 Dr Sands, could you review our 2 newest agents, the JAK inhibitor tofacitinib and the S1P [sphingosine-1-phosphate] receptor modulator ozanimod?

 Sure. Both tofacitinib and ozanimod, in contrast with what Dr Ungaro and Dr Hanauer have been talking about, are oral agents. They’re small molecule agents. At this point, they’re approved for only ulcerative colitis within the realm of IBD [inflammatory bowel disease]. Tofacitinib is a Janus kinase inhibitor, or a JAK inhibitor. It’s a pan-JAK inhibitor. It works by basically inhibiting downstream inflammatory responses within inflammatory cells. It’s an orally available agent, and it’s effective in ulcerative colitis. But it’s positioned in its use after patients have failed anti-TNF [tumor necrosis factor] agents, so it’s a second-line agent.

Furthermore, it has recently had the addition of black box warnings for venous thromboembolism and increase in mortality. This comes from data out of the rheumatoid arthritis population, but has been generalized to its application with ulcerative colitis as well. It’s an effective agent. As with all agents, it’s somewhat less effective after patients have already failed an anti-TNF, which paradoxically is exactly the patient we would use it for.

Ozanimod is the newest one. It had already been on the market for treatment of multiple sclerosis. It works mechanistically in a different way. It’s an S1P receptor agonist, or sphingosine-1-phosphate receptor agonist. Without going into great detail about what it does or how it does it, it basically sequesters lymphocytes in lymph nodes and keeps them trapped in the lymph nodes and out of circulation. In a way, it’s another approach of targeting the trafficking of inflammatory cells and lymphocytes into the gut mucosa. But here it’s just trapping them in the lymph nodes and not killing them. Consequently, you can expect to see lymphopenia. But interestingly, you don’t see very much increased risk of infections. You see a slight uptick in herpes zoster, but not much else of note.

There are some other safety issues with ozanimod. It’s given in uptitrated dosing because it has cardiac conduction effects, which are easily titratable. You see rapid tachyphylaxis to that effect. But you want to use it with caution in patients who have cardiac conduction abnormalities. There are also rare cases of liver function abnormalities. I mentioned the lymphopenia. It can also cause macular edema—you don’t want patients who are susceptible to that to get it—and rare cases of pulmonary function abnormalities. You don’t necessarily have to monitor for that, but just be aware of that. But it’s effective in ulcerative colitis and provides another oral option for treatment.

Videos

What to know in terms of integrating new oral, small molecule targeted drugs into treatment plans for patients with ulcerative colitis.

Oral, Small Molecule Agents for Ulcerative Colitis

 We’d now like to focus on the biologic treatments and overall treatment response. Dr Hanauer, one of the older drugs that’s been available for years and used very often is mesalamine. What role does mesalamine play in disease management for ulcerative colitis and Crohn disease?

 Mesalamine has been a long-standing drug for mild to moderate ulcerative colitis. It’s more of a topical agent, and it’s more effective in ulcerative colitis than in Crohn disease because ulcerative colitis tends to be a more superficial inflammation of the colon. We have less evidence for the role of mesalamine as an inductive or maintenance agent in the setting of Crohn disease, where we have moved more toward biologic agents, as Dr Sands mentioned. Once the biologic agents have been utilized, mesalamine has a lesser role in both ulcerative colitis and Crohn disease. But it has been a standard agent for induction and maintenance of mild to moderate ulcerative colitis.

 Thank you. With that, before we go into how we might treat this patient specifically, I’d like to ask the panel to review for our audience the different classes of biologics that we often use to treat inflammatory bowel disease, and their advantages and disadvantages. Dr Ungaro, could you start off with the anti-TNF [tumor necrosis factor] drugs and your thoughts about these agents?

