

PURPOSE OF REVIEW: To provide a general overview of the organizations dedicated to advance clinical and translational research in the field of psoriatic disease and to describe the current and future opportunities for team science approaches to overcome unmet needs in the field. Descriptions of initiatives from the NPF, PPACMAN, and GRAPPA are summarized. RECENT FINDINGS: Program projects have recently identified areas of knowledge gaps in diagnosis, treatment, and prevention of psoriasis and psoriatic arthritis (PsA). NPF's Psoriasis Prevention Initiative aims to identify interventions that can prevent the onset and relapse of psoriatic disease or related comorbidities. The Psorcast Study is a joint venture between PPACMAN and Sage Bionetworks based on patient-generated smartphone measurements of psoriatic disease. Similarly, GRAPPA is involved in a number of projects related to axial PsA, enthesitis prevalence, and biomarker discoveries. As important initiatives bring new targets for diagnosis and therapeutics in psoriatic disease, supra-endeavors such as the NIH-Accelerating Medicines Partnership (AMP) and the European Innovative Medicines Initiative (IMI) are promising public-private partnerships that can significantly catapult the field forward.

National Psoriasis Foundation COVID-19 Task Force Guidance for Management of Psoriatic Disease During the Pandemic: Version 1.

OBJECTIVE: To provide guidance about management of psoriatic disease during the coronavirus disease 2019 (COVID-19) pandemic. STUDY DESIGN: A task force (TF) of 18 physician voting members with expertise in dermatology, rheumatology, epidemiology, infectious diseases, and critical care was convened. The TF was supplemented by nonvoting members, which included fellows and National Psoriasis Foundation (NPF) staff. Clinical questions relevant to the psoriatic disease community were informed by questions received by the NPF. A Delphi process was conducted. RESULTS: The TF approved 22 guidance statements. The average of the votes was within the category of agreement for all statements. All guidance statements proposed were recommended, 9 with high consensus and 13 with moderate consensus. LIMITATIONS: The evidence behind many guidance statements is limited in quality. CONCLUSION: These statements provide guidance for the management of patients with psoriatic disease on topics ranging from how the disease and its treatments impact COVID-19 risk and outcome, how medical care can be optimized during the pandemic, what patients should do to lower their risk of getting infected with severe acute respiratory syndrome coronavirus 2 and what they should do if they develop COVID-19. The guidance is intended to be a living document that will be updated by the TF as data emerge.

Multiple-Ascending-Dose Phase 1 Clinical Study of the Safety, Tolerability, and Pharmacokinetics of CRS3123, a Narrow-Spectrum Agent with Minimal Disruption of Normal Gut Microbiota.

CRS3123 is a novel small molecule that potently inhibits methionyl-tRNA synthetase of Clostridioides difficile, inhibiting C. difficile toxin production and spore formation. CRS3123 has been evaluated in a multiple-ascending-dose placebo-controlled phase 1 trial. Thirty healthy subjects, ages 18 to 45 years, were randomized into three cohorts of 10 subjects each, receiving either 200, 400, or 600 mg of CRS3123 (8 subjects per cohort) or placebo (2 subjects per cohort) by oral administration twice daily for 10 days. CRS3123 was generally safe and well tolerated, with no serious adverse events (SAEs) or severe treatment-emergent adverse events (TEAEs) reported. All subjects completed their assigned treatment and follow-up visits, and there were no trends in systemic, vital sign, or laboratory TEAEs. There were no QTcF interval changes or any clinically significant changes in other electrocardiogram (ECG) intervals or morphology. CRS3123 showed limited but detectable systemic uptake; although absorption increased with increasing dose, the increase was less than dose proportional. Importantly, the bulk of the oral dose was not absorbed, and fecal concentrations were substantially above the MIC90 value of 1 µg/ml at all dosages tested. Subjects receiving either of the two lower doses of CRS3123 exhibited minimal disruption of normal gut microbiota after 10 days of twice-daily dosing. CRS3123 was inactive against important commensal anaerobes, including Bacteroides, bifidobacteria, and commensal clostridia. Microbiome data showed favorable differentiation compared to other CDI therapeutics. These results support further development of CRS3123 as an oral agent for the treatment of CDI. (This study has been registered at Clinicaltrials.gov under identifier NCT02106338.).

