Rheumatology News

Several relatively large real-world analyses of Janus kinase inhibitors (JAKi) in patients with rheumatoid arthritis appear to show that the oral small-molecule drugs are discontinued and retained at rates similar to or better than biologic disease-modifying antirheumatic drugs (bDMARDs), including tumor necrosis factor inhibitors (TNFi), according to studies presented at the annual meeting of the Canadian Rheumatology Association.

The findings of these studies, although conducted prior to the Food and Drug Administration’s September 2021 announcement of a boxed warning for JAKi, do not lend support to the warning’s message of higher risks of major adverse cardiovascular events (MACE), blood clots, cancer, and death associated with JAKi.

In one study, discontinuation of JAKi-class drugs was less common than discontinuation of bDMARD-class drugs, including tumor necrosis factor inhibitors (TNFi), according to a multicenter team of investigators led by Janet Pope, MD, a professor in the division of rheumatology at the University of Western Ontario, London.

The greater durability of the JAKi relative to TNFi “seem to be driven by a greater loss of efficacy in bDMARDs over time,” reported Samir Magdy Iskander, a medical student at the university, who presented the data.
 

JAKi rival bDMARDs for long-term retention

In a separate but larger analysis, the retention rates with the JAKi tofacitinib (Xeljanz) and TNFi in two RA registries in Canada were about the same after a mean follow-up of 23.2 months (36.9% vs. 37.5%), but the tofacitinib group was at a relative disadvantage. Relative to the bDMARD group, patients taking JAKi were more likely to have had prior treatment with a bDMARD (66.9% vs. 33.9%), to have a higher median baseline Clinical Disease Activity Index (CDAI) score (22.1 vs. 20.0; P < .05), and to be older (59.5 vs. 57.6 years).

In this study, 1,318 patients with RA enrolled in the Ontario Best Practices Research Initiative (OBRI) or a Quebec cohort called RHUMADATA were evaluated, reported Mohammad Movahedi, MD, PhD, of the Institute of Health Policy, Management, and Evaluation at the University of Toronto.

“We have not yet analyzed the reasons for discontinuation, but the data show that retention is about the same, meaning that selection of one agent over the other should be tailored according to patient characteristics,” Dr. Movahedi said.

Reasons for discontinuation were presented in the other observational study, which included 333 adult patients with RA from two centers in Ontario. The discontinuation rate for adverse events was approximately 20% in both groups (HR, 1.0005; P = .98). However, the discontinuation rate for lack of efficacy favored the JAKi, reaching statistical significance.
 

TNFi failure for lack of efficacy is higher

“For lack of efficacy, the discontinuation rate was about 35% lower on the JAKi [HR, 0.6543; P = .029],” Mr. Iskander reported. Relative to those taking a TNFi, those on a JAKi demonstrated “greater durability regardless of gender, age, disease duration, and prior lines of therapy.”

In a population of patients who have not achieved an adequate response to conventional synthetic DMARDs (csDMARDs), which describes the study population from the two Ontario centers, JAKi “may be considered as a preferable method of treatment,” Mr. Iskander said.

Pointing out that many clinicians have interpreted the boxed warning as a relative contraindication for use of JAKi as first-line therapy in patients with an inadequate response to csDMARDs, Marinka Twilt, MD, PhD, the moderator of the scientific session where these data were presented, questioned the conclusion. In the boxed warning, clinicians and patients are advised to consider an increased risk of serious infections, malignancy, and cardiovascular-related mortality in individuals older than 50 years.

In response, Mr. Iskander said that the data were collected and analyzed prior to the change in labeling. He acknowledged that this study was not designed to capture long-term risks, such as cardiovascular disease or malignancy. In this analysis, the safety and tolerability of JAKi and bDMARDs appeared comparable.
 

NEJM published study leading to boxed warning

Just a week prior to the CRA annual meeting, the New England Journal of Medicine published an FDA-mandated postmarketing trial of tofacitinib that was used by the agency to justify the boxed warning for JAKi with indications for artitis and other inflammatory diseases. In that open-label trial, more than 4,000 patients aged 50 years or older with at least one additional cardiovascular risk factor were randomized to 5 mg tofacitinib twice daily, 10 mg tofacitinib twice daily, or a TNFi (adalimumab or etanercept).

The efficacy of the therapies was similar, but tofacitinib failed to meet predefined noninferiority criteria for the co–primary endpoints of MACE or cancer (excluding nonmelanoma skin cancer). For tofacitinib relative to TNFi, the hazard ratio was 1.33 for MACE and 1.48 for cancers. The JAKi was also associated with higher incidences of opportunistic infections.

Mr. Iskander noted that Canadian clinical practice guidelines currently identify JAKi as a reasonable first-line alternative to bDMARDs after inadequate response to csDMARDs. While his data support that position, Dr. Twilt indicated that the benefit-to-risk ratio of JAKi might need recalculation based on the data that led the FDA to issue its boxed warning. She questioned whether the language regarding the relative role of JAKi and bDMARDs will change in coming RA guideline revisions.

Dr. Iskander reported no potential conflicts of interest. Dr. Movahedi did not list any personal conflicts of interest but acknowledged that OBRI received unrestricted grants from a variety of pharmaceutical companies, including those that manufacture bDMARDs and JAKi. Dr. Twilt reported no potential conflicts of interest.

Several relatively large real-world analyses of Janus kinase inhibitors (JAKi) in patients with rheumatoid arthritis appear to show that the oral small-molecule drugs are discontinued and retained at rates similar to or better than biologic disease-modifying antirheumatic drugs (bDMARDs), including tumor necrosis factor inhibitors (TNFi), according to studies presented at the annual meeting of the Canadian Rheumatology Association.

The findings of these studies, although conducted prior to the Food and Drug Administration’s September 2021 announcement of a boxed warning for JAKi, do not lend support to the warning’s message of higher risks of major adverse cardiovascular events (MACE), blood clots, cancer, and death associated with JAKi.

In one study, discontinuation of JAKi-class drugs was less common than discontinuation of bDMARD-class drugs, including tumor necrosis factor inhibitors (TNFi), according to a multicenter team of investigators led by Janet Pope, MD, a professor in the division of rheumatology at the University of Western Ontario, London.

The greater durability of the JAKi relative to TNFi “seem to be driven by a greater loss of efficacy in bDMARDs over time,” reported Samir Magdy Iskander, a medical student at the university, who presented the data.
 

JAKi rival bDMARDs for long-term retention

In a separate but larger analysis, the retention rates with the JAKi tofacitinib (Xeljanz) and TNFi in two RA registries in Canada were about the same after a mean follow-up of 23.2 months (36.9% vs. 37.5%), but the tofacitinib group was at a relative disadvantage. Relative to the bDMARD group, patients taking JAKi were more likely to have had prior treatment with a bDMARD (66.9% vs. 33.9%), to have a higher median baseline Clinical Disease Activity Index (CDAI) score (22.1 vs. 20.0; P < .05), and to be older (59.5 vs. 57.6 years).

In this study, 1,318 patients with RA enrolled in the Ontario Best Practices Research Initiative (OBRI) or a Quebec cohort called RHUMADATA were evaluated, reported Mohammad Movahedi, MD, PhD, of the Institute of Health Policy, Management, and Evaluation at the University of Toronto.

“We have not yet analyzed the reasons for discontinuation, but the data show that retention is about the same, meaning that selection of one agent over the other should be tailored according to patient characteristics,” Dr. Movahedi said.

Reasons for discontinuation were presented in the other observational study, which included 333 adult patients with RA from two centers in Ontario. The discontinuation rate for adverse events was approximately 20% in both groups (HR, 1.0005; P = .98). However, the discontinuation rate for lack of efficacy favored the JAKi, reaching statistical significance.
 

TNFi failure for lack of efficacy is higher

“For lack of efficacy, the discontinuation rate was about 35% lower on the JAKi [HR, 0.6543; P = .029],” Mr. Iskander reported. Relative to those taking a TNFi, those on a JAKi demonstrated “greater durability regardless of gender, age, disease duration, and prior lines of therapy.”

In a population of patients who have not achieved an adequate response to conventional synthetic DMARDs (csDMARDs), which describes the study population from the two Ontario centers, JAKi “may be considered as a preferable method of treatment,” Mr. Iskander said.

Pointing out that many clinicians have interpreted the boxed warning as a relative contraindication for use of JAKi as first-line therapy in patients with an inadequate response to csDMARDs, Marinka Twilt, MD, PhD, the moderator of the scientific session where these data were presented, questioned the conclusion. In the boxed warning, clinicians and patients are advised to consider an increased risk of serious infections, malignancy, and cardiovascular-related mortality in individuals older than 50 years.

In response, Mr. Iskander said that the data were collected and analyzed prior to the change in labeling. He acknowledged that this study was not designed to capture long-term risks, such as cardiovascular disease or malignancy. In this analysis, the safety and tolerability of JAKi and bDMARDs appeared comparable.
 

NEJM published study leading to boxed warning

Just a week prior to the CRA annual meeting, the New England Journal of Medicine published an FDA-mandated postmarketing trial of tofacitinib that was used by the agency to justify the boxed warning for JAKi with indications for artitis and other inflammatory diseases. In that open-label trial, more than 4,000 patients aged 50 years or older with at least one additional cardiovascular risk factor were randomized to 5 mg tofacitinib twice daily, 10 mg tofacitinib twice daily, or a TNFi (adalimumab or etanercept).

The efficacy of the therapies was similar, but tofacitinib failed to meet predefined noninferiority criteria for the co–primary endpoints of MACE or cancer (excluding nonmelanoma skin cancer). For tofacitinib relative to TNFi, the hazard ratio was 1.33 for MACE and 1.48 for cancers. The JAKi was also associated with higher incidences of opportunistic infections.

Mr. Iskander noted that Canadian clinical practice guidelines currently identify JAKi as a reasonable first-line alternative to bDMARDs after inadequate response to csDMARDs. While his data support that position, Dr. Twilt indicated that the benefit-to-risk ratio of JAKi might need recalculation based on the data that led the FDA to issue its boxed warning. She questioned whether the language regarding the relative role of JAKi and bDMARDs will change in coming RA guideline revisions.

Dr. Iskander reported no potential conflicts of interest. Dr. Movahedi did not list any personal conflicts of interest but acknowledged that OBRI received unrestricted grants from a variety of pharmaceutical companies, including those that manufacture bDMARDs and JAKi. Dr. Twilt reported no potential conflicts of interest.

Several relatively large real-world analyses of Janus kinase inhibitors (JAKi) in patients with rheumatoid arthritis appear to show that the oral small-molecule drugs are discontinued and retained at rates similar to or better than biologic disease-modifying antirheumatic drugs (bDMARDs), including tumor necrosis factor inhibitors (TNFi), according to studies presented at the annual meeting of the Canadian Rheumatology Association.

The findings of these studies, although conducted prior to the Food and Drug Administration’s September 2021 announcement of a boxed warning for JAKi, do not lend support to the warning’s message of higher risks of major adverse cardiovascular events (MACE), blood clots, cancer, and death associated with JAKi.

In one study, discontinuation of JAKi-class drugs was less common than discontinuation of bDMARD-class drugs, including tumor necrosis factor inhibitors (TNFi), according to a multicenter team of investigators led by Janet Pope, MD, a professor in the division of rheumatology at the University of Western Ontario, London.

The greater durability of the JAKi relative to TNFi “seem to be driven by a greater loss of efficacy in bDMARDs over time,” reported Samir Magdy Iskander, a medical student at the university, who presented the data.
 

JAKi rival bDMARDs for long-term retention

In a separate but larger analysis, the retention rates with the JAKi tofacitinib (Xeljanz) and TNFi in two RA registries in Canada were about the same after a mean follow-up of 23.2 months (36.9% vs. 37.5%), but the tofacitinib group was at a relative disadvantage. Relative to the bDMARD group, patients taking JAKi were more likely to have had prior treatment with a bDMARD (66.9% vs. 33.9%), to have a higher median baseline Clinical Disease Activity Index (CDAI) score (22.1 vs. 20.0; P < .05), and to be older (59.5 vs. 57.6 years).

In this study, 1,318 patients with RA enrolled in the Ontario Best Practices Research Initiative (OBRI) or a Quebec cohort called RHUMADATA were evaluated, reported Mohammad Movahedi, MD, PhD, of the Institute of Health Policy, Management, and Evaluation at the University of Toronto.

“We have not yet analyzed the reasons for discontinuation, but the data show that retention is about the same, meaning that selection of one agent over the other should be tailored according to patient characteristics,” Dr. Movahedi said.

Reasons for discontinuation were presented in the other observational study, which included 333 adult patients with RA from two centers in Ontario. The discontinuation rate for adverse events was approximately 20% in both groups (HR, 1.0005; P = .98). However, the discontinuation rate for lack of efficacy favored the JAKi, reaching statistical significance.
 

TNFi failure for lack of efficacy is higher

“For lack of efficacy, the discontinuation rate was about 35% lower on the JAKi [HR, 0.6543; P = .029],” Mr. Iskander reported. Relative to those taking a TNFi, those on a JAKi demonstrated “greater durability regardless of gender, age, disease duration, and prior lines of therapy.”

In a population of patients who have not achieved an adequate response to conventional synthetic DMARDs (csDMARDs), which describes the study population from the two Ontario centers, JAKi “may be considered as a preferable method of treatment,” Mr. Iskander said.

Pointing out that many clinicians have interpreted the boxed warning as a relative contraindication for use of JAKi as first-line therapy in patients with an inadequate response to csDMARDs, Marinka Twilt, MD, PhD, the moderator of the scientific session where these data were presented, questioned the conclusion. In the boxed warning, clinicians and patients are advised to consider an increased risk of serious infections, malignancy, and cardiovascular-related mortality in individuals older than 50 years.

