High cardiorespiratory fitness levels may attenuate, but not eliminate, the increased risk of death from 

 in men with elevated systolic blood pressure, according to new research.

Investigators from the University of Eastern Finland suggested high blood pressure and low fitness levels, in turn, are each associated with an increased risk of CVD mortality independent of established and emerging risk factors.

“This was the first study to evaluate the joint effects of fitness and blood pressure on the risk of dying from cardiovascular disease,” said Jari Laukkanen, MD, PhD, Institute of Public Health and Clinical Nutrition, University of Eastern Finland.

 “The results suggest that being fit helps protect against some of the negative effects of high blood pressure.”

Over 1 billion adults over the age of 30 globally have hypertension, a major risk factor for CVD and stroke, as well as a leading cause of premature death. Cardiorespiratory fitness, a measure of aerobic exercise capacity, is a strong predictor of all-cause and CVD mortality. It has been shown to modify the association between adverse levels of risk factors and adverse outcomes, with higher fitness levels linked to reduced risks of adverse outcomes.

To better understand this association, Laukkanen and colleagues examined the interplay between blood pressure, fitness, and CVD mortality risk in a prospective cohort of 2280 middle-aged and older men enrolled in the Kuopio Ischemic Heart Disease (KIHD) Risk Factor Study. The screening and baseline assessments were conducted between March 1984 and December 1989, including blood pressure and cardiorespiratory fitness.

Investigators assessed fitness as peak oxygen uptake (VO2peak) while riding a stationary bicycle. Study participants were grouped according to blood pressure level and fitness level: normal blood pressure–high fitness (reference comparison); normal blood pressure–low fitness; high blood pressure–high fitness; and high blood pressure–low fitness. Data showed the average age of participants at baseline was 53 years, mean blood pressure was 134 mmHg, and fitness level was 30.3 mL/kg/min, respectively.

Of the 2280 men followed up for a median duration of 29 years, there were 644 deaths due to CVD, according to investigators. Risk of death from CVD was analyzed after adjustments for age, body mass index (BMI), smoking status, type 2 diabetes (T2D), coronary heart disease, antihypertensive medication-use, alcohol consumption, physical activity, socioeconomic status, and high sensitivity C-reactive protein.

Upon analysis, results indicated high blood pressure was associated with a 39% increased risk of cardiovascular mortality (hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.17 – 1.63). When considering fitness levels, compared with high levels, low fitness was associated with a 74% increased risk of CVD mortality (HR, 1.74; 95% CI, 1.35 – 2.23).

Individuals with high blood pressure and low fitness had more than double the risk of CVD mortality compared to those with normal blood pressure and high fitness levels (HR, 2.35; 95% CI, 1.81 – 3.04). When men with high blood pressure had high fitness levels, the data showed their elevated risk of CVD mortality persisted, but was weaker, being only 55% higher than those with normal levels in each category (HR, 1.55; 95% CI, 1.16 - 2.07).

Laukannen and colleagues noted the inability of higher fitness levels to fully eliminate the risk of CVD mortality in individuals with high blood pressure may have to do with the strong, independent causal relationship between blood pressure and CVD.

“Getting blood pressure under control should remain a goal in those with elevated levels,” Laukannen said.

 “Our study indicates that men with high blood pressure should also aim to improve their fitness levels with regular physical activity. In addition to habitual exercise, avoiding excess body weight may enhance fitness.”

Jari A Laukkanen, Sae Young Jae, Sudhir Kurl, Setor K Kunutsor, High fitness levels attenuate the increased risk of cardiovascular deaths in individuals with high systolic blood pressure, European Journal of Preventive Cardiology, 2023;, zwad034, 

2. Escardio. (2023, March 23). Being fit partially offsets negative impact of high blood pressure. EurekAlert! Retrieved March 24, 2023, from https://www.eurekalert.org/news-releases/983748

Articles

High blood pressure and low fitness levels were each associated with an increased risk of CVD mortality independently of established and emerging risk factors in new findings. 

High Fitness Levels May Lessen CVD Mortality Risk in Men With Hypertension

Topical lovastatin 2% cream by itself was as safe and efficacious in treating 

disseminated superficial actinic porokeratosis (DSAP)

 as was the more commonly-studied lovastatin-cholesterol cream, new findings suggest.

DSAP—an inherited or sporadic disorder of keratinization causing dry, scaly patches—is associated with germline variations, and there is not an effective standard of care for the condition.

This research had been conducted to compare the efficacy of topical lovastatin cream to a combination of lovastatin 2% cream and cholesterol 2% (lovastatin-cholesterol cream), the latter of which had shown some promise in prior research.