Safety, Tolerability, Systemic Exposure, and Metabolism of CRS3123, a Methionyl-tRNA Synthetase Inhibitor Developed for Treatment of Clostridium difficile, in a Phase 1 Study.

Clostridium difficile causes antibiotic-associated diarrhea and is a major public health concern. Current therapies disrupt the protective intestinal flora, do not reliably prevent recurrent infections, and will be decreasingly effective should less susceptible strains emerge. CRS3123 is an oral agent that inhibits bacterial methionyl-tRNA synthetase and has potent activity against C. difficile and aerobic Gram-positive bacteria but little activity against Gram-negative bacteria, including anaerobes. This first-in-human, double-blind, placebo-controlled, dose escalation study evaluated the safety and systemic exposure of CRS3123 after a single oral dose in healthy adults. Five cohorts of eight subjects each received CRS3123 or placebo in a 3:1 ratio. Doses for the respective active arms were 100 mg, 200 mg, 400 mg, 800 mg, and 1,200 mg. Blood and urine were collected for pharmacokinetic analysis. CRS3123 concentrations were measured with validated LC-MS/MS techniques. There were no serious adverse events or immediate allergic reactions during administration of CRS3123. In the CRS3123-treated groups, the most frequent adverse events were decreased hemoglobin, headache, and abnormal urine analysis; all adverse events in the active-treatment groups were mild to moderate, and their frequency did not increase with dose. Although CRS3123 systemic exposure increased at higher doses, the increase was less than dose proportional. The absorbed drug was glucuronidated at reactive amino groups on the molecule, which precluded accurate pharmacokinetic analysis of the parent drug. Overall, CRS3123 was well tolerated over this wide range of doses. This safety profile supports further investigation of CRS3123 as a treatment for C. difficile infections. (This study has been registered at ClinicalTrials.gov under identifier NCT01551004.).

Understanding potential participation barriers to improve trial design and outcomes: clinical trial simulation in palmoplantar pustulosis as a case study.

OBJECTIVES: Evaluate the experiences and perceptions of patients participating in a simulated clinical trial and identify ways to enhance future patient-centric trial designs. DESIGN: International, multicentre, non-interventional, virtual clinical trial visits with patient debriefs and advisory boards. SETTING: Virtual clinic visits and accompanying advisory boards. PARTICIPANTS: Nine patients with palmoplantar pustulosis for simulated trial visits; 14 patients and patient representatives for advisory boards. MAIN OUTCOME MEASURES: Qualitative responses to trial documentation, visit schedule and logistics, and trial design were collected during patient debriefs. Results were discussed at two virtual advisory board meetings. RESULTS: Patients identified key barriers to participation and potential difficulties encountered when attending trial visits and completing assessments. They also proposed recommendations to overcome these challenges. Patients recognised the need for comprehensive informed consent forms, but recommended use of non-technical language, brevity and additional support to aid understanding. Other trial documentations should be relevant to the disease and include known efficacy and safety of the study drug. Patients were concerned about receiving placebo, stopping existing medications and being unable to receive the study drug after trial completion; therefore, patients and physicians recommended an open-label extension following trial completion. Trial visits were too numerous (n=20) and too long (3-4 hours each); patients recommended improvements to the design to make best use of their time and reduce unnecessary waiting. They also requested financial and logistical support. Patients expressed a desire for study outcomes that matter to them, related to their ability to undertake normal daily activities and not be a burden to others. CONCLUSIONS: Simulated trials are an innovative method for assessing trial design and acceptance from a patient-centric perspective, enabling specific improvements to be made prior to trial initiation. Incorporation of recommendations from simulated trials could enhance trial recruitment and retention, and optimise trial outcomes and data quality.

Management of Psoriatic Arthritis in Patients With Comorbidities: An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations.