 Sure. The anti-TNF drugs, or anti–tumor necrosis factor agents, are our oldest class of biologic and the most tried-and-true agents. The main medications in this class are 3 injectables and 1 intravenous. The intravenous agent, the original anti-TNF, is infliximab. Then there are 3 subcutaneous formulations of anti-TNF: adalimumab, golimumab, and certolizumab, which patients are able to administer on their own. These are very efficacious and have a long track record of working well in both ulcerative colitis and Crohn disease. They tend to work fairly quickly. Compared with some of the other classes of agents, you can usually see response as soon as a couple weeks, and certainly within 6 to 12 weeks. The relative trade-offs between the different types of anti-TNF drugs often come down to patient convenience. Are they close to and able to get to an infusion center? You can use infliximab in that case. Or are they traveling a lot? Are they away at school or prefer the convenience of a subcutaneous injection? You can go for one of the injectables in that case.

 Thank you. Dr Hanauer, could you go over some of the relatively newer agents, the IL-12/23 inhibitor ustekinumab and the anti-integrin inhibitor vedolizumab?

 Similar to the TNF inhibitors that are effective in both ulcerative colitis and Crohn disease as Dr Ungaro mentioned, they’re also approved for other conditions: inflammatory diseases such as rheumatoid arthritis and psoriasis, and a number of less common immune diseases.

Ustekinumab, the IL-12/23 inhibitor, likewise has been effective for over a decade in the treatment of psoriatic arthritis. There’s a long safety experience in this with both psoriasis and psoriatic arthritis. Over the past several years, ustekinumab has also been demonstrated to be effective in both moderate to severe ulcerative colitis and Crohn disease, but as we’ve seen with the TNF inhibitors, at a somewhat higher dose than are used in other immune-mediated diseases, psoriasis in particular.

One of the advantages of ustekinumab is, No. 1, the ease of administration. In ulcerative colitis and Crohn disease, it begins with a single intravenous infusion and then 90 mg subcutaneously every 8 weeks, in contrast with some of the more frequent administration of the subcutaneous TNF inhibitors. In addition, I mentioned the safety, and TNF inhibitors are associated with risks for infections, such as pneumonia, and of course, tuberculosis [TB]. With ustekinumab, we also rule out TB exposure. But while there may be a slight increased risk of other infections, it appears to be less than that of the TNF inhibitors.

In contrast, vedolizumab is an agent that affects lymphocyte trafficking. In order for inflammation to occur in the bowel, inflammatory cells need to get into the intestine. Vedolizumab is an antagonist of alpha-4 beta-7 integrins, which are associated with about 3% of lymphocytes that are likely to be targeted into the intestine. Ustekinumab is a monoclonal antibody that blocks the interaction of the integrin on lymphocytes with the addressin, or the receptor on blood vessels within the intestine. Vedolizumab has been shown to be effective in moderate to severe ulcerative colitis and Crohn disease, is administered intravenously in maintenance every 8 weeks, and because of this gut selectivity, has seemed to be a very safe agent because it’s not associated with systemic inflammation. Likewise, it’s not as effective in patients who have systemic or extraintestinal manifestations that aren’t associated with gut inflammation.

A review of various classes of biologic therapies available to treat patients with ulcerative colitis or Crohn's disease.

Treatment Options for Ulcerative Colitis and Crohn's Disease

In the management of chronic pain, the primary goal is to maximize the patient’s level of functioning; usually the focus is on the ability to perform at work or school or to accomplish household chores.

One important area of life for many people, however, is often overlooked by healthcare professionals: sexual functioning.

A recent systematic review published in Pain Medicine examined the current research on how chronic musculoskeletal pain may affect sexual functioning.* The review included studies of patients with pain persisting for ≥3 months and sexual difficulty before any intervention. Studies were excluded if participants had other disorders, such as diabetes, that could impact sexual function or where the pain disorder was located in the sexual organs.

The slide show below offers the review's top-line findings. 

Sexual difficulties in the population with musculoskeletal chronic pain: a systematic review. 

Slideshows

The impact on sexual function of chronic pain conditions has received little research inquiry and requires much more focused clinical attention. 

Sexual Function & Chronic Pain: Results of a Systematic Review 

How widespread is the Delta variant (B.1.617.2) in the US?