The study also aimed to examine the role of cholesterol in improving lesion clearance for DSAP, as well as to look into demographic factors and barriers to care among DSAP patients. It was authored by Gabriella Santa Lucia, MD, MSCR, of Medical University of South Carolina.

“In this study, we sought to elucidate basic demographic characteristics, current treatment regimens, and medical comorbidities associated with DSAP, the most common porokeratosis variant,” Santa Lucia and colleagues wrote.

The investigators conducted a patient-blinded and assessor-blinded, randomized clinical trial at the Medical University of South Carolina in the period between August of 2020 and April of 2021. They allowed adults with a prior diagnosis of DSAP and who were not pregnant to be eligible.

The team randomized the patients to once- or twice-per-day treatment with either lovastatin-cholesterol cream or lovastatin cream to regions of the body that were symptomatic for a total of 12 weeks.

During this 12-week evaluation period, the primary efficacy measure decided upon was the treatments’ impacts on DSAP, assessed through the use of the DSAP General Assessment Severity Index (DSAP-GASI). The index is scored from 0 to 4, with 0 representing clear and 4 representing severe.

Along with the primary measure, both treatments’ effectiveness were also examined through secondary measures, including patient-reported outcomes, application frequency, and adverse events.

Of the 87 study participants, 32 were enrolled in the treatment. Lovastatin-cholesterol was given to 17 of the patients and lovastatin was given to 14 of the patients. Disease severity was found to have reduced substantially in both study arms after 12 weeks of treatment.

The investigators reported that the lovastatin-cholesterol arm showed a 50.0% reduction in disease severity, and the lovastatin arm showed a 51.4% reduction, indicating that the benefit of adding cholesterol to the treatment is not obvious.

Furthermore, adverse events were reported by a few patients, including myalgia, elevation in creatine kinase levels, application discomfort, and rash. That being said, no serious adverse events were reported, and all participants were able to finish the study.

“This preliminary study provides a signal of effect to power future subsequent studies,” they wrote. “A larger, longer-term, in-person clinical trial with a validated assessment scale may benefit this patient population.”

Santa Lucia G, Snyder A, Lateef A, et al. Safety and Efficacy of Topical Lovastatin Plus Cholesterol Cream vs Topical Lovastatin Cream Alone for the Treatment of Disseminated Superficial Actinic Porokeratosis: A Randomized Clinical Trial. 

Published online March 22, 2023. doi:10.1001/jamadermatol.2023.0205.

Atzmony L﻿, Lim YH﻿, Hamilton C﻿, et al. Topical cholesterol/lovastatin for the treatment of porokeratosis: a pathogenesis-directed therapy. 

. 2020;82(1):123-131. doi:10.1016/j.jaad.2019.08.043

New data on topical lovastatin cream 2% demonstrated similar efficacy results to the combination of lovastatin and cholesterol in treating the skin disorder DSAP.


Topical Lovastatin Cream Effective for Disseminated Superficial Actinic Porokeratosis

New data from the phase 3 MOJAVE trial indicate NOV03 (perfluorohexyloctane) consistently met primary endpoints for the signs and symptoms of 

dry eye disease (DED) associated with meibomian gland dysfunction (MGD)

The trial findings followed positive results from the first pivotal phase 3 trial, GOBI, announced by Bausch + Lomb and Novaliq in early 2023.

 An investigational ophthalmic drop, NOV03 has been assigned a Prescription Drug User Fee Act (PDUFA) action date of June 28, 2023 by the US Food and Drug Administration (FDA).

“In addition to meeting both primary sign and symptom efficacy endpoints, NOV03 was shown to be very well tolerated in the MOJAVE study,” said Yehia Hashad, MD, executive vice president, Research & Development, and chief medical officer, Bausch + Lomb.

 “These are all critical factors that must be considered when determining a treatment plan for someone with a chronic and progressive condition like DED associated with MGD. Excess tear evaporation is a major factor in DED associated with MGD, which remains largely unaddressed.”

Millions of Americans are affected by DED and it is considered one of the most common ocular surface disorders. NOV03 is an investigational, proprietary, water-free, single-component, preservative-free, ophthalmic drop indicated for DED associated with MGD. Results from the GOBI trial suggests NOV03 dosed 4 times daily demonstrated significant reductions in the signs and symptoms of DED compared to hypotonic saline (0.6%).