OBJECTIVE: The 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations provide an evidence-based guide for selecting therapy based on the individual's disease features. Beyond the disease features and associated conditions (eg, uveitis and inflammatory bowel disease), comorbidities play an important role in selecting therapy for an individual patient. METHODS: We performed a systematic literature review. We examined the available evidence to inform treatment selection based on the presence or absence of comorbidities in psoriatic arthritis (PsA). RESULTS: Common comorbidities in PsA that may affect treatment selection include presence of baseline cardiovascular disease (CVD) or high risk for CVD, obesity and metabolic syndrome, liver disease, mood disorders, including depression in particular, chronic infections, malignancies, osteoporosis, and fibromyalgia and/or central sensitization. CONCLUSION: Comorbidities may influence both the effectiveness of a given therapy but also the potential for adverse events. It is important to assess for the presence of comorbidities prior to therapy selection.

Treatment Goals for Psoriasis as Measured by Patient Benefit Index: Results of a National Psoriasis Foundation Survey.

INTRODUCTION: This cross-sectional survey was conducted with National Psoriasis Foundation (NPF) to capture treatment perspectives and expectations in patients with psoriasis (PsO) using Patient Needs Questionnaire (PNQ) of Patient Benefit Index (PBI). METHODS: Adult participants with self-reported diagnosis of PsO responded to the PNQ portion of PBI by indicating how much they valued different treatment attributes. All the treatment goals were captured on a five-point Likert scale (0 = "Not important", 4 = "Very important"). Treatment goals were obtained for overall population and subgroups based on severity of disease Patient Global Assessment (PGA), age, gender, and Dermatology Life Quality Index (DLQI) total score. All data were expressed as mean and standard deviation [SD]. RESULTS: A total of 1200 participants completed the survey (mean age 51.5 years). Top treatment goal in the overall population was "to have confidence in the therapy" (3.46 [1.01]). Unique to the higher severity subgroup (PGA ≥ 3), "to find a clear diagnosis and therapy" was a top five goal and "to get better skin quickly" was for those with lesser severity (PGA < 3). "To be free of itching" (3.36 [0.99]) was the unique goal in the < 40 age group whereas it was "to get better skin quickly" (3.27 [1.12]) in the ≥ 40 group. In women and men, "to be free of itching" (3.38 [1.13]) and "to get better skin quickly" (3.20 [1.09]) were top five goals, respectively. Patients with ≥ 10 DLQI scores expressed higher treatment goal "to regain control of the disease" (3.66 [0.67]) compared to those with ≤ 10 DLQI scores who expressed "to have confidence in the therapy" (3.40 [1.11]) as the topmost treatment goal. CONCLUSION: Our results suggest that in patients with PsO, treatment preferences can vary with different characteristics such as age, severity, and gender as measured by using PNQ. Further exploration of this data will help inform treatment decisions and optimize patient outcomes.

Demographic and Clinical Factors Associated with Patient-Reported Remission in Psoriasis.

INTRODUCTION: Achievement of remission in psoriasis is a key goal for patients and providers, yet definitions of remission may vary. Some treat-to-target initiatives in psoriasis have focused on degree of skin involvement, while others have also incorporated quality of life (QoL) measures. The goal of this study is to identify factors associated with patient-reported psoriasis remission. METHODS: The National Psoriasis Foundation conducted a survey of a random stratified sample of 1570 individuals with psoriatic disease in the USA. The survey contained questions regarding provider diagnosis of psoriasis and/or psoriatic arthritis, as well as comorbid conditions and participant demographics. Psoriasis severity was assessed using the Patient Report of Extent of Psoriasis Involvement (PREPI), a validated self-reported measure of body surface area (BSA). Dermatologic-related quality of life was assessed using the Dermatology Life Quality Index (DLQI). Individuals reporting BSA ≤ 3% were asked if they believed their psoriasis was in remission. Multivariate logistic regression was used to identify factors associated with remission. RESULTS: Of 930 participants reporting BSA ≤ 3%, 479 (51.7%) believed their psoriasis was in remission, with an average remission duration of 31 months. Of those in remission, 79.1% reported current treatment. Multivariate regression revealed that psoriasis remission was independently associated with female sex, lower BSA, less impairment in the Dermatology Life Quality Index and global QoL, biologic use, and concomitant diagnosis of psoriatic arthritis. There was no association with age, race, body mass index, or number of comorbidities. CONCLUSION: Overall, patient perception of psoriasis remission was not solely associated with BSA, but also with sex, quality of life, and treatment type.