Centers for Disease Control and Prevention (CDC)

, as of October 9, 2021, the SARS-CoV-2 Delta variant made up 

The CDC estimates for the week ending on October 9, 2021, the 5 states with the highest unweighted proportion of new cases attributed to the SARS-CoV-2 Delta variant are:

How many people in the US have been vaccinated against COVID-19?

 as of today, October 19, 2021, at 3:15 PM, EDT:

The 5 states/territories with the highest percentage of population fully vaccinated are:

How many cases of COVID-19 have been confirmed in the US?

, as of today, October 19, 2021 at 5:22 PM, EDT, there have been:

The 5 states with the highest total confirmed cases are:

 California has the highest number of deaths due to COVID-19

 with 70 870 reported fatalities, followed by 

How many cases of COVID-19 have been confirmed globally?

Articles

Data from the CDC on the Delta variant and US vaccination rates and from the Johns Hopkins COVID-19 interactive map on cases and deaths in the US and worldwide.

COVID-19 Updates: Delta Variant, US Vaccinations, & Global Data as of October 19, 2021

A hypertension (HTN) self-management program with a blood pressure (BP) monitor and connected smartphone application was associated with mean reductions in systolic BP of as much as 20.9 mm Hg, according to new research published in 

Specifically, investigators reported that more than 84% of study participants with stage 2 HTN who participated for 3 years achieved the average 20.9 mm Hg systolic BP reduction, more than 2 times that seen in comparable published results.

Researchers conducted a cohort study of 28 189 US adults (median age, 51 years; 59.6% men) with 

 who used the self-management program, which includes a BP monitor and connected smartphone application with clinically based digital coaching (Hello Heart program, Hello Heart Inc.) via employer-sponsored coverage.

"The level of engagement is something I have not seen in other digital hypertension management programs."

“This is the first peer-reviewed, published study reporting the long-term experience of a digital health application for 

, with a magnitude of association that is clinically meaningful,” said lead author Alexis Beatty, MD, MAS, cardiologist, associate professor, University of California, San Francisco, in a 

Participants were enrolled between January 1, 2015 and July 1, 2020. Systolic and diastolic BP were measured by a Food and Drug Administration-cleared BP monitor, with categories defined as normal (systolic BP <120 mm Hg), elevated (systolic BP 120-129 mm Hg), stage 1 HTN (systolic BP 130-139 mm Hg), and stage 2 HTN (systolic BP 140 mm Hg), according to the study.

Overall, median baseline systolic BP was 129.5 mm Hg and diastolic BP was 81.7 mm Hg. Median systolic BP at 1 year improved at least 1 category for 53% of participants with elevated BP, 69.7% of those with stage 1 HTN, and 85.7% of those with stage 2 HTN at baseline.

According to investigators, participants in the program for 3 years had a mean systolic BP reduction of 7.2 mm Hg, 12.2 mm Hg, and 20.9 mm Hg compared with baseline for those starting with elevated, stage 1 HTN, and stage 2 HTN, respectively.

“The level of engagement is something I have not seen in other digital hypertension management programs. Sustained engagement and decreases in systolic blood pressure of more than 20 mmHg could reduce a person’s chances of heart attack, stroke, kidney disease, and death,” added Beatty in the press release.

Over time, greater engagement in the program was associated with lower systolic BP (high-engagement group, 131.2 mm Hg; medium-engagement group, 133.4 mm Hg; low-engagement group, 135.5 mm Hg; 

<.001), wrote researchers who noted that these results persisted after adjusting for age, gender, depression, anxiety, diabetes, hypercholesterolemia, smoking, area deprivation index rank, and region.

Another key finding was that greater engagement was associated with lower risk of very high BP (systolic BP >180 mm Hg). The estimated probability of a very high BP was greater in the low-engagement group (1.42%; 95% CI, 1.26%-1.59%) than the medium-engagement group (0.79%; 95% CI, 0.71%-0.87%) and the high-engagement group (0.53%; 95% CI, 0.45%-0.60%; 

<.001 for comparison with both groups), according to the study.