Similarly designed to GOBI, the phase 3 MOJAVE trial was conducted at 42 sites in the US between November 2020 and August 2021. Eligible patients were randomized via an interactive system in a 1:1 ratio to receive either NOV03 or hypotonic saline solution (0.6%). Patients were instructed in the study to instill 1 drop of into each eye 4 times daily for 8 weeks.

The full analysis population consisted of 620 subjects aged 18 years and older: 311 in the NOV03 group and 309 in the control group. The two primary endpoints were considered the change from baseline at Week 8 (Day 57 ± 2 days) in total corneal fluorescein staining (tCFS) and eye dryness Visual Analog Scale (VAS) score. The key secondary endpoints included the change from baseline in eye dryness VAS score and tCFS at week Week 2 (Day 15 ± 1), as well as eye burning/stinging VAS score, and central corneal fluorescein at week 8.

Those treated with NOV03 experienced significantly greater reduction from baseline at Week 8 in both tCFS score and VAS dryness score versus patients in the control saline group (least-squares mean treatment difference, -1.2; 95% confidence interval [CI], -1.7 to -0.8; 

 <.001). The least-squares mean treatment difference for change from baseline to Week 8 in VAS dryness score was –10.2 (95% CI, –14.4 to –6.1; 

For all key secondary endpoints, MOJAVE investigators found the mean improvement from baseline was significantly greater for NOV03 versus saline control. At Week 2, data showed tCFS and VAS dryness scores were statistically significant compared to saline, with a least-squares mean treatment difference for changing from baseline in tCFS of -0.6 (95% CI, -1.0 to -0.2; 

 = .001) and VAS score of -7.8 (95% CI, -11.3 to -4.3; 

 <.001). Additionally, at week 8, VAS burning/stinging score and cCFS favored the NOV03 group, with a least-squares mean treatment difference for change from baseline of -7.3 (95% CI, -11.3 to -3.4; 

The therapy was well-tolerated in MOJAVE and ocular adverse events were experienced by 12.9% of patients in the NOV03 group and 12.3% of patients in the saline group, with most mild or moderate in severity. Ocular adverse events were considered related to treatment in 6.4% of the NOV03 group and 6.8% in the saline group, but none led to treatment discontinuation or study withdrawal. The most common events (incidence ≥1%) reported in the NOV03 group were blepharitis, conjunctival hyperemia, conjunctival papillae, ocular hyperemia, blurred vision, hordeolum, and visual acuity reduction.

“Currently there are no FDA-approved prescription therapies available which directly target evaporation, leaving patients with limited treatment options,” said Christina Ackermann, president, Ophthalmic Pharmaceuticals, Bausch + Lomb.

 “These data are consistent with the results seen in the first Phase 3 trial, and further support NOV03 as a new potential therapy designed to alleviate the signs and symptoms of DED associated with MGD.”

Sheppard JD, Kurata F, Epitropoulos AT, Krösser S, Vittitow JL; MOJAVE STUDY GROUP. NOV03 for Signs and Symptoms of Dry Eye Disease Associated With Meibomian Gland Dysfunction: the Randomized Phase 3 MOJAVE Study: NOV03 for Dry Eye Disease Associated With Meibomian Gland Dysfunction (69 characters; limit, 60) [published online ahead of print, 2023 Mar 20]. Am J Ophthalmol. 2023;S0002-9394(23)00098-3. doi:10.1016/j.ajo.2023.03.008

Bausch + Lomb and Novaliq Announce Publication of Pivotal Phase 3 Data on NOV03 (Perfluorohexyloctane) in Ophthalmology. Bausch + Lomb News Releases. (2023, January 4). Retrieved March 24, 2023, from https://www.bausch.com/news/releases/?id=131

Bausch + Lomb and Novaliq Announce Publication of Second Pivotal Phase 3 Data on NOV03 (Perfluorohexyloctane) in American Journal of Ophthalmology. Bausch + Lomb News Releases. (2023, March 22). Retrieved March 24, 2023, from https://www.bausch.com/news/releases/?id=143

Nov03 eye drops exhibit improvement in signs, symptoms of dry eye disease

. HCP Live. Retrieved March 24, 2023, from https://www.hcplive.com/view/nov03-eye-drops-improvement-signs-symptoms-dry-eye-disease

The second pivotal Phase 3 trial reported NOV03 consistently met primary endpoints for signs and symptoms of DED associated with meibomian gland dysfunction.

Phase 3 MOJAVE Trial Reports Efficacy of NOV03 for Dry Eye Disease 

The US Food and Drug Administration (FDA) approved leniolisib (Joenja) for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adult and pediatric patients 12 years of age and older. According to an announcement from Pharming, the drug is anticipated to launch in early April.