Demographic and Clinical Factors Associated with Patient-Reported Remission in Psoriatic Arthritis.

INTRODUCTION: Achievement of remission in psoriatic arthritis is a key goal for patients and clinicians, yet definitions of remission may vary. Previous efforts have utilized multidomain measures such as minimal disease activity that assess the status of joints, skin, and function to determine current level of psoriatic arthritis (PsA) disease activity. The goal of this study is to identify factors associated with patient-reported psoriatic arthritis remission. METHODS: The National Psoriasis Foundation conducted a cross-sectional study using an online survey of a random stratified sample of 1570 individuals with psoriatic disease in the USA. Participants were asked about a provider diagnosis of psoriasis and/or psoriatic arthritis, comorbid conditions, and psoriatic arthritis impact and disease activity, and demographic questions. All participants reporting a physician-given diagnosis of psoriatic arthritis were asked if they felt their psoriatic arthritis was in remission ("Do you feel your psoriatic arthritis is in remission?" Yes/No/Unsure) and, if so, length of remission. Individuals with psoriasis and psoriatic arthritis reporting a body surface area impacted by psoriasis 3% or less were asked if they felt their psoriasis was in remission. Psoriatic arthritis disease activity and impact was assessed using the nine-question Psoriatic Arthritis Impact of Disease (PsAID-9) instrument and a global PsA-related quality of life question. PsAID-9 scores ≤ 4 were used to indicate acceptable disease state. Multivariate logistic regression was used to identify factors associated with patient-perceived PsA remission. RESULTS: Of 834 participants with PsA, including 76 (4.8%) with PsA without skin involvement ever, 144 (17.3%) felt their psoriatic arthritis was in remission, with an average remission duration of 43 months. Of those in remission, 116 (78.4%) reported currently using a treatment for their PsA, with most (75.7%) reporting using a biologic therapy for their PsA in the past 12 months. Multivariate logistic regression revealed that patient-perceived psoriatic arthritis remission was independently associated with experiencing acceptable disease state (PsAID-9 ≤ 4), perception of psoriasis remission, lower impact of PsA on global quality of life, and non-white race. Age, sex, body mass index, or biologic use in the last 12 months were not associated with patient-reported PsA remission. CONCLUSION: Overall, patient perception of PsA remission was most strongly associated with patient-reported psoriasis remission.

Psoriasis Prevalence in Adults in the United States.

IMPORTANCE: Determining psoriasis prevalence is fundamental to understanding the burden of the disease, the populations most affected, and health policies to address the disease. OBJECTIVE: (1) To determine the prevalence of psoriasis among adults in the US and (2) to evaluate the change in psoriasis prevalence over time since the 2003-2004 National Health and Nutrition Examination Survey (NHANES) data. DESIGN, SETTING, AND PARTICIPANTS: This population-based cross-sectional study used 2011-2014 NHANES data (collected from January 1, 2011, to December 31, 2014) with sampling from a general, noninstitutionalized US civilian population. Participants were 20 years or older and were selected via a multistage probability sampling design to ensure that surveys were nationally representative. Eligible participants had an in-person interview followed by a medical examination by medical professionals. Data were analyzed from July 15, 2019, to December 23, 2020. EXPOSURES: None. MAIN OUTCOMES AND MEASURES: Psoriasis prevalence in the US, as measured by the percentage of people in the representative sample with psoriasis, and trend statistics comparing prevalence estimates from the 2003-2004, 2009-2010, and 2011-2014 NHANES cycles. RESULTS: A total of 12 625 participants (mean [SD] age, 32.8 [24.1] years; 6492 women [51.4%]; and 4828 non-Hispanic White participants [38.2%]) answered the question of whether they were given the diagnosis of psoriasis by a physician or another health care professional. Psoriasis prevalence among US adults 20 years or older was 3.0% (95% CI, 2.6%-3.4%). Based on the 2020 US census data, this outcome translates to an estimated 7.55 million US adults with psoriasis. Psoriasis prevalence was similar between women and men, with 3.2% (95% CI, 2.6%-3.8%) in women and 2.8% (95% CI, 2.4%-3.3%) in men. Psoriasis prevalence was highest in White individuals at 3.6% (95% CI, 2.9%-4.2%), followed by other racial/ethnic groups (non-Hispanic, including multiracial) at 3.1% (95% CI, 1.2%-5.1%), Asian individuals at 2.5% (95% CI, 1.6%-3.3%), Hispanic individuals (including Mexican American and other Hispanic individuals) at 1.9% (95% CI, 1.3%-2.5%), and Black individuals at 1.5% (95% CI, 1.0%-2.0%). Psoriasis prevalence was not different based on patients' marital status, education, income, or medical insurance status. The prevalence of psoriasis among US adults did not differ significantly since 2003. CONCLUSIONS AND RELEVANCE: The results of this cross-sectional study suggest that psoriasis remains a common, immune-mediated disease that affects 3.0% of the US adult population, or more than 7.5 million adults. Its prevalence has not differed since evaluation in 2003. These prevalence data are foundational to determining the burden of psoriasis and for supporting efforts in research, education, and health policy.