In response, Mr. Iskander said that the data were collected and analyzed prior to the change in labeling. He acknowledged that this study was not designed to capture long-term risks, such as cardiovascular disease or malignancy. In this analysis, the safety and tolerability of JAKi and bDMARDs appeared comparable.
 

NEJM published study leading to boxed warning

Just a week prior to the CRA annual meeting, the New England Journal of Medicine published an FDA-mandated postmarketing trial of tofacitinib that was used by the agency to justify the boxed warning for JAKi with indications for artitis and other inflammatory diseases. In that open-label trial, more than 4,000 patients aged 50 years or older with at least one additional cardiovascular risk factor were randomized to 5 mg tofacitinib twice daily, 10 mg tofacitinib twice daily, or a TNFi (adalimumab or etanercept).

The efficacy of the therapies was similar, but tofacitinib failed to meet predefined noninferiority criteria for the co–primary endpoints of MACE or cancer (excluding nonmelanoma skin cancer). For tofacitinib relative to TNFi, the hazard ratio was 1.33 for MACE and 1.48 for cancers. The JAKi was also associated with higher incidences of opportunistic infections.

Mr. Iskander noted that Canadian clinical practice guidelines currently identify JAKi as a reasonable first-line alternative to bDMARDs after inadequate response to csDMARDs. While his data support that position, Dr. Twilt indicated that the benefit-to-risk ratio of JAKi might need recalculation based on the data that led the FDA to issue its boxed warning. She questioned whether the language regarding the relative role of JAKi and bDMARDs will change in coming RA guideline revisions.

Dr. Iskander reported no potential conflicts of interest. Dr. Movahedi did not list any personal conflicts of interest but acknowledged that OBRI received unrestricted grants from a variety of pharmaceutical companies, including those that manufacture bDMARDs and JAKi. Dr. Twilt reported no potential conflicts of interest.

In the clinical experience of George Han, MD, PhD, treatment of psoriasis currently is often taxing for patients, with wait times to see a dermatologist exceeding 30 days in many markets and patients who present to him having cycled through many providers seeking relief from their disease.

“They come in with bags of topical products to show you what they’ve tried,” Dr. Han, associate professor of dermatology at Hofstra University, Hempstead, N.Y., said during the ODAC Dermatology, Aesthetic & Surgical Conference. “And you’re supposed to see this patient, talk to them, and counsel them in about 10 minutes. How do you make time to conduct an efficient psoriasis visit?”

Patients have a long-term battle to get clear, and spending a little longer on the initial visit “pays a lot of dividends,” he said. “Some of these patients are the most thankful patients in our practices, and it truly is gratifying” to see how much they can improve.
 

Questions about diet

Dr. Han said that psoriasis patients often ask him if, what, or how much they’re eating affects their disease. “But how do you counsel patients about diet when we’re not dietitians? We can at least give some guidance based on available data.”

He referred to a nationwide study of psoriasis patient-reported outcomes and dietary behaviors, which found that the percentage of patients who reported skin improvement was greatest after reducing intake of alcohol (53.8%); gluten (53.4%); and nightshade vegetables, such as tomatoes, potatoes, and peppers (52.1%); and after adding fish oil/omega-3 (44.6%), vegetables (42.5%), and oral vitamin D (41%). He noted that there is a threefold increased incidence of celiac disease in patients with psoriasis.

As for nightshade vegetables, intake leads to increased alkaloids, “which have been known to worsen bowel inflammation such as in IBD [inflammatory bowel disease], but there is a lack of controlled trials examining this in the overall psoriasis population,” Dr. Han said. The Mediterranean diet, he added, “is sensible, and adding olive oil to your diet seems to have a positive effect on ... PASI, while fish oil seems to reduce C-reactive protein.” The data on the effect of vitamin D supplements are mixed, he said.

A separate randomized study evaluated the impact of weight loss in overweight or obese patients with psoriasis, who had not achieved clearance after 4 weeks of systemic treatment. Significantly more of those in the dietary intervention arm reached the weight loss goal of 5% at 20 weeks, and patients in this arm had a median reduction in the Psoriasis Area and Severity Index (PASI) score of almost 50%, compared with almost 26% among those without an active dietary intervention.
 

Joint pain, PsA

For psoriasis patients who complain of joint pain, he recommends administering quick measures like the five-question Psoriasis Epidemiology Screening Test (PEST) to screen for psoriatic arthritis (PsA), which is available on the National Psoriasis Foundation web site. “I ask patients about swollen, tender joints – specifically hands, wrists, ankles, feet, and toes,” Dr. Han said. Joint stiffness in the morning is a “concerning finding,” which is “more indicative of psoriatic arthritis than vague knee or back pain that worsens with use. If you have a younger patient with back pain who has a reduced ability to flex their spine, think axial disease.”

Tumor necrosis factor (TNF)–alpha inhibitors are considered first- and second-line treatment for PsA, but interleukin (IL)–17 inhibitors are generally considered just as effective overall. “The IL-23 inhibitors have mixed signals,” said Dr. Han, who is also on the NPF’s medical board. “We know that guselkumab is effective against psoriatic arthritis, but there is no inhibition of joint progression at the approved dosage on the label – though it was pretty close.”

Risankizumab (Skyrizi), an IL-23 inhibitor, was approved in January 2022 for adults with PsA and while the American College of Rheumatology response data “look reasonably good, the results for inhibition of radiographic progression are quite far off and it’s not in the label,” he said. Tildrakizumab (Ilumya), an IL-23 inhibitor, “looks impressive in phase 2b trials. It will be interesting to see if there is differentiation between the IL-23 agents in treating joint disease going forward.”

Dr. Han considers biologic therapy a good option for patients with questionable joint involvement or very limited joint disease. “If the patient has some evidence of PsA, as long as it’s a medication that has approval for that, I’m OK with starting it,” he said. “However, for patients whose joint pain dominates over the skin, or [who] have severe joint disease at presentation, I would prioritize the TNF-alpha inhibitors and IL-17s and refer them to rheumatology for shared management.”
 

Topical, oral treatments

As for topical approaches to treating psoriasis, adding halobetasol propionate 0.01% to tazarotene 0.045% may have a synergistic effect, while tapinarof 1% cream holds promise, he said. Tapinarof, which is expected to be approved this year, is an investigative aryl hydrocarbon agonist that inhibits an array of proinflammatory cytokines, including interferon-gamma and TNF-alpha. “It has been shown to have inhibitory effects both on Th17 cytokines and Th2 cytokines,” Dr. Han said. “What’s nice about this is that patients still appear to have treatment effect 1-2 months after stopping the drug.”

Another topical agent now under FDA review for psoriasis, is roflumilast, a phosphodiesterase type 4 (PDE4) inhibitor, which has been shown to have a treatment efficacy of 30% or more. “We’ll see how this works into our treatment regimen for psoriasis,” he said, as strategies targeting PDE4 have already been reported to help treat psoriasis.

With regards to oral therapies, he said that there are concerns about the efficacy of the oral PDE4 inhibitor apremilast, approved for psoriasis, compared with other biologics. Deucravacitinib, an oral selective tyrosine kinase 2 (TYK2) inhibitor also under FDA review for psoriasis, “may fill this gap, because its efficacy seems much stronger and really capitalizes on blocking IL-23, which we know is a central pathway in the pathogenesis of psoriasis.”

Phototherapy is another treatment option. Home narrowband-UVB devices cost $3,000-$5,000, “which is a fraction of 1 year of biologic treatment,” Dr. Han said. Older data on phototherapy suggest that “lesions can clear within 2-3 months, depending on how often you do the phototherapy, while newer data suggest that 75% of patients can achieve clear or minimal disease” with phototherapy.

Biologic therapy

If patients meet criteria for treatment with a biologic, he begins the conversation by saying, “I don’t want to give you an immunosuppressant, but your psoriasis represents an overactivation of inflammation in your body, so in some way we have to bring that down. Ideally, we would target your immune system in a way that targets psoriasis very narrowly, while leaving it to do what it needs to: protecting against infections and neoplasia.”

XXXIL-17 inhibitors generally have the fastest onset of action, Dr. Han noted. Authors of a review paper found that achievement of Psoriasis Area and Severity Index (PASI) 50 was 1.8 weeks with brodalumab, 1.9 weeks for ixekizumab, 3 weeks for high-dose secukinumab, 3.5 weeks for adalimumab, 3.7 weeks for infliximab, 5.1 weeks for low-dose ustekinumab, 6.5 weeks for high-dose etanercept, and 10.9 weeks with low-dose etanercept, while achievement of PASI 50 was closer to 1 month for IL-23 inhibitors.

“The conversation I have with patients on IL-23 inhibitors is, ‘we’re in this for the long haul,’ otherwise they come in 2 months later,” he said. “They may have gotten clearer but we’re talking about getting well over half of our patients to PASI 100, or to clear or minimal disease, and they may not have gotten there yet. It helps to frame expectations.”

Dr. Han disclosed that he is a consultant to, a speaker for, or has received research support from Beiersdorf, CeraVe, Celgene, Janssen, Lilly, MC2, Pfizer, UCB, Boehringer Ingelheim, Bond Avillion, Athenex, Amgen, AbbVie, Regeneron/Sanofi, LEO Pharma, Ortho Dermatologics, BMS, Sun Pharma, Dermavant, Dermtech, MedX, Novartis, and Castle Biosciences.

In the clinical experience of George Han, MD, PhD, treatment of psoriasis currently is often taxing for patients, with wait times to see a dermatologist exceeding 30 days in many markets and patients who present to him having cycled through many providers seeking relief from their disease.

“They come in with bags of topical products to show you what they’ve tried,” Dr. Han, associate professor of dermatology at Hofstra University, Hempstead, N.Y., said during the ODAC Dermatology, Aesthetic & Surgical Conference. “And you’re supposed to see this patient, talk to them, and counsel them in about 10 minutes. How do you make time to conduct an efficient psoriasis visit?”

Patients have a long-term battle to get clear, and spending a little longer on the initial visit “pays a lot of dividends,” he said. “Some of these patients are the most thankful patients in our practices, and it truly is gratifying” to see how much they can improve.
 

Questions about diet

Dr. Han said that psoriasis patients often ask him if, what, or how much they’re eating affects their disease. “But how do you counsel patients about diet when we’re not dietitians? We can at least give some guidance based on available data.”

He referred to a nationwide study of psoriasis patient-reported outcomes and dietary behaviors, which found that the percentage of patients who reported skin improvement was greatest after reducing intake of alcohol (53.8%); gluten (53.4%); and nightshade vegetables, such as tomatoes, potatoes, and peppers (52.1%); and after adding fish oil/omega-3 (44.6%), vegetables (42.5%), and oral vitamin D (41%). He noted that there is a threefold increased incidence of celiac disease in patients with psoriasis.

As for nightshade vegetables, intake leads to increased alkaloids, “which have been known to worsen bowel inflammation such as in IBD [inflammatory bowel disease], but there is a lack of controlled trials examining this in the overall psoriasis population,” Dr. Han said. The Mediterranean diet, he added, “is sensible, and adding olive oil to your diet seems to have a positive effect on ... PASI, while fish oil seems to reduce C-reactive protein.” The data on the effect of vitamin D supplements are mixed, he said.

A separate randomized study evaluated the impact of weight loss in overweight or obese patients with psoriasis, who had not achieved clearance after 4 weeks of systemic treatment. Significantly more of those in the dietary intervention arm reached the weight loss goal of 5% at 20 weeks, and patients in this arm had a median reduction in the Psoriasis Area and Severity Index (PASI) score of almost 50%, compared with almost 26% among those without an active dietary intervention.
 

Joint pain, PsA

For psoriasis patients who complain of joint pain, he recommends administering quick measures like the five-question Psoriasis Epidemiology Screening Test (PEST) to screen for psoriatic arthritis (PsA), which is available on the National Psoriasis Foundation web site. “I ask patients about swollen, tender joints – specifically hands, wrists, ankles, feet, and toes,” Dr. Han said. Joint stiffness in the morning is a “concerning finding,” which is “more indicative of psoriatic arthritis than vague knee or back pain that worsens with use. If you have a younger patient with back pain who has a reduced ability to flex their spine, think axial disease.”

Tumor necrosis factor (TNF)–alpha inhibitors are considered first- and second-line treatment for PsA, but interleukin (IL)–17 inhibitors are generally considered just as effective overall. “The IL-23 inhibitors have mixed signals,” said Dr. Han, who is also on the NPF’s medical board. “We know that guselkumab is effective against psoriatic arthritis, but there is no inhibition of joint progression at the approved dosage on the label – though it was pretty close.”

Risankizumab (Skyrizi), an IL-23 inhibitor, was approved in January 2022 for adults with PsA and while the American College of Rheumatology response data “look reasonably good, the results for inhibition of radiographic progression are quite far off and it’s not in the label,” he said. Tildrakizumab (Ilumya), an IL-23 inhibitor, “looks impressive in phase 2b trials. It will be interesting to see if there is differentiation between the IL-23 agents in treating joint disease going forward.”

Dr. Han considers biologic therapy a good option for patients with questionable joint involvement or very limited joint disease. “If the patient has some evidence of PsA, as long as it’s a medication that has approval for that, I’m OK with starting it,” he said. “However, for patients whose joint pain dominates over the skin, or [who] have severe joint disease at presentation, I would prioritize the TNF-alpha inhibitors and IL-17s and refer them to rheumatology for shared management.”
 