The oral, selective PI3Kδ inhibitor is the first approved therapy for individuals living with APDS, a 

 primary immunodeficiency disease affecting 1-2 people per million. The condition results from genetic variants in either PIK3CD or PIK3R1 genes.

"The FDA approval of Joenja is an exciting moment for the APDS community and offers to transform the treatment pathway for patients and families affected by this rare disease. This approval means that they will, for the first time, have access to an approved treatment, which has the potential to change the standard of care for the patient population suffering from APDS,” Eveline Wu, MD, Division Chief, Paediatric Rheumatology & Associate Professor of Paediatric Rheumatology and Allergy/Immunology at The University of North Carolina School of Medicine, said in a 

Findings from the phase 2/3 data supported the agency’s decision. The multinational, triple-blind, placebo-controlled, clinical trial demonstrated significant improvement in lymphoproliferation as measured by the reduction in lymph node size and increase in naïve B cells.

In the study of 31 patients with APDS, patients treated with a twice daily regimen of leniolisib 70mg exhibited significant progress compared with placebo, which fulfilled both endpoints.

"The FDA approval of a treatment option for one of the more than 450 primary immunodeficiencies is also a key moment for the broader primary immunodeficiency community,” Vicki Modell, co-founder, Jeffrey Modell Foundation stated.

Pharming announces US FDA approval of Joenja® (leniolisib) as the first and only treatment indicated for APDS. News release. Pharming. Published March 24, 2023. Accessed March 24, 2023. https://prnmedia.prnewswire.com/news-releases/pharming-announces-us-fda-approval-of-joenja-r-leniolisib-as-the-first-and-only-treatment-indicated-for-apds-860863616.html

Phase 2/3 data show significant improvement in lymphoproliferation as measured by the reduction in lymph node size and increase in naïve B cells in patients with activated phosphoinositide 3-kinase delta syndrome.

Leniolisib Becomes First FDA-Approved Treatment for Rare Immunodeficiency Disease

Investigators underline the importance of using a multidimensional approach when treating patients with 

, specifically when assessing whether poor symptom control is related to uncontrolled asthma or underlying comorbidities.

The need for individualized strategies of disease management to look beyond asthma is supported by results from a meta-analysis. Study findings suggest that comorbidities are highly prevalent in individuals with asthma and can significantly impact asthma severity, treatment response, and overall health outcomes.

Paola Rogliani, MD, Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome Tor Vergata, and the team of investigators aimed to evaluate the strength of association between asthma and comorbidities. They stated that this relationship has not been systematically ranked in relation to the prevalence of comorbidity in the non-asthma population.

Uncontrolled Asthma or Underlying Comorbidity?

Strong associations were displayed between asthma and allergic rhinitis, allergic conjunctivitis, bronchiectasis, hypertensive cardiomyopathy, and nasal congestion. Stronger associations were detected comorbidities and severe asthma.

An especially strong association was shown between chronic obstructive pulmonary disease (COPD) and asthma. However, the complexity of associations such as this was acknowledged in the research.

“The very strong level of association between COPD and asthma or severe asthma could be related to potential misclassification between the diseases due to the overlap of symptoms and clinical features, particularly in elderly patients and smokers who experience poor symptom control, frequent exacerbations, progressive lung function deterioration and impaired quality of life,” investigators wrote.

When analyzing psychiatric comorbidities, investigators observed some conditions like panic attack, phobia, psychiatric disorder, and suicidal ideation reached strong association levels.

Affective disorder, Alzheimer’s disease, anxiety, depression, migraine, panic attack, phobia, psychiatric disorder, somatoform disorder, and suicidal ideation exhibited moderate associations.

After more than 2000 records were screened for relevance, 33 studies were deemed eligible for qualitative and quantitative syntheses, including 15 cross-sectional studies, 14 cohort studies, and four case-control studies.

The final analysis included data from more than 5 million individuals. The dataset consisted of 878,224 patients with asthma, 1791 of whom were affected by severe asthma. Non-asthmatic individuals made up the remainder of the study population.

Observational studies with reported data on comorbidities in asthma and nonasthma populations were targeted using MEDLINE, Embase, and Web of Science databases, from inception to October 2021. 

Studies were included if they reported the odds ratios (ORs) and 95% confidence intervals (CIs) of comorbidities in asthma and nonasthma populations. The team performed a pairwise meta-analysis, and the strength of association was calculated using Cohen's d method, which anchored ORs and 95% CIs with the rate of comorbidities in nonasthma populations. 