New Frontiers in Psoriatic Disease Research, Part I: Genetics, Environmental Triggers, Immunology, Pathophysiology, and Precision Medicine.

Psoriasis is a chronic inflammatory condition characterized by systemic immune dysregulation. Over the past several years, advances in genetics, microbiology, immunology, and mouse models have revealed the complex interplay between the heritable and microenvironmental factors that drive the development of psoriatic inflammation. In the first of this two-part review series, the authors will discuss the newest insights into the pathogenesis of psoriatic disease and highlight how the evolution of these scientific fields has paved the way for a more personalized approach to psoriatic disease treatment.

New Frontiers in Psoriatic Disease Research, Part II: Comorbidities and Targeted Therapies.

Although psoriasis and psoriatic arthritis (PsA) have been classically considered to be diseases of the skin and joints, respectively, emerging evidence suggests that a combination of innate and environmental factors creates widespread immune dysfunction, affecting multiple organ systems. A greater understanding of the pathogenesis of psoriasis and the systemic effects of psoriatic inflammation has allowed for the development of new, more effective treatments. The second portion of this two-part review series examines the comorbidities associated with psoriasis and PsA as well as the most recent advances in targeted systemic therapies for these conditions.

A 12-month feasibility study to investigate the effectiveness of cryogen-cooled monopolar radiofrequency treatment for female stress urinary incontinence.

INTRODUCTION: The purpose of this early feasibility study was to evaluate the safety and efficacy of a non-ablative, cryogen-cooled, monopolar radiofrequency (CMRF) treatment for female stress urinary incontinence (SUI). METHODS: Subjects meeting all the inclusion and exclusion criteria were enrolled and randomized into two groups. Subjects in group 1 received one CMRF treatment and subjects in group 2 received two CMRF treatments six weeks apart. Followup visits were performed at one, four, six, and 12 months post-treatment. At each study visit, subjects performed an objective, standardized one-hour pad weight test and completed several patient-reported outcome measures, a seven-day bladder voiding diary, and safety assessments. RESULTS: Data indicate an improvement in SUI symptoms and quality of life for subjects, as determined by validated SUI-related patient-reported outcomes and the objective one-hour pad weight test, with a >50% reduction in pad weight from baseline for 52% of the subjects at 12 months. In addition to efficacy, the CMRF treatment was well-tolerated and safe. CONCLUSIONS: The outcome measures evaluated indicate an improvement in SUI symptoms and quality of life. The sustained benefit of the CMRF vaginal treatment at 12 months suggests potential use as an office-based, non-surgical approach to treat mild to moderate SUI.

Early Feasibility Study to Evaluate the Viveve System for Female Stress Urinary Incontinence: Interim 6-Month Report.