Topical, oral treatments

As for topical approaches to treating psoriasis, adding halobetasol propionate 0.01% to tazarotene 0.045% may have a synergistic effect, while tapinarof 1% cream holds promise, he said. Tapinarof, which is expected to be approved this year, is an investigative aryl hydrocarbon agonist that inhibits an array of proinflammatory cytokines, including interferon-gamma and TNF-alpha. “It has been shown to have inhibitory effects both on Th17 cytokines and Th2 cytokines,” Dr. Han said. “What’s nice about this is that patients still appear to have treatment effect 1-2 months after stopping the drug.”

Another topical agent now under FDA review for psoriasis, is roflumilast, a phosphodiesterase type 4 (PDE4) inhibitor, which has been shown to have a treatment efficacy of 30% or more. “We’ll see how this works into our treatment regimen for psoriasis,” he said, as strategies targeting PDE4 have already been reported to help treat psoriasis.

With regards to oral therapies, he said that there are concerns about the efficacy of the oral PDE4 inhibitor apremilast, approved for psoriasis, compared with other biologics. Deucravacitinib, an oral selective tyrosine kinase 2 (TYK2) inhibitor also under FDA review for psoriasis, “may fill this gap, because its efficacy seems much stronger and really capitalizes on blocking IL-23, which we know is a central pathway in the pathogenesis of psoriasis.”

Phototherapy is another treatment option. Home narrowband-UVB devices cost $3,000-$5,000, “which is a fraction of 1 year of biologic treatment,” Dr. Han said. Older data on phototherapy suggest that “lesions can clear within 2-3 months, depending on how often you do the phototherapy, while newer data suggest that 75% of patients can achieve clear or minimal disease” with phototherapy.

Biologic therapy

If patients meet criteria for treatment with a biologic, he begins the conversation by saying, “I don’t want to give you an immunosuppressant, but your psoriasis represents an overactivation of inflammation in your body, so in some way we have to bring that down. Ideally, we would target your immune system in a way that targets psoriasis very narrowly, while leaving it to do what it needs to: protecting against infections and neoplasia.”

XXXIL-17 inhibitors generally have the fastest onset of action, Dr. Han noted. Authors of a review paper found that achievement of Psoriasis Area and Severity Index (PASI) 50 was 1.8 weeks with brodalumab, 1.9 weeks for ixekizumab, 3 weeks for high-dose secukinumab, 3.5 weeks for adalimumab, 3.7 weeks for infliximab, 5.1 weeks for low-dose ustekinumab, 6.5 weeks for high-dose etanercept, and 10.9 weeks with low-dose etanercept, while achievement of PASI 50 was closer to 1 month for IL-23 inhibitors.

“The conversation I have with patients on IL-23 inhibitors is, ‘we’re in this for the long haul,’ otherwise they come in 2 months later,” he said. “They may have gotten clearer but we’re talking about getting well over half of our patients to PASI 100, or to clear or minimal disease, and they may not have gotten there yet. It helps to frame expectations.”

Dr. Han disclosed that he is a consultant to, a speaker for, or has received research support from Beiersdorf, CeraVe, Celgene, Janssen, Lilly, MC2, Pfizer, UCB, Boehringer Ingelheim, Bond Avillion, Athenex, Amgen, AbbVie, Regeneron/Sanofi, LEO Pharma, Ortho Dermatologics, BMS, Sun Pharma, Dermavant, Dermtech, MedX, Novartis, and Castle Biosciences.

In the clinical experience of George Han, MD, PhD, treatment of psoriasis currently is often taxing for patients, with wait times to see a dermatologist exceeding 30 days in many markets and patients who present to him having cycled through many providers seeking relief from their disease.

“They come in with bags of topical products to show you what they’ve tried,” Dr. Han, associate professor of dermatology at Hofstra University, Hempstead, N.Y., said during the ODAC Dermatology, Aesthetic & Surgical Conference. “And you’re supposed to see this patient, talk to them, and counsel them in about 10 minutes. How do you make time to conduct an efficient psoriasis visit?”

Patients have a long-term battle to get clear, and spending a little longer on the initial visit “pays a lot of dividends,” he said. “Some of these patients are the most thankful patients in our practices, and it truly is gratifying” to see how much they can improve.
 

Questions about diet

Dr. Han said that psoriasis patients often ask him if, what, or how much they’re eating affects their disease. “But how do you counsel patients about diet when we’re not dietitians? We can at least give some guidance based on available data.”

He referred to a nationwide study of psoriasis patient-reported outcomes and dietary behaviors, which found that the percentage of patients who reported skin improvement was greatest after reducing intake of alcohol (53.8%); gluten (53.4%); and nightshade vegetables, such as tomatoes, potatoes, and peppers (52.1%); and after adding fish oil/omega-3 (44.6%), vegetables (42.5%), and oral vitamin D (41%). He noted that there is a threefold increased incidence of celiac disease in patients with psoriasis.

As for nightshade vegetables, intake leads to increased alkaloids, “which have been known to worsen bowel inflammation such as in IBD [inflammatory bowel disease], but there is a lack of controlled trials examining this in the overall psoriasis population,” Dr. Han said. The Mediterranean diet, he added, “is sensible, and adding olive oil to your diet seems to have a positive effect on ... PASI, while fish oil seems to reduce C-reactive protein.” The data on the effect of vitamin D supplements are mixed, he said.

A separate randomized study evaluated the impact of weight loss in overweight or obese patients with psoriasis, who had not achieved clearance after 4 weeks of systemic treatment. Significantly more of those in the dietary intervention arm reached the weight loss goal of 5% at 20 weeks, and patients in this arm had a median reduction in the Psoriasis Area and Severity Index (PASI) score of almost 50%, compared with almost 26% among those without an active dietary intervention.
 

Joint pain, PsA

For psoriasis patients who complain of joint pain, he recommends administering quick measures like the five-question Psoriasis Epidemiology Screening Test (PEST) to screen for psoriatic arthritis (PsA), which is available on the National Psoriasis Foundation web site. “I ask patients about swollen, tender joints – specifically hands, wrists, ankles, feet, and toes,” Dr. Han said. Joint stiffness in the morning is a “concerning finding,” which is “more indicative of psoriatic arthritis than vague knee or back pain that worsens with use. If you have a younger patient with back pain who has a reduced ability to flex their spine, think axial disease.”

Tumor necrosis factor (TNF)–alpha inhibitors are considered first- and second-line treatment for PsA, but interleukin (IL)–17 inhibitors are generally considered just as effective overall. “The IL-23 inhibitors have mixed signals,” said Dr. Han, who is also on the NPF’s medical board. “We know that guselkumab is effective against psoriatic arthritis, but there is no inhibition of joint progression at the approved dosage on the label – though it was pretty close.”

Risankizumab (Skyrizi), an IL-23 inhibitor, was approved in January 2022 for adults with PsA and while the American College of Rheumatology response data “look reasonably good, the results for inhibition of radiographic progression are quite far off and it’s not in the label,” he said. Tildrakizumab (Ilumya), an IL-23 inhibitor, “looks impressive in phase 2b trials. It will be interesting to see if there is differentiation between the IL-23 agents in treating joint disease going forward.”

Dr. Han considers biologic therapy a good option for patients with questionable joint involvement or very limited joint disease. “If the patient has some evidence of PsA, as long as it’s a medication that has approval for that, I’m OK with starting it,” he said. “However, for patients whose joint pain dominates over the skin, or [who] have severe joint disease at presentation, I would prioritize the TNF-alpha inhibitors and IL-17s and refer them to rheumatology for shared management.”
 

Topical, oral treatments

As for topical approaches to treating psoriasis, adding halobetasol propionate 0.01% to tazarotene 0.045% may have a synergistic effect, while tapinarof 1% cream holds promise, he said. Tapinarof, which is expected to be approved this year, is an investigative aryl hydrocarbon agonist that inhibits an array of proinflammatory cytokines, including interferon-gamma and TNF-alpha. “It has been shown to have inhibitory effects both on Th17 cytokines and Th2 cytokines,” Dr. Han said. “What’s nice about this is that patients still appear to have treatment effect 1-2 months after stopping the drug.”

Another topical agent now under FDA review for psoriasis, is roflumilast, a phosphodiesterase type 4 (PDE4) inhibitor, which has been shown to have a treatment efficacy of 30% or more. “We’ll see how this works into our treatment regimen for psoriasis,” he said, as strategies targeting PDE4 have already been reported to help treat psoriasis.

With regards to oral therapies, he said that there are concerns about the efficacy of the oral PDE4 inhibitor apremilast, approved for psoriasis, compared with other biologics. Deucravacitinib, an oral selective tyrosine kinase 2 (TYK2) inhibitor also under FDA review for psoriasis, “may fill this gap, because its efficacy seems much stronger and really capitalizes on blocking IL-23, which we know is a central pathway in the pathogenesis of psoriasis.”

Phototherapy is another treatment option. Home narrowband-UVB devices cost $3,000-$5,000, “which is a fraction of 1 year of biologic treatment,” Dr. Han said. Older data on phototherapy suggest that “lesions can clear within 2-3 months, depending on how often you do the phototherapy, while newer data suggest that 75% of patients can achieve clear or minimal disease” with phototherapy.

Biologic therapy

If patients meet criteria for treatment with a biologic, he begins the conversation by saying, “I don’t want to give you an immunosuppressant, but your psoriasis represents an overactivation of inflammation in your body, so in some way we have to bring that down. Ideally, we would target your immune system in a way that targets psoriasis very narrowly, while leaving it to do what it needs to: protecting against infections and neoplasia.”

XXXIL-17 inhibitors generally have the fastest onset of action, Dr. Han noted. Authors of a review paper found that achievement of Psoriasis Area and Severity Index (PASI) 50 was 1.8 weeks with brodalumab, 1.9 weeks for ixekizumab, 3 weeks for high-dose secukinumab, 3.5 weeks for adalimumab, 3.7 weeks for infliximab, 5.1 weeks for low-dose ustekinumab, 6.5 weeks for high-dose etanercept, and 10.9 weeks with low-dose etanercept, while achievement of PASI 50 was closer to 1 month for IL-23 inhibitors.

“The conversation I have with patients on IL-23 inhibitors is, ‘we’re in this for the long haul,’ otherwise they come in 2 months later,” he said. “They may have gotten clearer but we’re talking about getting well over half of our patients to PASI 100, or to clear or minimal disease, and they may not have gotten there yet. It helps to frame expectations.”

Dr. Han disclosed that he is a consultant to, a speaker for, or has received research support from Beiersdorf, CeraVe, Celgene, Janssen, Lilly, MC2, Pfizer, UCB, Boehringer Ingelheim, Bond Avillion, Athenex, Amgen, AbbVie, Regeneron/Sanofi, LEO Pharma, Ortho Dermatologics, BMS, Sun Pharma, Dermavant, Dermtech, MedX, Novartis, and Castle Biosciences.

Current selection criteria for autologous hematopoietic stem cell transplant (AHSCT) in patients with rapidly progressing systemic sclerosis were validated in a study presented at the annual meeting of the Canadian Rheumatology Association.

The study, which associated AHSCT with improvement in overall survival and an acceptable risk of adverse events, “provides valuable real-world, long-term data pertaining to key clinical outcomes to support the use of AHSCT in patients with rapidly progressing systemic sclerosis,” reported Nancy Maltez, MD, a rheumatologist and clinical investigator who is on the faculty of the University of Ottawa.

Fnaq / Wikimedia Commons / CC BY-SA 4.0

The prospective study enrolled 85 patients in Canada and 41 patients in France with rapidly progressing systemic sclerosis. The patients in both countries were enrolled with the same eligibility criteria for AHSCT, but patients in France underwent AHSCT while the patients in Canada were treated with conventional therapies, such as cyclophosphamide.

On the primary outcome of overall survival, the Kaplan-Meier curve split almost immediately in favor of AHSCT. At 4 years, more than 25% of patients in the conventional therapy group had died versus less than 5% of those who underwent AHSCT. Although the mortality curve did slope downwards in the AHSCT group over the subsequent 6 years of follow-up, it largely paralleled and remained superior to convention therapy.
 

About 50% survival advantage seen for AHSCT

In this nonrandomized study, the statistical survival advantage of AHSCT was not provided, but the survival graph showed about 75% survival at 8 years of follow-up in the AHSCT group, compared with about 50% survival in the conventional-therapy group.

Many of the secondary outcomes, including those evaluating skin involvement, preservation of lung function, and absence of renal complications also favored AHSCT, according to Dr. Maltez.

On the modified Rodnan skin score, a significant difference (P < .001) observed at 12 months was sustained at 36 months, when the score was 4.48 points lower among patients treated with AHSCT. The difference in forced vital capacity (FVC) was about 10% higher (P < .0001) in the AHSCT group.

Over long-term follow-up, the incidence of scleroderma renal crisis per 100 person-years was 6.02 cases in the conventional therapy group versus 0.58 cases (P < .001) in the AHSCT group. There was no significant difference in the proportion of patients in the two groups receiving a pacemaker over the course of follow-up, but the rate of new malignancies per 100 person-years was 3.71 in the conventional care group versus 0.58 (P < .001) in the AHSCT group.

Significant complications attributed to AHSCT were uncommon. This is important, because AHSCT was not uniformly well tolerated in the initial trials. The first of three randomized trials with AHSCT in progressive systemic sclerosis was published more than 10 years ago after a series of promising early phase trials. Each associated AHSCT with benefit, but patient selection appeared to be important.

In the ASSIST trial of 2011, AHSCT was associated with significant reductions in skin involvement and improvements in pulmonary function relative to cyclophosphamide, but enrollment was stopped after only 19 patients, and follow-up extended to only 2 years.