“This real-world evidence of a BP self-management program with a BP monitor connected to a smartphone app with automated lifestyle coaching demonstrates the potential of this strategy to achieve better BP control,” concluded investigators. “Future studies should examine the efficacy and dissemination of mobile technology–facilitated BP self-management interventions and their real-world effectiveness in other settings and populations as well as deeper investigations into the mechanisms that drive their effects on BP control.”

Reference: Gazit T, Gutman M, Beatty AL. 

Assessment of hypertension control among adults participating in a mobile technology blood pressure self-management program

Novel peer-reviewed study found that a mobile hypertension self-management program can support long-term BP control and very high BP detection. 

Mobile App Helps Patients Achieve Sustained BP Reduction, Particularly in Stage 2 Hypertension

Real-world use of biologic agents for treatment of 

 (SA) is consistently associated with up to >50% reduction in disease exacerbations, according to findings from the ongoing CHRONICLE Study presented at the annual meeting of the American College of Chest Physicians (CHEST 2021), held in Orlando, Florida, and virtually between October 17-20, 2021.

The study focused specifically on groups of patients with SA whose response to biologic therapies has not been previously studied. 

The advent of biologic therapeutics (monoclonal antibodies [mAbs]) that target specific inflammatory pathways has significantly enhanced treatment for the 5% to 10% of asthma patients with SA. CHRONICLE investigators, led by Reynold Panettieri, Jr, MD, vice chancellor for translational medicine and science and director of the Rutgers Institute for Translational Medicine and Science,  were interested in the real-world effectiveness of mAbs in subgroups of SA patients who were not included in the original randomized clinical trials of the biologics. They included in that group those with pre-bronchodilator forced expiratory volume in 1 second (FEV

) ≥80%, comorbid COPD, or significant smoking history.

The noninterventional study is ongoing with the objective to examine use of biologics and outcomes among patient subgroups with SA who initiate mAb therapy in treatment with allergists/immunologists or pulmonologists. They also are interested in the effect on SA exacerbation of switching between biologics and switching from biologics to other agents for SA. 

Patients eligible for the study are adults aged ≥18 years with a diagnosis of SA who are receiving FDA-approved biologics and/or maintenance systemic corticosteroids, plus those uncontrolled on high-dose inhaled corticosteroids with additional controller medications.

Participating sites report asthma exacerbations and medications for 12 months prior to enrollment and every 6 months after enrollment. For participants initiating a biologic agent or who switch between 2 biologics, investigators calculated exacerbation rates 6 months before and after the initiation or the change.

For the period between February 2018 and February 2021 there were 2793 patients enrolled in CHRONICLE; at enrollment 66% (n=1832) were receiving biologics. During the study, researchers report that 2025 patients were using biologics at any point, with 1810 reporting ongoing use. Among those using biologic agents, 324 (16%) reported switching between agents.

Decline in exacerbation rates 6 months before/after biologic initiation

Overall, patients starting biologics experienced a 58% reduction in exacerbations (from 1.80 to 0.76 per patient-year), with a greater reduction observed among those starting non–anti-IgE biologics (62%) vs anti-IgE agents (44%).

Biologic use among CHRONICLE participants

Patients who switched biologics experienced a 49% reduction in exacerbations (1.47 vs 0.75 per person-year).

Switching from anti-IgE therapy to anti–interleukin (IL)-5/IL-5R/IL-4R therapy was associated with greater reduction in exacerbations than was switching among anti–IL-5/IL-5R/IL-4R therapies (58% vs 46%, respectively).

Reductions in exacerbation rates were significant in patients who had pre-biologic FEV

 ≥80% (66% and 54%, respectively); never smokers and current/former smokers (63% and 50%, respectively); and patients with/without a 

Similar decline in exacerbation rates 12 months before/after biologic initiation

For all patients, the exacerbation rate declined by 70% after biologic initiation (from 1.72 to 0.5 per patient-year). Exacerbation rates were reduced in all subgroups and reductions were statistically significant (P<.0001) in patients with pre-biologic FEV

< 80%, never smokers, current/former smokers, and patients without a COPD diagnosis.