It was noted that quality assessment showed two cohort studies and two case-control studies were considered high quality, while 12 cohort studies and two case-control studies were regarded as of low quality. The inter-rater and intra-rater reliability for data abstraction were both excellent.

The study stressed the need for further research to facillitate better understanding of the complex relationships between asthma and comorbidities, along with the development of effective treatment strategies for individuals with asthma.

Rogliani P, Laitano R, Ora J, Beasley R, Calzetta L. Strength of association between comorbidities and asthma: a meta-analysis. 

The results of a comprehensive meta-analysis indicate a high prevalence of comorbidities among asthma patients, emphasizing the importance of effective treatment strategies.

Beyond Asthma: Study Examines the Strength of Comorbidity Associations

Results of a phase 2 trial reported upadacitinib (RINVOQ, 30 mg), given either alone or as a part of combination with a Bruton's Tyrosine Kinase inhibitor (elsubrutinib, 60 mg), was able to improve responses in adult patients with moderate-to-severe 

 (SLE). The study met its primary endpoint of the SLE Responder Index (SRI-4) with a steroid dose of ≤ 10 mg prednisone once daily at week 24 in the upadacitinib cohort, according to a press release from AbbVie.

SLE, a complex autoimmune disorder, impacts the musculoskeletal system, kidneys, skin, and other organs, and often results in impaired function, joint pain, and fatigue.

) enrolled and categorized 341 patients into 5 experimental treatment groups: upadacitinib and placebo combination therapy; elsubrutinib and placebo combination therapy, 2 different doses of upadacitinib combined with elsubrutinib treatment, and placebo only. The primary outcome, SRI-4, was defined as a ≥ 4-point reduction in the SLE Disease Activity Index 2000 score (SLEDAI-2K) without worsening of the patient’s overall condition or without development of significant disease activity in new organ systems.

Secondary outcomes included the achievement of British Isles Lupus Assessment Group (BILAG) Based Combined Lupus Assessment (BICLA), Lupus Low Disease Activity State (LLDAS), changes in steroid burden from baseline, and number of flares.

Eligible patients had a clinical diagnosis of SLE, a SLEDAI-2K ≥ 6 despite background therapy, a Physician’s Global Assessment (PhGA) ≥ 1 during the screening period, and were required to be on background treatment with antimalarials, prednisone or its equivalent, azathioprine, mycophenolate, leflunomide, cyclosporine, tacrolimus, and/or methotrexate.

Adverse events in the upadacitinib 30 mg cohort were consistent with the known safety profile of the drug, a selective and reversible Janus kinase (JAK) inhibitor, with no new safety signals identified. Similar results were demonstrated in those receiving upadacitinib and elsubrutinib combination therapy (ABBV-599). Common adverse reactions of upadacitinib treatment include upper respiratory tract infections, shingles, herpes simplex virus infection, fever, headache, nausea, and allergic reactions. Upadacitinib and elsubrutinib are not approved for the treatment of SLE and their safety and efficacy have yet to be analyzed by regulatory authorities.

"Systemic lupus erythematosus is a very unpredictable life-long condition and the way it affects a patient can change over time. Therefore, there is a critical need for additional treatment options," wrote Roopal Thakkar, MD, senior vice president, development and regulatory affairs and chief medical officer, AbbVie. "With a quarter-century of experience and commitment to the treatment of rheumatic diseases, our focus remains on areas of high unmet need like systemic lupus erythematosus, and we look forward to further evaluation of the potential benefits that upadacitinib could bring to patients."

Upadacitinib is currently being studied for the treatment of rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, axial spondyloarthritis, and Crohn’s disease, among others. AbbVie is advancing its clinical program of upadacitinib in patients with SLE to phase 3 based on these promising results.

AbbVie. (2023, March 23). AbbVie advances upadacitinib (RINVOQ®) to phase 3 clinical trials in systemic lupus erythematosus. PR Newswire: press release distribution, targeting, monitoring and marketing. Retrieved March 23, 2023, from https://www.prnewswire.com/news-releases/abbvie-advances-upadacitinib-rinvoq-to-phase-3-clinical-trials-in-systemic-lupus-erythematosus-301779254.html

Upadacitinib, a selective and reversible Janus kinase (JAK) inhibitor, may be a promising treatment option for patients with systemic lupus erythematosus. 

Phase 2 Trial Reaches Primary Endpoint for Upadacitinib Treatment in Active SLE

An ablation strategy using routine delivery of a second circumferential line of ablation did not show additional benefit in preventing atrial arrhythmia recurrence in patients with 

Investigators from the University of Ottawa Heart Institute, led by Girish M. Nair, MBBS, MSc, thus suggested the potential for a ceiling effect to the single procedure success of catheter ablation in patients with paroxysmal AF.