Substantial AHSCT-related mortality in ASTIS

In the second trial, called ASTIS, AHSCT was associated with a higher rate of mortality than cyclophosphamide after 1 year of follow-up, although there was a significantly greater long-term event-free survival for AHSCT when patients were followed out to 4 years. This study reinforced the need for cardiac screening because of because of concern that severe cardiac compromise contributed to the increased risk of AHSCT-related mortality.

The SCOT trial employed a high-intensity myeloablative conditioning regimen and total body irradiation prior to AHSCT. It is not clear that these contributed to improved survival, particularly because of the risk for irradiation to exacerbate complications in the lung and kidney, but AHSCT-related mortality was only 3% at 54 months. Patient enrollment criteria in this trial were also suspected of having played a role in the favorable results.

In the Canadian-French collaborative study, patients were considered eligible for AHSCT if they met the enrollment criteria used in the ASTIS trial, according to Dr. Maltez. She attributed the low rates of early mortality and relative absence of transplant-related death to the lessons learned in the published trials.

Overall, the data support the routine but selective use of AHSCT in rapidly progressing systemic sclerosis, Dr. Maltez concluded.

Maria Carolina Oliveira, MD, of the department of internal medicine at the University of São Paulo, generally agreed. A coauthor of a recent review of AHSCT for systemic sclerosis, Dr. Oliveira emphasized that patient selection is critical.

“AHSCT for systemic sclerosis has very specific inclusion criteria. Indeed, it is indicated for patients with severe and progressive disease but under two specific conditions: severe and progressive diffuse skin involvement and/or progressive interstitial lung disease,” she said in an interview.

Because of the thin line between benefit and risk according to disease subtypes and comorbidities, she said that it is important to be aware of relative contraindications and to recognize the risks of AHSCT.

At this time, and in the absence of better biomarkers to identify those most likely to benefit, “patients with other forms of severe scleroderma, such as those with pulmonary hypertension, scleroderma renal crisis, or severe cardiac involvement, for example, are not eligible,” she said.

Dr. Maltez and Dr. Oliveira reported having no potential conflicts of interest.

Current selection criteria for autologous hematopoietic stem cell transplant (AHSCT) in patients with rapidly progressing systemic sclerosis were validated in a study presented at the annual meeting of the Canadian Rheumatology Association.

The study, which associated AHSCT with improvement in overall survival and an acceptable risk of adverse events, “provides valuable real-world, long-term data pertaining to key clinical outcomes to support the use of AHSCT in patients with rapidly progressing systemic sclerosis,” reported Nancy Maltez, MD, a rheumatologist and clinical investigator who is on the faculty of the University of Ottawa.

Fnaq / Wikimedia Commons / CC BY-SA 4.0

The prospective study enrolled 85 patients in Canada and 41 patients in France with rapidly progressing systemic sclerosis. The patients in both countries were enrolled with the same eligibility criteria for AHSCT, but patients in France underwent AHSCT while the patients in Canada were treated with conventional therapies, such as cyclophosphamide.

On the primary outcome of overall survival, the Kaplan-Meier curve split almost immediately in favor of AHSCT. At 4 years, more than 25% of patients in the conventional therapy group had died versus less than 5% of those who underwent AHSCT. Although the mortality curve did slope downwards in the AHSCT group over the subsequent 6 years of follow-up, it largely paralleled and remained superior to convention therapy.
 

About 50% survival advantage seen for AHSCT

In this nonrandomized study, the statistical survival advantage of AHSCT was not provided, but the survival graph showed about 75% survival at 8 years of follow-up in the AHSCT group, compared with about 50% survival in the conventional-therapy group.

Many of the secondary outcomes, including those evaluating skin involvement, preservation of lung function, and absence of renal complications also favored AHSCT, according to Dr. Maltez.

On the modified Rodnan skin score, a significant difference (P < .001) observed at 12 months was sustained at 36 months, when the score was 4.48 points lower among patients treated with AHSCT. The difference in forced vital capacity (FVC) was about 10% higher (P < .0001) in the AHSCT group.

Over long-term follow-up, the incidence of scleroderma renal crisis per 100 person-years was 6.02 cases in the conventional therapy group versus 0.58 cases (P < .001) in the AHSCT group. There was no significant difference in the proportion of patients in the two groups receiving a pacemaker over the course of follow-up, but the rate of new malignancies per 100 person-years was 3.71 in the conventional care group versus 0.58 (P < .001) in the AHSCT group.

Significant complications attributed to AHSCT were uncommon. This is important, because AHSCT was not uniformly well tolerated in the initial trials. The first of three randomized trials with AHSCT in progressive systemic sclerosis was published more than 10 years ago after a series of promising early phase trials. Each associated AHSCT with benefit, but patient selection appeared to be important.

In the ASSIST trial of 2011, AHSCT was associated with significant reductions in skin involvement and improvements in pulmonary function relative to cyclophosphamide, but enrollment was stopped after only 19 patients, and follow-up extended to only 2 years.

Substantial AHSCT-related mortality in ASTIS

In the second trial, called ASTIS, AHSCT was associated with a higher rate of mortality than cyclophosphamide after 1 year of follow-up, although there was a significantly greater long-term event-free survival for AHSCT when patients were followed out to 4 years. This study reinforced the need for cardiac screening because of because of concern that severe cardiac compromise contributed to the increased risk of AHSCT-related mortality.

The SCOT trial employed a high-intensity myeloablative conditioning regimen and total body irradiation prior to AHSCT. It is not clear that these contributed to improved survival, particularly because of the risk for irradiation to exacerbate complications in the lung and kidney, but AHSCT-related mortality was only 3% at 54 months. Patient enrollment criteria in this trial were also suspected of having played a role in the favorable results.

In the Canadian-French collaborative study, patients were considered eligible for AHSCT if they met the enrollment criteria used in the ASTIS trial, according to Dr. Maltez. She attributed the low rates of early mortality and relative absence of transplant-related death to the lessons learned in the published trials.

Overall, the data support the routine but selective use of AHSCT in rapidly progressing systemic sclerosis, Dr. Maltez concluded.

Maria Carolina Oliveira, MD, of the department of internal medicine at the University of São Paulo, generally agreed. A coauthor of a recent review of AHSCT for systemic sclerosis, Dr. Oliveira emphasized that patient selection is critical.

“AHSCT for systemic sclerosis has very specific inclusion criteria. Indeed, it is indicated for patients with severe and progressive disease but under two specific conditions: severe and progressive diffuse skin involvement and/or progressive interstitial lung disease,” she said in an interview.

Because of the thin line between benefit and risk according to disease subtypes and comorbidities, she said that it is important to be aware of relative contraindications and to recognize the risks of AHSCT.

At this time, and in the absence of better biomarkers to identify those most likely to benefit, “patients with other forms of severe scleroderma, such as those with pulmonary hypertension, scleroderma renal crisis, or severe cardiac involvement, for example, are not eligible,” she said.

Dr. Maltez and Dr. Oliveira reported having no potential conflicts of interest.

Current selection criteria for autologous hematopoietic stem cell transplant (AHSCT) in patients with rapidly progressing systemic sclerosis were validated in a study presented at the annual meeting of the Canadian Rheumatology Association.

The study, which associated AHSCT with improvement in overall survival and an acceptable risk of adverse events, “provides valuable real-world, long-term data pertaining to key clinical outcomes to support the use of AHSCT in patients with rapidly progressing systemic sclerosis,” reported Nancy Maltez, MD, a rheumatologist and clinical investigator who is on the faculty of the University of Ottawa.

Fnaq / Wikimedia Commons / CC BY-SA 4.0

The prospective study enrolled 85 patients in Canada and 41 patients in France with rapidly progressing systemic sclerosis. The patients in both countries were enrolled with the same eligibility criteria for AHSCT, but patients in France underwent AHSCT while the patients in Canada were treated with conventional therapies, such as cyclophosphamide.

On the primary outcome of overall survival, the Kaplan-Meier curve split almost immediately in favor of AHSCT. At 4 years, more than 25% of patients in the conventional therapy group had died versus less than 5% of those who underwent AHSCT. Although the mortality curve did slope downwards in the AHSCT group over the subsequent 6 years of follow-up, it largely paralleled and remained superior to convention therapy.
 

About 50% survival advantage seen for AHSCT

In this nonrandomized study, the statistical survival advantage of AHSCT was not provided, but the survival graph showed about 75% survival at 8 years of follow-up in the AHSCT group, compared with about 50% survival in the conventional-therapy group.

Many of the secondary outcomes, including those evaluating skin involvement, preservation of lung function, and absence of renal complications also favored AHSCT, according to Dr. Maltez.

On the modified Rodnan skin score, a significant difference (P < .001) observed at 12 months was sustained at 36 months, when the score was 4.48 points lower among patients treated with AHSCT. The difference in forced vital capacity (FVC) was about 10% higher (P < .0001) in the AHSCT group.

Over long-term follow-up, the incidence of scleroderma renal crisis per 100 person-years was 6.02 cases in the conventional therapy group versus 0.58 cases (P < .001) in the AHSCT group. There was no significant difference in the proportion of patients in the two groups receiving a pacemaker over the course of follow-up, but the rate of new malignancies per 100 person-years was 3.71 in the conventional care group versus 0.58 (P < .001) in the AHSCT group.

Significant complications attributed to AHSCT were uncommon. This is important, because AHSCT was not uniformly well tolerated in the initial trials. The first of three randomized trials with AHSCT in progressive systemic sclerosis was published more than 10 years ago after a series of promising early phase trials. Each associated AHSCT with benefit, but patient selection appeared to be important.

In the ASSIST trial of 2011, AHSCT was associated with significant reductions in skin involvement and improvements in pulmonary function relative to cyclophosphamide, but enrollment was stopped after only 19 patients, and follow-up extended to only 2 years.

Substantial AHSCT-related mortality in ASTIS

In the second trial, called ASTIS, AHSCT was associated with a higher rate of mortality than cyclophosphamide after 1 year of follow-up, although there was a significantly greater long-term event-free survival for AHSCT when patients were followed out to 4 years. This study reinforced the need for cardiac screening because of because of concern that severe cardiac compromise contributed to the increased risk of AHSCT-related mortality.

The SCOT trial employed a high-intensity myeloablative conditioning regimen and total body irradiation prior to AHSCT. It is not clear that these contributed to improved survival, particularly because of the risk for irradiation to exacerbate complications in the lung and kidney, but AHSCT-related mortality was only 3% at 54 months. Patient enrollment criteria in this trial were also suspected of having played a role in the favorable results.

In the Canadian-French collaborative study, patients were considered eligible for AHSCT if they met the enrollment criteria used in the ASTIS trial, according to Dr. Maltez. She attributed the low rates of early mortality and relative absence of transplant-related death to the lessons learned in the published trials.

Overall, the data support the routine but selective use of AHSCT in rapidly progressing systemic sclerosis, Dr. Maltez concluded.

Maria Carolina Oliveira, MD, of the department of internal medicine at the University of São Paulo, generally agreed. A coauthor of a recent review of AHSCT for systemic sclerosis, Dr. Oliveira emphasized that patient selection is critical.

“AHSCT for systemic sclerosis has very specific inclusion criteria. Indeed, it is indicated for patients with severe and progressive disease but under two specific conditions: severe and progressive diffuse skin involvement and/or progressive interstitial lung disease,” she said in an interview.

Because of the thin line between benefit and risk according to disease subtypes and comorbidities, she said that it is important to be aware of relative contraindications and to recognize the risks of AHSCT.

At this time, and in the absence of better biomarkers to identify those most likely to benefit, “patients with other forms of severe scleroderma, such as those with pulmonary hypertension, scleroderma renal crisis, or severe cardiac involvement, for example, are not eligible,” she said.

Dr. Maltez and Dr. Oliveira reported having no potential conflicts of interest.

Aggressive up-front combination therapy, more lofty treatment goals, and earlier and more frequent reassessments to guide treatment are improving care of patients with pulmonary arterial hypertension (PAH) while at the same time making it more complex.

A larger number of oral and generic treatment options have in some respects ushered in more management ease. But overall, “I don’t know if management of these patients has ever been more complicated, given the treatment options and strategies,” said Murali M. Chakinala, MD, professor of medicine at Washington University, St. Louis. “We’re always thinking through approaches.”

Diagnosis continues to be challenging given the rarity of PAH and its nonspecific presentation – and in some cases it’s now harder. Experts such as Dr. Chakinala are seeing increasing number of aging patients with left heart disease, chronic kidney disease, and other comorbidities who have significant precapillary pulmonary hypertension and who exhibit hemodynamics consistent with PAH, or group 1 PH.

The question experts face is, do such patients have “true PAH,” as do a reported 25-50 people per million, or do they have another type of PH in the classification schema – or a mixture?

Deciding which patients “really fit into group 1 and should be managed like group 1,” Dr. Chakinala said, requires clinical acumen and has important implications, as patients with PAH are the main beneficiaries of vasodilator therapy. Most other patients with PH will not respond to or tolerate such treatment.

“These older patients may be getting PAH through different mechanisms than our younger patients, but because we define PAH through hemodynamic criteria and by ruling out other obvious explanations, they all get lumped together,” said Dr. Chakinala. “We need to parse these patients out better in the future, much like our oncology colleagues are doing.”

Yale Rosen/Wikimedia Commons/Creative Commons Attribution-Share Alike 2.0 Generi

Personalized medicine hopefully is the next horizon for this condition, characterized by severe remodeling of the distal pulmonary arteries. Researchers are pushing to achieve deep phenotyping, identify biomarkers and improve risk assessment tools.