In their summary points Pannetieri et al point out that the real-world results from CHRONICLE both validate and extend findings from randomized, placebo-controlled trials, providing data on patient groups with SA whose responses to biologic therapy have not been previously studied. The authors emphasize the significant reductions in exacerbations observed in patients who switched biologic therapies during the study, which they say highlights “the need for a personalized approach to biologic therapy and the value of switching if the response to a patient’s initial biologic treatment is suboptimal.”

Biologic medications for severe asthma are effective in the real-world, including in subgroups not studied in randomized trials: results from the CHRONICLE study.

CHEST2021: The CHRONICLE study of biologics to treat severe asthma found reductions in exacerbations of more than 50% in patient groups not included in clinical trials. 



Biologics Reduce Severe Asthma Exacerbations in Real-world Study of Vulnerable Patients 

Dupilumab may reduce exacerbations and improve lung function while reducing oral corticosteroid (OCS) use in patients with OCS-dependent severe asthma regardless of baseline OCS dose, according to new research.

The findings were presented at the annual meeting of the American College of Chest Physicians 

, held in Orlando, Florida, and virtually between October 17-20, 2021.

The study was a post hoc analysis of the phase 3 

 clinical trial, which showed that compared with placebo, 

 300 mg given every 2 weeks reduced OCS maintenance dose and severe asthma exacerbation rate and improved pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) independent of baseline eosinophils in patients aged ≥12 years with OCS-dependent 

Authors of the post hoc analysis, led by Mario Castro, MD, from the University of Kansas School of Medicine, evaluated clinical outcomes in patients grouped by baseline optimized OCS, analyzing the following endpoints:

Proportion of patients no longer requiring OCS at week 24

Adjusted annualized severe exacerbation rate

Least squares (LS) mean change from baseline in pre- and post-BD FEV1 at week 24

Among patients who received an OCS dose of <10 mg per day at baseline, those in the dupilumab (n=46) and placebo (n=36) arms received a mean baseline OCS dose of 6.1 mg/day and 6.2 mg/day, respectively. Participants with a baseline OCS dose of ≥10 mg/day received mean OCS dosesof 14.5 mg/day in the dupilumab (n=57) group and 14.6 mg/day in the placebo (n=71) group at baseline.

Investigators found that compared with placebo, treatment with dupilumab was associated with a decrease in the daily OCS dose from baseline to week 24 in participants that received OCS doseof <10 mg/day (LS mean difference, 2.1 mg; 95% confidence interval [CI], 0.8–3.3; 

.01) and in those receiving ≥10 mg/day (LS mean difference, 3.3 mg; 95% CI, 1.0–5.5; 

In participants with a baseline OCS dose <10 mg/day, 72% of dupilumab-treated patients no longer required OCS at week 24, compared with 42% of placebo-treated patients (odds ratio [OR], 3.8; 95% CI, 1.4-10; 

<.01). Similarly, a higher proportion of dupilumab-treated patients with a baseline OCS dose of ≥10 mg/day stopped OCS at week 24 compared with placebo (37% vs 23%; OR, 2.3; 95% CI, 1.0-5.4; 

<.05). Researchers noted that not all patients with a baseline daily OCS dose of ≥10 mg were eligible for down-titration to 0 mg/day per the study’s protocol.

Dupilumab significantly reduced the annualized rate of

 by 71% among patients with a baseline daily OCS dose of <10 mg (

<.01) and 48% in those with a baseline daily OCS dose of ≥10 mg (

At week 24, treatment dupilumab compared to placebo was associated with improved pre-BD FEV1 in patients with a daily baseline OCS dose ≥10 mg compared with placebo (LS mean difference, 0.26 L; 95% CI, 0.09-0.43; 

<.01). Researchers also found dupilumab-associated improvements in pre-BD FEV1 among patients with a baseline daily OCS dose of <10 mg (LS mean difference, 0.2 L; -0.04 to -0.33; 

Compared with placebo, dupilumab was associated with significant improvements in post-BD FEV1 at week 24 in patients with baseline OCS <10 mg/day (LS mean difference, 0.20 L; 95% CI, 0.05–0.35; 

<.05) and ≥10 mg/day (LS mean difference, 0.18 L; 95% CI, 0.02–0.34; 

“Dupilumab significantly reduced OCS dose, improved the odds of no longer requiring OCS, and improved clinical outcomes regardless of BL OCS dose in pts [patients] with OCS-dependent severe asthma,” concluded authors.