“​​This is consistent with prior research in catheter ablation in patients with persistent AF, where empirical adjunctive ablation strategies failed to reduce AA recurrence,” Nair and colleagues wrote.

Recurrent AF often occurs after catheter ablation and has been associated with both patient morbidity and high healthcare costs. Nair and colleagues looked to compare the standard of care ablation technique of adenosine-guided wide-area circumferential ablation (WACA) with a novel augmented WACA technique. The team hypothesized that the wider area of atrial ablation would increase the change of durable pulmonary vein isolation and thus result in the reduction of atrial arrhythmias including atrial tachycardia, atrial flutter, or AF, without affecting procedural safety.

The pragmatic, prospective, randomized, open, blinded endpoint Augmented Wide Area Circumferential Catheter Ablation for Reduction of Atrial Fibrillation Recurrence (AWARE) trial enrolled patients at 10 university-affiliated centers in Canada from March 2015 to May 2017. Individuals included in the study were 18 years and older with symptomatic paroxysmal AF (refractory to, intolerant of, or unwilling to trial antiarrhythmic drugs). Analysis occurred between January – April 2022.

The population of 398 patients was randomized 1:1 to receive radiofrequency catheter ablation for pulmonary vein isolation with either a standard single WACA (n = 195, 49%) or an augmented double WACA (n = 203, 51%). Overall, 52 patients (26.7%) in the control arm and 50 patients (24.6%) in the experimental arm had recurrent atrial arrhythmia at 1 year (relative risk [RR], 0.92; 95% CI, 0.66 - 1.29; 

Data showed 20 of 195 (10.3%) in the control arm and 15 of 203 patients (7.4%) in the experimental arm underwent repeated catheter ablation due to symptomatic atrial arrhythmia recurrence (RR, 0.72; 95% CI, 0.38 - 1.36). Investigators found no differences in atrial arrhythmia or atrial arrhythmia-related emergency department visits or hospitalizations between the 2 arms of the trial.

Quality of life and patient satisfaction score outcomes showed no significant difference in outcomes between the 2 treatment arms, according to the data. Additional subgroup analysis investigating the influence of high-power ablation showed no difference between the primary outcomes in those undergoing high-power ablation versus those undergoing ablation using standard settings. Safety was reported, with investigators noting adjudicated serious adverse events occurred in 13 patients (6.7%) in the control arm and 14 patients (6.9%) in the experimental arm.

Once more, investigators noted the results suggest a ceiling effect to the single procedure success of empirical WACA in a population with paroxysmal AF. Potential success and adverse event rates can potentially be used for shared decision-making with patients.

“The experimental strategy using additional ablation lesions did not reduce the recurrence of atrial arrhythmia,” they wrote. “This suggests that more is not necessarily better when it comes to ablation of paroxysmal AF.”

Nair GM, Birnie DH, Nery PB, et al. Standard vs Augmented Ablation of Paroxysmal Atrial Fibrillation for Reduction of Atrial Fibrillation Recurrence: The AWARE Randomized Clinical Trial. JAMA Cardiol. Published online March 22, 2023. doi:10.1001/jamacardio.2023.0212

The randomized AWARE trial indicates patients with paroxysmal AF did not have improved freedom from recurrent atrial arrhythmia with a double ablation lesion set compared with a single procedure. 


Augmented Ablation Adds No Benefit in Prevention of Recurrent Atrial Arrhythmia

, Herbert S B Baraf, MD, FACP, MACR, Clinical Professor of Medicine, George Washington University School of Medicine and Health Sciences and Principal Investigator of the DISSOLVE Program, discusses the phase 3 DISSOLVE program that evaluated SEL-212 combination therapy in adult patients with 

Image Credit: National Institute of Arthritis and Musculoskeletal and Skin Diseases

The program was comprised of 2 double-blind, placebo-controlled studies randomized patients to receive ImmTOR (0.1 mg/kg or 0.15 mg/kg), which hinders the formation of anti-drug antibodies, co-administered with pegadricase (0.2 mg/kg), or placebo. SEL-212 was designed to reduce serum urate (SU) levels in patients with chronic refractory gout, a more severe form of the condition.

What prompted your team to analyze the effects of SEL-212 in patients with chronic refractory gout?