And with 80 or so centers now accredited by the Pulmonary Hypertension Association as Pulmonary Hypertension Care Centers, referred patients are accessing clinical trials of new nonvasodilatory drugs. Currently available therapies improve hemodynamics and symptoms, and can slow disease progression, but are not truly disease modifying, sources say.

“The endothelin, nitric oxide, and prostacyclin pathways have been exhaustively studied and we now have great drugs for those pathways,” said Dr. Chakinala, who leads the PHA’s scientific leadership council. But “we’re not going to put a greater dent into this disease until we have new drugs that work on different biologic pathways.”
 

Diagnostic challenges

The diagnosis of PAH – a remarkably heterogeneous condition that encompasses heritable forms and idiopathic forms, and that comprises a broad mix of predisposing conditions and exposures, from scleroderma to methamphetamine use – is still too often missed or delayed. Delayed diagnoses and misdiagnoses of PAH and other types of PH have been reported in up to 85% of at-risk patients, according to a 2016 literature review.

Being able to pivot from thinking about common pulmonary ailments or heart failure to considering PAH is a key part of earlier diagnosis and better treatment outcomes. “If someone has unexplained dyspnea or if they’re treated for other lung diseases and are not improving, think about a screening echocardiogram,” said Timothy L. Williamson, MD, vice president of quality and safety and a pulmonary and critical care physician at the University of Kansas Health Center, Kansas City.

One of the most common reasons Dr. Chakinala sees for missed diagnoses are right heart catheterizations that are incomplete or misinterpreted. (Right heart catheterizations are required to confirm the diagnosis.) “One can’t simply measure pressures and stop,” he said. “We need the full hemodynamic profile to know that it’s truly precapillary PAH ... and we need proper interpretation of [elements like] the waveforms.”

The 2019 World Symposium on Pulmonary Hypertension shifted the definition of PH from an arbitrarily defined mean pulmonary arterial pressure of at least 25 mm Hg at rest (as measured by right heart catheterization) to a more scientifically determined mPAP of at least 20 mm Hg.

The classification document also requires pulmonary vascular resistance (PVR) of at least 3 Wood units in the definition of all forms of precapillary PH. PAH specifically is defined as the presence of mPAP of at least 20 mm Hg, PVR of at least 3 Wood units, and pulmonary arterial wedge pressure 15 mm Hg or less.
 

Trends in treatment

The value of initial combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 (PDE5) inhibitor in treatment-naive PAH was cemented in 2015 by the AMBITION trial. The primary endpoint (death, PAH hospitalization, or unsatisfactory clinical response) occurred in 18%, 34%, and 28% of patients who were randomized, respectively, to combination therapy, monotherapy with the ERA ambrisentan, or monotherapy with the PDE-5 inhibitor tadalafil – and in 31% of the two monotherapy groups combined.

The trial reported a 50% reduction in the primary endpoint in the combination-therapy group versus the pooled monotherapy group, as well as greater reductions in N-terminal of the prohormone brain natriuretic peptide levels, more satisfactory clinical response and greater improvement in 6-minute walking distance.

In practice, a minority of patients – typically older patients with multiple comorbidities – still receive initial monotherapy with sequential add-on therapies based on tolerance, but “for the most part PAH patients will start on combination therapy, most commonly with a ERA and PDE5 inhibitor,” Dr. Chakinala said.

For patients who are not improving on the ERA-PDE5 inhibitor approach – typically those who remain in the intermediate-risk category for intermediate-term mortality – substitution of the PDE5 inhibitor with the soluble guanylate cyclase stimulator riociguat may be considered, he and Dr. Williamson said. Clinical improvement with this substitution was demonstrated in the REPLACE trial.

Experts at PH care centers are also utilizing triple therapy for patients who do not improve to low-risk status after 2-4 months of dual combination therapy. The availability of oral prostacyclin analogues (selexipag and treprostinil) makes it easier to consider adding these agents early on, Dr. Chakinala and Dr. Richardson said.

Patients who fall into the high-risk category, at any point, are still best managed with parenteral prostacyclin analogues, Dr. Chakinala said.

In general, said Dr. Williamson, who also directs the University of Kansas Pulmonary Hypertension Comprehensive Care Center, “the PH community tends to be fairly aggressive up front, and with a low threshold for using prostacyclin analogues.”

The agents are “always part of the picture for someone who is really ill, in functional class IV, or has really impaired right ventricular function,” he said. “And we’re finding increased roles in patients who are not as ill but still have decompensated right ventricular dysfunction. It’s something we now consider.”

Recently published research on up-front oral triple therapy suggests possible benefit for some patients – but it’s far from conclusive, said Dr. Chakinala. The TRITON study randomized treatment-naive patients to the traditional ERA-PDE5 combination and either oral selexipag (a selective prostacyclin receptor agonist) or placebo as a third agent. It found no significant difference in reduction in PVR, the primary outcome, at week 26. However, the authors reported a “possible signal” for improved long-term outcomes with triple therapy.

“Based on this best evidence from a randomized clinical trial, I think it’s unfair to say that all patients should be on triple combination therapy right out of the gate,” he said. “Having said that, more recent [European] data showed that two drugs fell short of the mark in some patients, with high rates of clinical progression. And even in AMBITION, there were a number of patients in the combination arm who didn’t have a robust response.”

A 2021 retrospective analysis from the French Pulmonary Hypertension Registry – one of the European studies – assessed survival with monotherapy, dual therapy, or triple-combination therapy (two orals with a parenteral prostacyclin), and found no difference between monotherapy and dual therapy in high-risk patients.

Experts have been upping the ante, therefore, on early assessment and frequent reassessment of treatment response. Not long ago, patients were typically reassessed 6-12 months after the initiation of treatment. Now, experts at the PH care centers want to assess patients at 3-4 months and adjust or intensify treatment regimens for those who don’t yet qualify as low risk using a multidimensional risk score calculator.

The REVEAL (Registry to Evaluate Early and Long-Term PAH Management) risk score calculator, for instance, predicts the probability of 1-year survival and assigns patients to a strata of risk level based on either 12 or 6 variables (for the full or “lite” versions).]

Even better monitoring and risk assessment is needed, however, to “help sift out which patients are not improving enough on initial therapy or who are starting to fall off after being on a regimen for a period of time,” Dr. Chakinala said.

Today, with a network of accredited centers of expertise and a desire and need for many patients to remain close to home, Dr. Chakinala encourages finding a balance. Well-resourced clinicians can strive for early diagnosis and management – potentially initiating ERA–PDE-5 inhibitor combination therapy – but still should collaborate with PH experts.

“It’s a good idea to comanage these patients and let the experts see them periodically to help you determine when your patient may be declining,” he said. “The timetable for reassessment, the complexity of the reassessment, and the need to escalate to more advanced therapies has never been more important.”
 

Research highlights

Therapies that target inflammation and altered metabolism – including metformin – are among those being investigated for PAH. So are therapies targeting dysfunctional bone morphogenetic protein pathway signaling, which has been shown to be associated with hereditary, idiopathic, and likely other forms of PAH; one such drug, called sotatercept, is currently at the phase 3 trial stage.

Most promising for PAH may be the research efforts involving deep phenotyping, said Andrew J. Sweatt, MD, of Stanford (Calif.) University and the Vera Moulton Wall Center for Pulmonary Vascular Disease.

“It’s where a lot of research is headed – deep phenotyping to deconstruct the molecular and clinical heterogeneity that exists within PAH ... to detect distinct subphenotypes of patients who would respond to particular therapies,” said Dr. Sweatt, who led a review of PH clinical research presented at the 2020 American Thoracic Society International Conference

“Right now, we largely treat all patients the same ... [while] we know that patients have a wide response to therapies and there’s a lot of clinical heterogeneity in how their disease evolves over time,” he said.

Data from a large National Institutes of Health–funded multicenter phenotyping study of PH is being analyzed and should yield findings and publications starting this year, said Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn., and an investigator with the initiative, coined “Redefining Pulmonary Hypertension through Pulmonary Disease Phenomics (PVDOMICS).”

Patients have undergone advanced imaging (for example, echocardiography, cardiac MRI, chest CT, ventilation/perfusion scans), advanced testing through right heart catheterization, body composition testing, quality of life questionnaires, and blood draws that have been analyzed for DNA and RNA expression, proteomics, and metabolomics, said Dr. Hemnes, assistant director of Vanderbilt’s Pulmonary Vascular Center.

The initiative aims to refine the classification of all kinds of PH and “to bring precision medicine to the field so we’re no longer characterizing somebody [based on imaging] and right heart catheterization, but we also incorporating molecular pieces and biomarkers into the diagnostic evaluation,” she said.

In the short term, the results of deep phenotyping should “allow us to be more effective with our therapy recommendations,” Dr. Hemnes said. “Then hopefully in the longer term, [identified biomarkers] will help us to develop new, more effective therapies.”

Dr. Sweatt and Dr. Williamson reported that they have no relevant financial disclosures. Dr. Hemnes reported that she holds stock in Tenax (which is studying a tyrosine kinase inhibitor for PAH) and serves as a consultant for Acceleron, Bayer, GossamerBio, United Therapeutics, and Janssen. She also receives research funding from Imara. Dr. Chakinala reported that he is an investigator on clinical trials for a number of pharmaceutical companies. He also serves on advisory boards for Phase Bio, Liquidia/Rare Gen, Bayer, Janssen, Trio Health Analytics, and Aerovate.

Aggressive up-front combination therapy, more lofty treatment goals, and earlier and more frequent reassessments to guide treatment are improving care of patients with pulmonary arterial hypertension (PAH) while at the same time making it more complex.

A larger number of oral and generic treatment options have in some respects ushered in more management ease. But overall, “I don’t know if management of these patients has ever been more complicated, given the treatment options and strategies,” said Murali M. Chakinala, MD, professor of medicine at Washington University, St. Louis. “We’re always thinking through approaches.”

Diagnosis continues to be challenging given the rarity of PAH and its nonspecific presentation – and in some cases it’s now harder. Experts such as Dr. Chakinala are seeing increasing number of aging patients with left heart disease, chronic kidney disease, and other comorbidities who have significant precapillary pulmonary hypertension and who exhibit hemodynamics consistent with PAH, or group 1 PH.

The question experts face is, do such patients have “true PAH,” as do a reported 25-50 people per million, or do they have another type of PH in the classification schema – or a mixture?

Deciding which patients “really fit into group 1 and should be managed like group 1,” Dr. Chakinala said, requires clinical acumen and has important implications, as patients with PAH are the main beneficiaries of vasodilator therapy. Most other patients with PH will not respond to or tolerate such treatment.

“These older patients may be getting PAH through different mechanisms than our younger patients, but because we define PAH through hemodynamic criteria and by ruling out other obvious explanations, they all get lumped together,” said Dr. Chakinala. “We need to parse these patients out better in the future, much like our oncology colleagues are doing.”

Yale Rosen/Wikimedia Commons/Creative Commons Attribution-Share Alike 2.0 Generi

Personalized medicine hopefully is the next horizon for this condition, characterized by severe remodeling of the distal pulmonary arteries. Researchers are pushing to achieve deep phenotyping, identify biomarkers and improve risk assessment tools.

And with 80 or so centers now accredited by the Pulmonary Hypertension Association as Pulmonary Hypertension Care Centers, referred patients are accessing clinical trials of new nonvasodilatory drugs. Currently available therapies improve hemodynamics and symptoms, and can slow disease progression, but are not truly disease modifying, sources say.

“The endothelin, nitric oxide, and prostacyclin pathways have been exhaustively studied and we now have great drugs for those pathways,” said Dr. Chakinala, who leads the PHA’s scientific leadership council. But “we’re not going to put a greater dent into this disease until we have new drugs that work on different biologic pathways.”
 

Diagnostic challenges

The diagnosis of PAH – a remarkably heterogeneous condition that encompasses heritable forms and idiopathic forms, and that comprises a broad mix of predisposing conditions and exposures, from scleroderma to methamphetamine use – is still too often missed or delayed. Delayed diagnoses and misdiagnoses of PAH and other types of PH have been reported in up to 85% of at-risk patients, according to a 2016 literature review.

Being able to pivot from thinking about common pulmonary ailments or heart failure to considering PAH is a key part of earlier diagnosis and better treatment outcomes. “If someone has unexplained dyspnea or if they’re treated for other lung diseases and are not improving, think about a screening echocardiogram,” said Timothy L. Williamson, MD, vice president of quality and safety and a pulmonary and critical care physician at the University of Kansas Health Center, Kansas City.

One of the most common reasons Dr. Chakinala sees for missed diagnoses are right heart catheterizations that are incomplete or misinterpreted. (Right heart catheterizations are required to confirm the diagnosis.) “One can’t simply measure pressures and stop,” he said. “We need the full hemodynamic profile to know that it’s truly precapillary PAH ... and we need proper interpretation of [elements like] the waveforms.”

The 2019 World Symposium on Pulmonary Hypertension shifted the definition of PH from an arbitrarily defined mean pulmonary arterial pressure of at least 25 mm Hg at rest (as measured by right heart catheterization) to a more scientifically determined mPAP of at least 20 mm Hg.

The classification document also requires pulmonary vascular resistance (PVR) of at least 3 Wood units in the definition of all forms of precapillary PH. PAH specifically is defined as the presence of mPAP of at least 20 mm Hg, PVR of at least 3 Wood units, and pulmonary arterial wedge pressure 15 mm Hg or less.
 