Background: The purpose of this prospective, investigator-initiated feasibility study is to evaluate the efficacy and safety of nonablative, cryogen-cooled, monopolar radiofrequency (CMRF) treatment for stress urinary incontinence (SUI). Materials and Methods: Subjects meeting all the inclusion and exclusion criteria were enrolled and divided into two groups. Subjects in Group 1 received a single SUI treatment, and subjects in Group 2 received two SUI treatments ∼6 weeks apart. Follow-up visits are planned for 1, 4, 6, and 12 months post-treatment. At each study visit, subjects are asked to perform a 1-hour pad-weight test (PWT) and to complete the Urogenital Distress Inventory-6 (UDI-6), Incontinence Impact Questionnaire-Short Form (IIQ-7), and International Consultation on Incontinence Modular Questionnaire-Urinary Incontinence-Short Form (ICIQ-UI-SF) questionnaires. In addition, subjects completed 7-day bladder voiding diary and safety assessments. Results: Preliminary data indicate an improvement in SUI symptoms and quality of life for subjects, as determined by validated SUI-related patient-reported outcomes and the objective 1-hour PWT, with a >50% reduction in pad weight for 68.8% of the Group 1 subjects and 69.2% of the Group 2 subjects at 6 months. Initial review of the bladder voiding diaries suggests that subjects are having fewer urine leakage episodes per day. In addition to efficacy, the CMRF Viveve System was well tolerated and safe. Conclusions: The endpoints evaluated indicate an improvement in SUI symptoms and quality of life. The sustained benefit of the CMRF vaginal treatment at 6 months suggests potential use as a nonsurgical approach to treat SUI.

Inhibitory effect of REP3123 on toxin and spore formation in Clostridium difficile, and in vivo efficacy in a hamster gastrointestinal infection model.

OBJECTIVES: REP3123 is a fully synthetic methionyl-tRNA synthetase inhibitor in pre-clinical development as a novel agent to treat Clostridium difficile infection (CDI). This novel agent was investigated for its ability to block the production of toxins and spores, and was tested for efficacy in vivo in a hamster model. METHODS: Clostridial toxin levels were determined qualitatively using monoclonal antibodies and by cytotoxicity assays. Spores were detected by staining and by quantitative dilution plating after ethanol treatment. Efficacy of REP3123 was tested in a clindamycin-induced C. difficile hamster gastrointestinal (GI) infection model. RESULTS: REP3123 at concentrations as low as 1 mg/L inhibited de novo toxin production in high cell density, stationary phase cultures of C. difficile. Among comparator agents currently used for CDI therapy, vancomycin required much higher levels of 20 mg/L, and metronidazole had no effect on toxin levels. REP3123 caused a >10-fold reduction of the sporulation rate in vitro. Vancomycin and, in particular, metronidazole appeared to promote the formation of spores. REP3123, at concentrations as low as 0.5 mg/kg, demonstrated efficacy in the hamster model of CDI and was superior to vancomycin in the overall survival of the animals at the end of the study (33 days). CONCLUSIONS: REP3123 inhibited growth of C. difficile, affected the production of toxins and spores and demonstrated superior efficacy compared with vancomycin in the hamster GI infection model. This agent may be a promising candidate for CDI treatment; in particular, the inhibition of toxin production and spore formation may reduce the severity and spread of the disease, respectively.

An intranasal irritation assessment of antibacterial ointment alone or in combination with mupirocin versus Bactroban Nasal in rabbits.