I have a career-long interest in gout and have conducted clinical research on it. I was involved in the development of pegloticase, also known as KRYSTEXXA, and saw its transformative potential. However, many patients are sensitive to it and lose efficacy because they develop antibodies. This issue has been partially addressed with the use of methotrexate in conjunction with the drug. Pegloticase and pegadricase are uricase enzymes with polyethylene glycol moieties attached to them. While polyethylene glycol is meant to decrease immunogenicity and increase the half-life of these drugs, foreign proteins are inherently immunogenic. Thus, the value of these treatments is limited by their degree of immunogenicity. In the original phase 3 protocol with pegloticase, there was a 42% response rate, with many patients unable to tolerate the drug due to antibody formation and subsequent clearance of the drug from the system. Some patients also experienced infusion reactions. With the ImmTOR technology, however, pegadricase can be given more effectively, helping patients tolerate the drug and providing sustained benefits, as shown in this study.

Results indicated that SEL-212 was well tolerated, safe, showed significantly higher response rates, and a significant overall reduction in serum urate compared with the placebo. Were you surprised by these results?

I was surprised at how low the incidence of infusion-related reactions was in this fairly large population of patients. There were only 7 cases of anaphylaxis and true infusion reactions combined, which was under 5%, whereas I would have expected the overall infusion reaction rate to be close to 20%. I was also surprised by the robustness of response in the over-50 population, with a 65% response rate in the US cohort. The addition of methotrexate to pegloticase therapy was approved by the FDA in the last year or so and showed a 70% response rate in one double-blind study, which is very similar to the response rates for SEL-212.

SEL-212 has the advantage of being administered once a month, compared to pegloticase, which is administered every 2 weeks, making it more convenient for patients. This type of therapy is particularly helpful for patients with severe gout, who have been underserved by the medical community. It can restore function and improve disfiguring tuffaceous deposits on the hands and feet in just 3 to 6 months, whereas standard therapy takes 5 to 6 years. While both therapies are extremely effective, not all patients respond to either one, so having an alternative is great for patients. It is also great for doctors who can now feel more comfortable treating patients who need aggressive therapy. Having a second product in the pipeline for approval gives hope to those who need it.

SEL-212, an alternative to standard therapy that is administered once monthly, has proven to be particularly helpful for patients with severe gout, a historically underserved population.

Herbert S B Baraf, MD: SEL-212 Novel Combination Therapy for Gout

Credit: Icahn School of Medicine at Mount Sinai

 are more likely to develop pouchitis followed a total proctocolectomy with ileal pouch-anal anastomosis than patients who do not have acute severe ulcerative colitis.

A team, led by Maia Kayal, MD, MS, Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, calculated the likelihood of developing pouchitis for patients with acute severe ulcerative colitis following total proctocolectomy with ileal pouch-anal anastomosis.

Up to 80% of patients develop pouchitis following a total proctocolectomy with ileal pouch-anal anastomosis. In the past this has been associated with microbial and host-related immunological factors.

“We hypothesized that a more robust immune response at the time of colectomy, manifested by acute severe ulcerative colitis (ASUC), may be associated with subsequent acute pouchitis,” the authors wrote.

In the retrospective cohort study, the investigators examined all patients with ulcerative colitis or indeterminate colitis complicated by medically refractory disease or dysplasia who underwent total proctocolectomy with ileal pouch-anal anastomosis at Mount Sinai Hospital between 2008-2017.

Each participant had at least 1 subsequent pouchoscopy.

The investigators defined acute pouchitis in accordance with the Pouchitis Disease Activity Index and assessed unadjusted relationships between hypothesized risk factors and acute pouchitis using Cox regression.

There were 416 patients that met the inclusion criteria, 39.7% (n = 165) of which underwent urgent colectomy, 46.7% (n = 77) were admitted with acute severe ulcerative colitis.

The results show 54.8% (n = 228) developed acute pouchitis in a median of 1.3 years after the final surgical stage.

Acute severe ulcerative colitis (hazard ratio [HR], 1.50; 95% confidence interval [CI], 1.04-2.17) and a greater number of biologics precoloectomy (HR, 1.57; 95% CI, 1.06-2.31) were linked to an increased probability of acute pouchitis. On the other hand, older age at colectomy (HR, 0.98; 95% CI, 0.97-0.99) were associated with a decreased probability of acute pouchitis.

Finally, time to pouchitis was significantly less in patients admitted with acute severe ulcerative colitis compared to patients not (

“A severe [ulcerative colitis] disease phenotype at the time of colectomy was associated with an increased probability of acute pouchitis,” the authors wrote.