Trends in treatment

The value of initial combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 (PDE5) inhibitor in treatment-naive PAH was cemented in 2015 by the AMBITION trial. The primary endpoint (death, PAH hospitalization, or unsatisfactory clinical response) occurred in 18%, 34%, and 28% of patients who were randomized, respectively, to combination therapy, monotherapy with the ERA ambrisentan, or monotherapy with the PDE-5 inhibitor tadalafil – and in 31% of the two monotherapy groups combined.

The trial reported a 50% reduction in the primary endpoint in the combination-therapy group versus the pooled monotherapy group, as well as greater reductions in N-terminal of the prohormone brain natriuretic peptide levels, more satisfactory clinical response and greater improvement in 6-minute walking distance.

In practice, a minority of patients – typically older patients with multiple comorbidities – still receive initial monotherapy with sequential add-on therapies based on tolerance, but “for the most part PAH patients will start on combination therapy, most commonly with a ERA and PDE5 inhibitor,” Dr. Chakinala said.

For patients who are not improving on the ERA-PDE5 inhibitor approach – typically those who remain in the intermediate-risk category for intermediate-term mortality – substitution of the PDE5 inhibitor with the soluble guanylate cyclase stimulator riociguat may be considered, he and Dr. Williamson said. Clinical improvement with this substitution was demonstrated in the REPLACE trial.

Experts at PH care centers are also utilizing triple therapy for patients who do not improve to low-risk status after 2-4 months of dual combination therapy. The availability of oral prostacyclin analogues (selexipag and treprostinil) makes it easier to consider adding these agents early on, Dr. Chakinala and Dr. Richardson said.

Patients who fall into the high-risk category, at any point, are still best managed with parenteral prostacyclin analogues, Dr. Chakinala said.

In general, said Dr. Williamson, who also directs the University of Kansas Pulmonary Hypertension Comprehensive Care Center, “the PH community tends to be fairly aggressive up front, and with a low threshold for using prostacyclin analogues.”

The agents are “always part of the picture for someone who is really ill, in functional class IV, or has really impaired right ventricular function,” he said. “And we’re finding increased roles in patients who are not as ill but still have decompensated right ventricular dysfunction. It’s something we now consider.”

Recently published research on up-front oral triple therapy suggests possible benefit for some patients – but it’s far from conclusive, said Dr. Chakinala. The TRITON study randomized treatment-naive patients to the traditional ERA-PDE5 combination and either oral selexipag (a selective prostacyclin receptor agonist) or placebo as a third agent. It found no significant difference in reduction in PVR, the primary outcome, at week 26. However, the authors reported a “possible signal” for improved long-term outcomes with triple therapy.

“Based on this best evidence from a randomized clinical trial, I think it’s unfair to say that all patients should be on triple combination therapy right out of the gate,” he said. “Having said that, more recent [European] data showed that two drugs fell short of the mark in some patients, with high rates of clinical progression. And even in AMBITION, there were a number of patients in the combination arm who didn’t have a robust response.”

A 2021 retrospective analysis from the French Pulmonary Hypertension Registry – one of the European studies – assessed survival with monotherapy, dual therapy, or triple-combination therapy (two orals with a parenteral prostacyclin), and found no difference between monotherapy and dual therapy in high-risk patients.

Experts have been upping the ante, therefore, on early assessment and frequent reassessment of treatment response. Not long ago, patients were typically reassessed 6-12 months after the initiation of treatment. Now, experts at the PH care centers want to assess patients at 3-4 months and adjust or intensify treatment regimens for those who don’t yet qualify as low risk using a multidimensional risk score calculator.

The REVEAL (Registry to Evaluate Early and Long-Term PAH Management) risk score calculator, for instance, predicts the probability of 1-year survival and assigns patients to a strata of risk level based on either 12 or 6 variables (for the full or “lite” versions).]

Even better monitoring and risk assessment is needed, however, to “help sift out which patients are not improving enough on initial therapy or who are starting to fall off after being on a regimen for a period of time,” Dr. Chakinala said.

Today, with a network of accredited centers of expertise and a desire and need for many patients to remain close to home, Dr. Chakinala encourages finding a balance. Well-resourced clinicians can strive for early diagnosis and management – potentially initiating ERA–PDE-5 inhibitor combination therapy – but still should collaborate with PH experts.

“It’s a good idea to comanage these patients and let the experts see them periodically to help you determine when your patient may be declining,” he said. “The timetable for reassessment, the complexity of the reassessment, and the need to escalate to more advanced therapies has never been more important.”
 

Research highlights

Therapies that target inflammation and altered metabolism – including metformin – are among those being investigated for PAH. So are therapies targeting dysfunctional bone morphogenetic protein pathway signaling, which has been shown to be associated with hereditary, idiopathic, and likely other forms of PAH; one such drug, called sotatercept, is currently at the phase 3 trial stage.

Most promising for PAH may be the research efforts involving deep phenotyping, said Andrew J. Sweatt, MD, of Stanford (Calif.) University and the Vera Moulton Wall Center for Pulmonary Vascular Disease.

“It’s where a lot of research is headed – deep phenotyping to deconstruct the molecular and clinical heterogeneity that exists within PAH ... to detect distinct subphenotypes of patients who would respond to particular therapies,” said Dr. Sweatt, who led a review of PH clinical research presented at the 2020 American Thoracic Society International Conference

“Right now, we largely treat all patients the same ... [while] we know that patients have a wide response to therapies and there’s a lot of clinical heterogeneity in how their disease evolves over time,” he said.

Data from a large National Institutes of Health–funded multicenter phenotyping study of PH is being analyzed and should yield findings and publications starting this year, said Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn., and an investigator with the initiative, coined “Redefining Pulmonary Hypertension through Pulmonary Disease Phenomics (PVDOMICS).”

Patients have undergone advanced imaging (for example, echocardiography, cardiac MRI, chest CT, ventilation/perfusion scans), advanced testing through right heart catheterization, body composition testing, quality of life questionnaires, and blood draws that have been analyzed for DNA and RNA expression, proteomics, and metabolomics, said Dr. Hemnes, assistant director of Vanderbilt’s Pulmonary Vascular Center.

The initiative aims to refine the classification of all kinds of PH and “to bring precision medicine to the field so we’re no longer characterizing somebody [based on imaging] and right heart catheterization, but we also incorporating molecular pieces and biomarkers into the diagnostic evaluation,” she said.

In the short term, the results of deep phenotyping should “allow us to be more effective with our therapy recommendations,” Dr. Hemnes said. “Then hopefully in the longer term, [identified biomarkers] will help us to develop new, more effective therapies.”

Dr. Sweatt and Dr. Williamson reported that they have no relevant financial disclosures. Dr. Hemnes reported that she holds stock in Tenax (which is studying a tyrosine kinase inhibitor for PAH) and serves as a consultant for Acceleron, Bayer, GossamerBio, United Therapeutics, and Janssen. She also receives research funding from Imara. Dr. Chakinala reported that he is an investigator on clinical trials for a number of pharmaceutical companies. He also serves on advisory boards for Phase Bio, Liquidia/Rare Gen, Bayer, Janssen, Trio Health Analytics, and Aerovate.

Aggressive up-front combination therapy, more lofty treatment goals, and earlier and more frequent reassessments to guide treatment are improving care of patients with pulmonary arterial hypertension (PAH) while at the same time making it more complex.

A larger number of oral and generic treatment options have in some respects ushered in more management ease. But overall, “I don’t know if management of these patients has ever been more complicated, given the treatment options and strategies,” said Murali M. Chakinala, MD, professor of medicine at Washington University, St. Louis. “We’re always thinking through approaches.”

Diagnosis continues to be challenging given the rarity of PAH and its nonspecific presentation – and in some cases it’s now harder. Experts such as Dr. Chakinala are seeing increasing number of aging patients with left heart disease, chronic kidney disease, and other comorbidities who have significant precapillary pulmonary hypertension and who exhibit hemodynamics consistent with PAH, or group 1 PH.

The question experts face is, do such patients have “true PAH,” as do a reported 25-50 people per million, or do they have another type of PH in the classification schema – or a mixture?

Deciding which patients “really fit into group 1 and should be managed like group 1,” Dr. Chakinala said, requires clinical acumen and has important implications, as patients with PAH are the main beneficiaries of vasodilator therapy. Most other patients with PH will not respond to or tolerate such treatment.

“These older patients may be getting PAH through different mechanisms than our younger patients, but because we define PAH through hemodynamic criteria and by ruling out other obvious explanations, they all get lumped together,” said Dr. Chakinala. “We need to parse these patients out better in the future, much like our oncology colleagues are doing.”

Yale Rosen/Wikimedia Commons/Creative Commons Attribution-Share Alike 2.0 Generi

Personalized medicine hopefully is the next horizon for this condition, characterized by severe remodeling of the distal pulmonary arteries. Researchers are pushing to achieve deep phenotyping, identify biomarkers and improve risk assessment tools.

And with 80 or so centers now accredited by the Pulmonary Hypertension Association as Pulmonary Hypertension Care Centers, referred patients are accessing clinical trials of new nonvasodilatory drugs. Currently available therapies improve hemodynamics and symptoms, and can slow disease progression, but are not truly disease modifying, sources say.

“The endothelin, nitric oxide, and prostacyclin pathways have been exhaustively studied and we now have great drugs for those pathways,” said Dr. Chakinala, who leads the PHA’s scientific leadership council. But “we’re not going to put a greater dent into this disease until we have new drugs that work on different biologic pathways.”
 

Diagnostic challenges

The diagnosis of PAH – a remarkably heterogeneous condition that encompasses heritable forms and idiopathic forms, and that comprises a broad mix of predisposing conditions and exposures, from scleroderma to methamphetamine use – is still too often missed or delayed. Delayed diagnoses and misdiagnoses of PAH and other types of PH have been reported in up to 85% of at-risk patients, according to a 2016 literature review.

Being able to pivot from thinking about common pulmonary ailments or heart failure to considering PAH is a key part of earlier diagnosis and better treatment outcomes. “If someone has unexplained dyspnea or if they’re treated for other lung diseases and are not improving, think about a screening echocardiogram,” said Timothy L. Williamson, MD, vice president of quality and safety and a pulmonary and critical care physician at the University of Kansas Health Center, Kansas City.

One of the most common reasons Dr. Chakinala sees for missed diagnoses are right heart catheterizations that are incomplete or misinterpreted. (Right heart catheterizations are required to confirm the diagnosis.) “One can’t simply measure pressures and stop,” he said. “We need the full hemodynamic profile to know that it’s truly precapillary PAH ... and we need proper interpretation of [elements like] the waveforms.”

The 2019 World Symposium on Pulmonary Hypertension shifted the definition of PH from an arbitrarily defined mean pulmonary arterial pressure of at least 25 mm Hg at rest (as measured by right heart catheterization) to a more scientifically determined mPAP of at least 20 mm Hg.

The classification document also requires pulmonary vascular resistance (PVR) of at least 3 Wood units in the definition of all forms of precapillary PH. PAH specifically is defined as the presence of mPAP of at least 20 mm Hg, PVR of at least 3 Wood units, and pulmonary arterial wedge pressure 15 mm Hg or less.
 

Trends in treatment

The value of initial combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 (PDE5) inhibitor in treatment-naive PAH was cemented in 2015 by the AMBITION trial. The primary endpoint (death, PAH hospitalization, or unsatisfactory clinical response) occurred in 18%, 34%, and 28% of patients who were randomized, respectively, to combination therapy, monotherapy with the ERA ambrisentan, or monotherapy with the PDE-5 inhibitor tadalafil – and in 31% of the two monotherapy groups combined.

The trial reported a 50% reduction in the primary endpoint in the combination-therapy group versus the pooled monotherapy group, as well as greater reductions in N-terminal of the prohormone brain natriuretic peptide levels, more satisfactory clinical response and greater improvement in 6-minute walking distance.

In practice, a minority of patients – typically older patients with multiple comorbidities – still receive initial monotherapy with sequential add-on therapies based on tolerance, but “for the most part PAH patients will start on combination therapy, most commonly with a ERA and PDE5 inhibitor,” Dr. Chakinala said.

For patients who are not improving on the ERA-PDE5 inhibitor approach – typically those who remain in the intermediate-risk category for intermediate-term mortality – substitution of the PDE5 inhibitor with the soluble guanylate cyclase stimulator riociguat may be considered, he and Dr. Williamson said. Clinical improvement with this substitution was demonstrated in the REPLACE trial.

Experts at PH care centers are also utilizing triple therapy for patients who do not improve to low-risk status after 2-4 months of dual combination therapy. The availability of oral prostacyclin analogues (selexipag and treprostinil) makes it easier to consider adding these agents early on, Dr. Chakinala and Dr. Richardson said.

Patients who fall into the high-risk category, at any point, are still best managed with parenteral prostacyclin analogues, Dr. Chakinala said.

In general, said Dr. Williamson, who also directs the University of Kansas Pulmonary Hypertension Comprehensive Care Center, “the PH community tends to be fairly aggressive up front, and with a low threshold for using prostacyclin analogues.”

The agents are “always part of the picture for someone who is really ill, in functional class IV, or has really impaired right ventricular function,” he said. “And we’re finding increased roles in patients who are not as ill but still have decompensated right ventricular dysfunction. It’s something we now consider.”

Recently published research on up-front oral triple therapy suggests possible benefit for some patients – but it’s far from conclusive, said Dr. Chakinala. The TRITON study randomized treatment-naive patients to the traditional ERA-PDE5 combination and either oral selexipag (a selective prostacyclin receptor agonist) or placebo as a third agent. It found no significant difference in reduction in PVR, the primary outcome, at week 26. However, the authors reported a “possible signal” for improved long-term outcomes with triple therapy.