Reference: Ribas CD, Maspero J, Castro M, et al. 

Dupilumab reduced oral corticosteroid use and improved clinical outcomes regardless of baseline OCS dose in patients with uncontrolled, severe asthma in the Liberty Asthma VENTURE study

In patients with severe asthma dependent on OCS, dupilumab reduced OCS dose and improved the odds of no longer requiring OCS, suggests research presented at CHEST 2021.

Dupilumab Associated with Reduced Oral Corticosteroids in Severe Asthma, Regardless of Baseline OCS Dose

 as of today, October 18, 2021, at 2:27 PM, EDT:

, as of today, October 18, 2021 at 3:21 PM, EDT, there have been:

 with 70 811 reported fatalities, followed by 

COVID-19 Updates: Delta Variant, US Vaccinations, & Global Data as of October 18, 2021

 as of today, October 15, 2021, at 2:05 PM, EDT:

, as of today, October 15, 2021 at 4:21 PM, EDT, there have been:

 with 70 580 reported fatalities, followed by 

COVID-19 Updates: Delta Variant, US Vaccinations, & Global Data as of October 15, 2021

A vaccine advisory committee to the US Food and Drug Administration (FDA) on Thursday unanimously endorsed booster shots of the Moderna mRNA vaccine for Moderna recipients who are aged ≥65 years, those aged ≥18 years at risk of severe COVID-19 infection, and those who are at risk for extended occupational or residential exposure to the virus. 

The populations that qualify for the Moderna booster mirror those eligible under the emergency use authorization (EUA) granted for the Pfizer-BioNTech vaccine booster in September

The Vaccines and Related Biological Products Advisory Committee (VRBPAC) support an EUA for the booster dose to be administered at least 6 months after completion of the original 2-shot series. The third shot will be a 50-µg injection, ie, half the 100-µg dose given in the first 2 doses.

The VRBPAC recommendation was based on part on analysis of data from Moderna’s phase 2 clinical study of the mRNA-1273 vaccine which the manufacturer amended to offer the 50-µg booster dose to interested study participants 6 to 8 months after completion of the original series, according to a 

 Before the booster administration, neutralizing antibodies had waned at approximately 6 months, the statement notes, and particularly against circulating variants of concern, including the Delta variant. The 50-µg Moderna booster increased neutralizing titers significantly above the benchmark level established for the phase 3 trial. A similar rise in titers was seen across age groups and, most notably, in adults aged ≥65 years. There were no new safety signals, the company said.

 the Associated Press, VRBPAC also unanimously recommended that the FDA authorize a booster shot of the Johnson & Johnson (J&J) adenovirus-based COVID-19 vaccine. The recommendation is that the booster be administered at least 2 months after the initial shot.

, a booster dose at between 2 to 6 months can boost the vaccine's efficacy to 94% against symptomatic COVID-19, increasing antibody levels 4- to6-fold when given at 2 months post-original injection and as much as 12-fold when given at 6 months. 

FDA regulators are not obligated to follow the advisory panel’s recommendations, but they typically do.

If EUA is granted to either the Moderna and/or J&J boosters, the Centers for Disease Control and Prevention vaccine advisors will convene to discuss final recommendations for which population groups will be eligible. The CDC’s Advisory Committee on Immunization Practices is scheduled to discuss boosters on October 21, 2021.

The Vaccines and Related Biological Products Advisory Committee unanimously recommended the Moderna booster on Thurday, the J&J booster on Friday. 