The purpose of this study was to evaluate the potential irritating effects and the systemic exposure level of an antibacterial ointment containing REP8839 as a single agent or in combination with mupirocin versus Bactroban Nasal in rabbits. Additionally, the reversibility of REP8839 effects during a 14-day recovery period was assessed. Five treatment groups of six male and six female New Zealand White rabbits received dose levels of 1%, 2%, and 4% REP8839, 2% Bactroban Nasal, or 2% REP8839/2% mupirocin combination. One additional group of six animals/sex served as the control and received the vehicle, Petrolatum/Softisan 649. The test article or vehicle was administered to all groups via topical administration to the external nares, twice a day (approx. 8h intervals between the doses) for 21 consecutive days, at a dose volume of 100 microL per nare/dose for a total of 400 microL per day (200 microL per nare). Two animals/sex/group were maintained for a 14-day recovery period. The external nares were reflected back and the mucosal lining was evaluated and scored for erythema and edema within 30-60 min following the first dose each day. Blood samples were collected from all animals at designated time points on Day 21 of the study to assess systemic exposure levels. Cross-sectioning of the nasal tract was conducted in all the groups for microscopic evaluation. Mucosal scoring of the nares did not reveal any edema or erythema in any of the dose groups with the antibacterial alone, with the combination product, or with Bactroban Nasal. Mean body weights and food consumption were not adversely impacted by the test articles. Minimal plasma exposure was observed in the rabbits (<5 ng/mL). The REP8839 groups did appear to have dose-responsive exposure (from below the limit of quantitation to 5 ng/mL with 1%, 2%, and 4% REP8839, respectively). Microscopic changes on the nasal sectioning noted in these animals were infrequent and considered incidental findings unrelated to administration of the test articles. In conclusion doses of up to 4% of REP8839 ointment as a single agent or 2% in the combination product, as well as 2% Bactroban Nasal, were not found to induce mucosal irritation when applied topically to the external nares twice a day for 21 consecutive days. Additionally, no delayed effects were observed in the recovery animals.

Factors Influencing Sleep Difficulty and Sleep Quantity in the Citizen Pscientist Psoriatic Cohort.

INTRODUCTION: Sleep is essential for overall health and well-being, yet more than one-third of adults report inadequate sleep. The prevalence is higher among people with psoriasis, with up to 85.4% of the psoriatic population reporting sleep disruption. Poor sleep among psoriasis patients is particularly concerning because psoriasis is independently associated with many of the same comorbidities as sleep dysfunction, including cardiovascular disease, obesity, and depression. Given the high prevalence and serious consequences of disordered sleep in psoriasis, it is vital to understand the nature of sleep disturbance in this population. This study was designed to help meet this need by using survey data from Citizen Pscientist, an online patient portal developed by the National Psoriasis Foundation. METHODS: Our analysis included 3118 participants who identified as having a diagnosis by a physician of psoriasis alone or psoriasis with psoriatic arthritis. Demographic information, psoriasis severity and duration, sleep apnea status, smoking and alcohol consumption, itch timing, and sleep characteristics were included. Two separate multivariate logistic regression models in STATA were used to determine whether the presence of psoriatic arthritis, age, gender, body mass index, comorbid sleep apnea, psoriasis severity, timing of worst itch, smoking status, or high-risk alcohol consumption were associated with sleep difficulty or low sleep quantity, defined by the American Academy of Sleep Medicine as less than 7 h of sleep per night on average. RESULTS: Results from the multivariate logistic regressions found that sleep difficulty was associated with psoriatic arthritis (OR 2.15, 95% CI [1.79-2.58]), female gender (2.03 [1.67-2.46]), obese body mass index (BMI ≥ 30) (1.25 [1.00-1.56]), sleep apnea (1.41 [1.07-1.86]), psoriasis severity of moderate (1.59 [1.30-1.94]) or severe (2.40 [1.87-3.08]), and smoking (1.60 [1.26-2.02]). Low sleep quantity was associated with obese BMI (1.62 [1.29-2.03]), sleep apnea (1.30 [1.01-1.68]), psoriasis severity of moderate (1.41 [1.16-1.72]) or severe (1.40 [1.11-1.76]), and smoking (1.62 [1.31-2.00]). Sleep difficulty and low sleep quantity were not associated with age, alcohol consumption, or timing of worst itch. CONCLUSION: These results are potentially meaningful in several aspects. We identify an important distinction between sleep difficulty and sleep quantity in psoriatic disease, whereby having psoriatic arthritis and being female are each associated with sleep difficulty despite no association with low sleep quantity. Furthermore, there is conflicting evidence from prior studies as to whether psoriasis severity is associated with sleep difficulty, but this well-powered, large study revealed a strong, graded relationship between psoriasis severity and both sleep difficulty and low sleep quantity. Overall, our results show that both sleep difficulty and low sleep quantity were associated with multiple factors in this analysis of a large psoriatic cohort. These findings suggest that dermatologists may gather clinically useful information by screening psoriatic patients for trouble sleeping and low sleep quantity to identify potential comorbidities and to more effectively guide disease management.