“Based on this best evidence from a randomized clinical trial, I think it’s unfair to say that all patients should be on triple combination therapy right out of the gate,” he said. “Having said that, more recent [European] data showed that two drugs fell short of the mark in some patients, with high rates of clinical progression. And even in AMBITION, there were a number of patients in the combination arm who didn’t have a robust response.”

A 2021 retrospective analysis from the French Pulmonary Hypertension Registry – one of the European studies – assessed survival with monotherapy, dual therapy, or triple-combination therapy (two orals with a parenteral prostacyclin), and found no difference between monotherapy and dual therapy in high-risk patients.

Experts have been upping the ante, therefore, on early assessment and frequent reassessment of treatment response. Not long ago, patients were typically reassessed 6-12 months after the initiation of treatment. Now, experts at the PH care centers want to assess patients at 3-4 months and adjust or intensify treatment regimens for those who don’t yet qualify as low risk using a multidimensional risk score calculator.

The REVEAL (Registry to Evaluate Early and Long-Term PAH Management) risk score calculator, for instance, predicts the probability of 1-year survival and assigns patients to a strata of risk level based on either 12 or 6 variables (for the full or “lite” versions).]

Even better monitoring and risk assessment is needed, however, to “help sift out which patients are not improving enough on initial therapy or who are starting to fall off after being on a regimen for a period of time,” Dr. Chakinala said.

Today, with a network of accredited centers of expertise and a desire and need for many patients to remain close to home, Dr. Chakinala encourages finding a balance. Well-resourced clinicians can strive for early diagnosis and management – potentially initiating ERA–PDE-5 inhibitor combination therapy – but still should collaborate with PH experts.

“It’s a good idea to comanage these patients and let the experts see them periodically to help you determine when your patient may be declining,” he said. “The timetable for reassessment, the complexity of the reassessment, and the need to escalate to more advanced therapies has never been more important.”
 

Research highlights

Therapies that target inflammation and altered metabolism – including metformin – are among those being investigated for PAH. So are therapies targeting dysfunctional bone morphogenetic protein pathway signaling, which has been shown to be associated with hereditary, idiopathic, and likely other forms of PAH; one such drug, called sotatercept, is currently at the phase 3 trial stage.

Most promising for PAH may be the research efforts involving deep phenotyping, said Andrew J. Sweatt, MD, of Stanford (Calif.) University and the Vera Moulton Wall Center for Pulmonary Vascular Disease.

“It’s where a lot of research is headed – deep phenotyping to deconstruct the molecular and clinical heterogeneity that exists within PAH ... to detect distinct subphenotypes of patients who would respond to particular therapies,” said Dr. Sweatt, who led a review of PH clinical research presented at the 2020 American Thoracic Society International Conference

“Right now, we largely treat all patients the same ... [while] we know that patients have a wide response to therapies and there’s a lot of clinical heterogeneity in how their disease evolves over time,” he said.

Data from a large National Institutes of Health–funded multicenter phenotyping study of PH is being analyzed and should yield findings and publications starting this year, said Anna R. Hemnes, MD, associate professor of medicine at Vanderbilt University Medical Center, Nashville, Tenn., and an investigator with the initiative, coined “Redefining Pulmonary Hypertension through Pulmonary Disease Phenomics (PVDOMICS).”

Patients have undergone advanced imaging (for example, echocardiography, cardiac MRI, chest CT, ventilation/perfusion scans), advanced testing through right heart catheterization, body composition testing, quality of life questionnaires, and blood draws that have been analyzed for DNA and RNA expression, proteomics, and metabolomics, said Dr. Hemnes, assistant director of Vanderbilt’s Pulmonary Vascular Center.

The initiative aims to refine the classification of all kinds of PH and “to bring precision medicine to the field so we’re no longer characterizing somebody [based on imaging] and right heart catheterization, but we also incorporating molecular pieces and biomarkers into the diagnostic evaluation,” she said.

In the short term, the results of deep phenotyping should “allow us to be more effective with our therapy recommendations,” Dr. Hemnes said. “Then hopefully in the longer term, [identified biomarkers] will help us to develop new, more effective therapies.”

Dr. Sweatt and Dr. Williamson reported that they have no relevant financial disclosures. Dr. Hemnes reported that she holds stock in Tenax (which is studying a tyrosine kinase inhibitor for PAH) and serves as a consultant for Acceleron, Bayer, GossamerBio, United Therapeutics, and Janssen. She also receives research funding from Imara. Dr. Chakinala reported that he is an investigator on clinical trials for a number of pharmaceutical companies. He also serves on advisory boards for Phase Bio, Liquidia/Rare Gen, Bayer, Janssen, Trio Health Analytics, and Aerovate.

Vasculitis of the coronary arteries is a well-recognized acute complication of Kawasaki disease, but the long-term risk of cardiovascular (CV) sequelae does not appear to be clinically meaningful for most patients, according to results from an analysis of data presented at the annual meeting of the Canadian Rheumatology Association.

For patients and parents, these data provide “a message of reassurance,” according to Jennifer J.Y. Lee, MD, a pediatric rheumatologist affiliated with the Hospital for Sick Children, Toronto.

The long-term outcomes were characterized as reassuring even though rates of hypertension, major adverse cardiac events (MACE), and death from CV events were higher in patients with Kawasaki disease relative to controls in a retrospective data-linkage study. In fact, these differences were highly statistically significant, but the absolute differences were extremely small.

For this analysis, the 1,174 patients diagnosed with Kawasaki disease at Dr. Lee’s institution between 1991 and 2008 were compared in a 10:1 ratio to 11,740 controls matched for factors such as age, sex, ethnicity, and geographic region. The median follow-up period was 20 years, and the maximum was 28 years.
 

Adjusted CV risks are significant

In an adjusted Cox proportional hazard ratio model, patients in the Kawasaki group had a more than twofold increase in risk for hypertension (aHR, 2.3; P < .0001) and all-cause mortality (aHR, 2.5; P = .009). They also had more than a 10-fold increase in risk for MACE (aHR, 10.3; P < .0001).

These statistics belie the clinical relevance, according to Dr. Lee. Because of the very low rates of all the measured events in both groups, there was just one more case of hypertension per 1,250 patient-years of follow-up, one more case of MACE per 833 patient-years of follow-up, and one more death for 3,846 patient years of follow-up.

Moreover, when these outcomes were graphed over time, most events occurred during the acute period or in the initial years of follow-up.

“There was not a constant increase in risk of these outcomes over time for patients with Kawasaki disease relative to the controls,” Dr. Lee reported. “The long-term prognosis for Kawasaki patients remains favorable.”

European group reports similar results

Similar results from a single-center experience were published 3 years ago. In that study, 207 Kawasaki patients treated at the University of Lausanne (Switzerland) were followed for 30 years. Complications after the acute phase were characterized as “rare.”

For example, only three patients (1.4%) had a subsequent episode of myocardial ischemia. All three had developed a coronary aneurysm during the acute phase of Kawasaki disease. The authors of that study reported that children who had not received immunoglobulins during the acute phase or who developed Kawasaki disease outside of the usual age range were more likely to have subsequent events, such as disease recurrence.

Other studies of long-term CV outcomes in patients with Kawasaki disease generally show similar data, according to James T. Gaensbauer, MD, a pediatric infectious disease specialist at the Mayo Clinic, Rochester, Minn.

“I generally agree with the premise that major complications are rare when you compare a cohort of patients with Kawasaki disease with the general population,” Dr. Gaensbauer said. However, he added, “I do not think you can say no one needs to worry.”
 

Severity of acute disease might matter

During the acute phase of Kawasaki disease, the arterial damage varies. As suggested in the University of Lausanne follow-up, patients with significant coronary aneurysms do appear to be at greater risk of long-term complications. Dr. Gaensbauer cited a statement from the American Heart Association that noted a higher risk of CV sequelae from Kawasaki disease with a greater or more severe coronary aneurysm or in the face of other evidence of damage to the arterial tree.

“The clinical course within the first 2 years of Kawasaki disease appears to be important for risk of CV complications after this time,” Dr. Gaensbauer said.

The absolute risk of CV events in patients with a more complicated acute course of Kawasaki disease remains incompletely understood, but Dr. Gaensbauer said that there are several sets of data, including these new data from the Hospital for Sick Children, that suggest that the overall prognosis is good. However, he cautioned that this reassurance does not necessarily apply to children with a difficult acute course.

According to the 2017 AHA statement on Kawasaki disease, risk stratification based on echocardiography and other measures after the acute phase of Kawasaki disease are reasonable to determine if long-term follow-up is needed. In those without abnormalities, it is reasonable to forgo further cardiology assessment.

Dr. Lee and Dr. Gaensbauer reported having no potential conflicts of interest.

Vasculitis of the coronary arteries is a well-recognized acute complication of Kawasaki disease, but the long-term risk of cardiovascular (CV) sequelae does not appear to be clinically meaningful for most patients, according to results from an analysis of data presented at the annual meeting of the Canadian Rheumatology Association.

For patients and parents, these data provide “a message of reassurance,” according to Jennifer J.Y. Lee, MD, a pediatric rheumatologist affiliated with the Hospital for Sick Children, Toronto.

The long-term outcomes were characterized as reassuring even though rates of hypertension, major adverse cardiac events (MACE), and death from CV events were higher in patients with Kawasaki disease relative to controls in a retrospective data-linkage study. In fact, these differences were highly statistically significant, but the absolute differences were extremely small.

For this analysis, the 1,174 patients diagnosed with Kawasaki disease at Dr. Lee’s institution between 1991 and 2008 were compared in a 10:1 ratio to 11,740 controls matched for factors such as age, sex, ethnicity, and geographic region. The median follow-up period was 20 years, and the maximum was 28 years.
 

Adjusted CV risks are significant

In an adjusted Cox proportional hazard ratio model, patients in the Kawasaki group had a more than twofold increase in risk for hypertension (aHR, 2.3; P < .0001) and all-cause mortality (aHR, 2.5; P = .009). They also had more than a 10-fold increase in risk for MACE (aHR, 10.3; P < .0001).

These statistics belie the clinical relevance, according to Dr. Lee. Because of the very low rates of all the measured events in both groups, there was just one more case of hypertension per 1,250 patient-years of follow-up, one more case of MACE per 833 patient-years of follow-up, and one more death for 3,846 patient years of follow-up.

Moreover, when these outcomes were graphed over time, most events occurred during the acute period or in the initial years of follow-up.

“There was not a constant increase in risk of these outcomes over time for patients with Kawasaki disease relative to the controls,” Dr. Lee reported. “The long-term prognosis for Kawasaki patients remains favorable.”

European group reports similar results

Similar results from a single-center experience were published 3 years ago. In that study, 207 Kawasaki patients treated at the University of Lausanne (Switzerland) were followed for 30 years. Complications after the acute phase were characterized as “rare.”

For example, only three patients (1.4%) had a subsequent episode of myocardial ischemia. All three had developed a coronary aneurysm during the acute phase of Kawasaki disease. The authors of that study reported that children who had not received immunoglobulins during the acute phase or who developed Kawasaki disease outside of the usual age range were more likely to have subsequent events, such as disease recurrence.

Other studies of long-term CV outcomes in patients with Kawasaki disease generally show similar data, according to James T. Gaensbauer, MD, a pediatric infectious disease specialist at the Mayo Clinic, Rochester, Minn.

“I generally agree with the premise that major complications are rare when you compare a cohort of patients with Kawasaki disease with the general population,” Dr. Gaensbauer said. However, he added, “I do not think you can say no one needs to worry.”
 

Severity of acute disease might matter

During the acute phase of Kawasaki disease, the arterial damage varies. As suggested in the University of Lausanne follow-up, patients with significant coronary aneurysms do appear to be at greater risk of long-term complications. Dr. Gaensbauer cited a statement from the American Heart Association that noted a higher risk of CV sequelae from Kawasaki disease with a greater or more severe coronary aneurysm or in the face of other evidence of damage to the arterial tree.

“The clinical course within the first 2 years of Kawasaki disease appears to be important for risk of CV complications after this time,” Dr. Gaensbauer said.

The absolute risk of CV events in patients with a more complicated acute course of Kawasaki disease remains incompletely understood, but Dr. Gaensbauer said that there are several sets of data, including these new data from the Hospital for Sick Children, that suggest that the overall prognosis is good. However, he cautioned that this reassurance does not necessarily apply to children with a difficult acute course.

According to the 2017 AHA statement on Kawasaki disease, risk stratification based on echocardiography and other measures after the acute phase of Kawasaki disease are reasonable to determine if long-term follow-up is needed. In those without abnormalities, it is reasonable to forgo further cardiology assessment.

Dr. Lee and Dr. Gaensbauer reported having no potential conflicts of interest.

Vasculitis of the coronary arteries is a well-recognized acute complication of Kawasaki disease, but the long-term risk of cardiovascular (CV) sequelae does not appear to be clinically meaningful for most patients, according to results from an analysis of data presented at the annual meeting of the Canadian Rheumatology Association.

For patients and parents, these data provide “a message of reassurance,” according to Jennifer J.Y. Lee, MD, a pediatric rheumatologist affiliated with the Hospital for Sick Children, Toronto.

The long-term outcomes were characterized as reassuring even though rates of hypertension, major adverse cardiac events (MACE), and death from CV events were higher in patients with Kawasaki disease relative to controls in a retrospective data-linkage study. In fact, these differences were highly statistically significant, but the absolute differences were extremely small.

For this analysis, the 1,174 patients diagnosed with Kawasaki disease at Dr. Lee’s institution between 1991 and 2008 were compared in a 10:1 ratio to 11,740 controls matched for factors such as age, sex, ethnicity, and geographic region. The median follow-up period was 20 years, and the maximum was 28 years.
 