Recent research has indicated that cyclosporine fared better in the long-term than infliximab in patients with acute severe 

In the retrospective analysis, the investigators examined 121 patients admitted to a single gastroenterology center between 2010-2020 with acute severe ulcerative colitis, defined by the Truelove & Witts criteria. This included 119 patients who initially received intravenous corticosteroids and 2 patients who underwent an emergency colectomy on the first day.

The results show 55% (n = 66) of the patient population responded to intravenous corticosteroids and 45% (n = 53) failed to respond to steroid therapy. In addition, 37% (n = 45) of patients received second-line rescue therapy, 29 with cyclosporine, 16 with infliximab.

There was no significant difference between the 2 drugs in short-term efficacy.

During admission, colectomies were performed in 10.3% of the cyclosporine group, compared to 12.5% of the infliximab group (

For the long-term efficacy analysis, the investigators found the difference was not statistically significant (10.3% vs. 31.2%, 

Maia Kayal, MD MS, Hannah Posner, BS, Hadar Meringer Milwidsky, MD, Michael Plietz, MD, Sergey Khaitov, MD, Patricia Sylla, MD, Alexander Greenstein, MD MPH, Marla C Dubinsky, MD, Saurabh Mehandru, MD, Jean Frederic Colombel, MD, Acute Severe Ulcerative Colitis Is Associated With an Increased Risk of Acute Pouchitis, 

Acute severe ulcerative colitis and a greater number of biologics precoloectomy were linked to an increased probability of acute pouchitis, while older age at colectomy was associated with a decreased probability of acute pouchitis. 

Severe Acute Ulcerative Colitis Increases Risk of Pouchitis

 were more likely to present with advanced disease compared to White and Hispanic patients but had similar survival outcomes, according to new findings.

MCC—a rare and aggressive skin cancer that mostly affects patients that are White—is more and more common, and the majority of research shows that Black MCC patients have higher rates of presenting advanced disease.

The purpose of this study was, in part, to assess whether Black patients with MCC have worse overall survival than White patients, for which available data is conflicting.

 The research was authored by Noreen Mohsin, BS, with the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

“The composition of the US population is rapidly changing,” Mohnsin and colleagues wrote. “As such, it is imperative to understand how disease characteristics and outcomes differ by race and ethnicity. Accordingly, in this cohort study we sought to characterize racial and ethnic differences among patients with MCC.”

The investigators analyzed patient data from March to November of 2022, conducting a retrospective cohort analysis of 9,557 patients with MCC diagnoses. The team collected data from 2000 through to 2018, using 18 population-based cancer registries at the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program.

The researchers conducted a Cox proportional hazards regression to assess the different associations between demographics such as race, age, sex, income, and ethnicity and clinical information such as diagnosis stage, primary site of MCC, and year of diagnosis.

Overall, the investigators noted that the majority of the 9,557 MCC patients were male and aged 70 years or older. Among them, 89.9% were reported as White, 5.7% Hispanic, 1.5% Black, and 2.3% Asian American or Pacific Islander.

The biggest findings the team reported were that Hispanic patients had better MCC-specific survival than White patients, whereas Black patients technically had the lowest MCC-specific survival. That said, the difference was not statistically significant and despite Black patients showing advanced disease earlier, the rates were roughly the same.

Additionally, the investigators noted that Hispanic and Black patients were less likely to have the primary site of the head and neck compared to White patients, and they confirmed that Black patients were more likely to have advanced disease at diagnosis than Whites (40.4% versus 29.2%, respectively; 

“Although MCC incidence was lower among AAPI patients than White patients, the disease presentation and prognosis were generally similar,” they wrote. “The finding that lower income was independently associated with worse MCC outcomes was consistent with prior studies and suggests there are socioeconomic disparities in MCC care.”

Mohsin N, Martin MR, Reed DJ, et al. Differences in Merkel Cell Carcinoma Presentation and Outcomes Among Racial and Ethnic Groups. 

. Published online March 15, 2023. doi:10.1001/jamadermatol.2023.0061.

Trofymenko O﻿, Zeitouni NC﻿, Kurtzman DJB﻿. Factors associated with advanced-stage Merkel cell carcinoma at initial diagnosis and the use of radiation therapy: results from the National Cancer Database.

Sridharan V﻿, Muralidhar V﻿, Margalit DN﻿, et al. Merkel cell carcinoma: a population analysis on survival.

. 2016;14(10):1247-1257. doi:10.6004/jnccn.2016.0134.

New data highlighted racial and ethnic differences between patients with Merkel cell carcinoma, indicating that rates for survival were roughly similar but other distinctions remained.


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