Adjusted CV risks are significant

In an adjusted Cox proportional hazard ratio model, patients in the Kawasaki group had a more than twofold increase in risk for hypertension (aHR, 2.3; P < .0001) and all-cause mortality (aHR, 2.5; P = .009). They also had more than a 10-fold increase in risk for MACE (aHR, 10.3; P < .0001).

These statistics belie the clinical relevance, according to Dr. Lee. Because of the very low rates of all the measured events in both groups, there was just one more case of hypertension per 1,250 patient-years of follow-up, one more case of MACE per 833 patient-years of follow-up, and one more death for 3,846 patient years of follow-up.

Moreover, when these outcomes were graphed over time, most events occurred during the acute period or in the initial years of follow-up.

“There was not a constant increase in risk of these outcomes over time for patients with Kawasaki disease relative to the controls,” Dr. Lee reported. “The long-term prognosis for Kawasaki patients remains favorable.”

European group reports similar results

Similar results from a single-center experience were published 3 years ago. In that study, 207 Kawasaki patients treated at the University of Lausanne (Switzerland) were followed for 30 years. Complications after the acute phase were characterized as “rare.”

For example, only three patients (1.4%) had a subsequent episode of myocardial ischemia. All three had developed a coronary aneurysm during the acute phase of Kawasaki disease. The authors of that study reported that children who had not received immunoglobulins during the acute phase or who developed Kawasaki disease outside of the usual age range were more likely to have subsequent events, such as disease recurrence.

Other studies of long-term CV outcomes in patients with Kawasaki disease generally show similar data, according to James T. Gaensbauer, MD, a pediatric infectious disease specialist at the Mayo Clinic, Rochester, Minn.

“I generally agree with the premise that major complications are rare when you compare a cohort of patients with Kawasaki disease with the general population,” Dr. Gaensbauer said. However, he added, “I do not think you can say no one needs to worry.”
 

Severity of acute disease might matter

During the acute phase of Kawasaki disease, the arterial damage varies. As suggested in the University of Lausanne follow-up, patients with significant coronary aneurysms do appear to be at greater risk of long-term complications. Dr. Gaensbauer cited a statement from the American Heart Association that noted a higher risk of CV sequelae from Kawasaki disease with a greater or more severe coronary aneurysm or in the face of other evidence of damage to the arterial tree.

“The clinical course within the first 2 years of Kawasaki disease appears to be important for risk of CV complications after this time,” Dr. Gaensbauer said.

The absolute risk of CV events in patients with a more complicated acute course of Kawasaki disease remains incompletely understood, but Dr. Gaensbauer said that there are several sets of data, including these new data from the Hospital for Sick Children, that suggest that the overall prognosis is good. However, he cautioned that this reassurance does not necessarily apply to children with a difficult acute course.

According to the 2017 AHA statement on Kawasaki disease, risk stratification based on echocardiography and other measures after the acute phase of Kawasaki disease are reasonable to determine if long-term follow-up is needed. In those without abnormalities, it is reasonable to forgo further cardiology assessment.

Dr. Lee and Dr. Gaensbauer reported having no potential conflicts of interest.

Long COVID continues to be a moving target – continuously evolving and still surprising doctors and patients who have sometimes incapacitating long-term symptoms.

Little about the disorder seems predictable at this point. People can have long COVID after asymptomatic, mild, or severe COVID-19, for example. And when a person gets long COVID – also known as long-haul COVID – symptoms can vary widely.

To address all the uncertainty, the New York State Department of Health gathered experts in primary care, pediatrics, physical medicine, rehabilitation, and pulmonology to answer some pressing questions.

New York in 2020 was the first epicenter of the pandemic in the United States, making it also the center of the long COVID epidemic, says Emily Lutterloh, MD, director of the Division of Epidemiology at the New York State Department of Health.
 

What do you do when you’re seeing a patient with long COVID for the first time?

The first exam varies because there are so many different ways long COVID presents itself, says Benjamin Abramoff, MD, a physical medicine and rehabilitation specialist at Penn Medicine in Philadelphia.

I’ve now been seriously ill with #LongCovid for 11 months. I was never hospitalized. I didn’t even have a “mild” covid case. Instead, I developed Long Covid from an asymptomatic infection.

I’m far from unique. Up to 1/5 of asymptomatic patients go on to have long-term symptoms.

— Ravi Veriah Jacques (@RaviHVJ) February 3, 2022

Assessing their previous and current care also helps to direct their ongoing management, says Zijian Chen, MD, medical director of the Center for Post-COVID Care at Mount Sinai Health System in New York.
 

Can vaccination help people with long COVID?

Anything that we can do to help prevent people from being critically ill or being hospitalized with COVID-19 is helpful to prevent long COVID, says Dr. Abramoff, who is also director of the long COVID clinic at the University of Pennsylvania, Philadelphia.

“So that’s something I always discuss with patients. In some research, sometimes patients do feel better after the vaccine,” he says.
 

What kind of therapies do you find helpful for your patients?

Rehabilitation is a key part of recovery from long COVID, Dr. Abramoff says. “It is very important to make this very patient-specific.”

“We have patients that are working. They’re already going to the gym in some cases but don’t feel like they have the same endurance,” he says. “And then we have patients who are so crippled by their fatigue that they can’t get out of bed.”
 

1/ What is #LongCOVID?!

A disabling malady from ongoing inflammation, autoimmunity, & potential viral reservoirs (GI, brain?)

NEW DATA: The Lungs “light up” on special MRI Scans 3 to 9 months later in patients never hospitalized for COVID.https://t.co/I2kyZ4cK5F pic.twitter.com/dL1P67L2DK

— WesElyMD (@WesElyMD) February 2, 2022

An exercise program can help people who have long COVID.

“There’s a big role for therapy services in the recovery of these patients,” says John Baratta, MD, of the department of physical medicine and rehabilitation at the University of North Carolina at Chapel Hill.

But the limited number of long COVID clinics can mean some people are unable to get to therapists trained on the needs of patients with lingering COVID symptoms. Educating community physical and occupational therapists is one solution.
 

How long does it take for people with long COVID to recover and get back to 100% if they can?

Specific numbers aren’t really available, Dr. Baratta says.

“But I can tell you the general trend that I see is that a lot of patients have a gradual improvement of symptoms. The slow but steady improvement with time may be the body’s natural healing process, a result of medical interventions, or both.”

It can help to reassure people with long COVID that they will not be discharged from care until they feel they’ve maximized their health, says Sharagim Kemp, DO, medical director of the COVID Recovery Program for Nuvance Health, a health system in New York and Connecticut.

It’s essential to set realistic recovery expectations and tell patients that not everyone will return to 100% of their pre-COVID functioning, she says.

“Once we are able to help them reset their expectations, there’s almost an accelerated recovery because they are not putting that pressure on themselves anymore,” Dr. Kemp says.
 

What are the most common symptoms you’re seeing in long COVID?

It’s helpful to think of long COVID as a very broad umbrella term, Dr. Abramoff says.

Echoing what many others have observed, fatigue, cognitive dysfunction or “brain fog,“ and shortness of breath or troubled breathing appear to be the most common symptoms, he says.

Some reported vague symptoms, Dr. Kemp says.

People may go to the doctor “not even realizing that they had COVID. That’s one of the important points here – to have a high index of suspicion for patients who come in with multiple symptoms,” she says.

For this reason, patients can report symptoms that don’t necessarily fit into any specialty, says Sarah J. Ryan, MD, an internal medicine doctor at Columbia University Irving Medical Center in New York. People say they are “just not themselves” or they are tired after their COVID-19 recovery.
 

Is there a connection between severe COVID cases and severe long COVID?

“It’s not like that at all. I would say that more than 80% of the patients that we see had mild to moderate illness and they were not hospitalized,” Dr. Baratta says.

Long COVID is a bit different in children and teenagers, says Ixsy Ramirez, MD, a pediatric pulmonologist at University of Michigan Health, Ann Arbor. Most patients in the long COVID clinic at the University of Michigan were previously healthy, and not children with asthma or other lung conditions as one might expect. In fact, many are student athletes, or were before they had long COVID.

In this population, shortness of breath is most common, followed by chest pain and fatigue. Unfortunately, the symptoms are so serious for many kids that their performance is limited, even if they can return to competitive play.
 

Are there defined criteria you use to diagnose long COVID? How do you give someone a diagnosis?

That’s an ever-evolving question, Dr. Kemp says. The generally accepted definition centers on persistent or new symptoms 4 weeks or more after the original COVID-19 illness, but there are exceptions.

Researchers are working on lab tests to help confirm the diagnosis. But without a definitive blood biomarker, getting to the diagnosis requires “some thorough detective work,” Dr. Ryan says.
 

Do you bring in mental health providers to help with treatment?

“We focus on mental health quite a bit actually,” says, Dr. Chen, cofounder of his institution’s COVID recovery clinic. Mount Sinai offers one-on-one and group mental health services, for example.

“Personally, I’ve seen patients that I did not expect to have such severe mental health changes” with long COVID.
 

One of the most powerful accounts and testimonies I have seen on what most #LongCovid patients experience when interacting with their doctors.

“I did not fit in a box, so they chose not to see me, even worse they made me feel like it was my fault for not fitting in their box” pic.twitter.com/7GQLBucuO5

— charlos (@loscharlos) February 3, 2022

Examples include severe depression, cases of acute psychosis, hallucinations, and other problems “that are really unexpected after a viral illness.”

Stony Brook University Hospital in New York has a long COVID clinic staffed by multiple primary care doctors who do exams and refer patients to services. A bonus of offering psychological services to all post-COVID patients is doctors get a more complete picture of each person and a better understanding of what they are going through, says Abigail Chua, MD, a pulmonologist at Stony Brook.

Some empathy is essential, Dr. Baratta says. “It’s important to recognize that a lot of these patients present with a sense of grief or loss for their prior life.”
 

What does the future hold?

A simple test to diagnose long COVID, combined with an effective treatment that helps people feel better within a week, would be ideal, Dr. Abramoff says.

“That would be lovely. But you know, we’re just not at that point.”

And it would be helpful to start identifying subtypes of long COVID so diagnosis and treatment can be more targeted, Dr. Abramoff says. Otherwise, “It’s going to be a very challenging approach to try to treat all of our patients with long COVID symptoms the same way.”

Good clinical trials likewise are needed to address all the subtleties of long COVID.

A number of long COVID centers are collaborating on research to find out more, Dr. Chen says. Actions include setting up a bank of tissue samples from people with long COVID so researchers can continue to figure out the condition.

One goal, Dr. Chen says, would be the ability to treat long COVID rather than just its symptoms.

Long COVID emphasizes the need to prevent people from getting COVID in the first place, Dr. Ramirez says. This will continue to be important, particularly when some people dismiss the seriousness of COVID, comparing it to a cold if they get it. That attitude discounts the large number of people who unfortunately go on to develop long-term, often debilitating, symptoms.

A version of this article first appeared on WebMD.com.

Long COVID continues to be a moving target – continuously evolving and still surprising doctors and patients who have sometimes incapacitating long-term symptoms.

Little about the disorder seems predictable at this point. People can have long COVID after asymptomatic, mild, or severe COVID-19, for example. And when a person gets long COVID – also known as long-haul COVID – symptoms can vary widely.

To address all the uncertainty, the New York State Department of Health gathered experts in primary care, pediatrics, physical medicine, rehabilitation, and pulmonology to answer some pressing questions.

New York in 2020 was the first epicenter of the pandemic in the United States, making it also the center of the long COVID epidemic, says Emily Lutterloh, MD, director of the Division of Epidemiology at the New York State Department of Health.
 

What do you do when you’re seeing a patient with long COVID for the first time?

The first exam varies because there are so many different ways long COVID presents itself, says Benjamin Abramoff, MD, a physical medicine and rehabilitation specialist at Penn Medicine in Philadelphia.

I’ve now been seriously ill with #LongCovid for 11 months. I was never hospitalized. I didn’t even have a “mild” covid case. Instead, I developed Long Covid from an asymptomatic infection.

I’m far from unique. Up to 1/5 of asymptomatic patients go on to have long-term symptoms.

— Ravi Veriah Jacques (@RaviHVJ) February 3, 2022

Assessing their previous and current care also helps to direct their ongoing management, says Zijian Chen, MD, medical director of the Center for Post-COVID Care at Mount Sinai Health System in New York.
 

Can vaccination help people with long COVID?

Anything that we can do to help prevent people from being critically ill or being hospitalized with COVID-19 is helpful to prevent long COVID, says Dr. Abramoff, who is also director of the long COVID clinic at the University of Pennsylvania, Philadelphia.

“So that’s something I always discuss with patients. In some research, sometimes patients do feel better after the vaccine,” he says.
 

What kind of therapies do you find helpful for your patients?

Rehabilitation is a key part of recovery from long COVID, Dr. Abramoff says. “It is very important to make this very patient-specific.”

“We have patients that are working. They’re already going to the gym in some cases but don’t feel like they have the same endurance,” he says. “And then we have patients who are so crippled by their fatigue that they can’t get out of bed.”
 

1/ What is #LongCOVID?!

A disabling malady from ongoing inflammation, autoimmunity, & potential viral reservoirs (GI, brain?)

NEW DATA: The Lungs “light up” on special MRI Scans 3 to 9 months later in patients never hospitalized for COVID.https://t.co/I2kyZ4cK5F pic.twitter.com/dL1P67L2DK

— WesElyMD (@WesElyMD) February 2, 2022

An exercise program can help people who have long COVID.

“There’s a big role for therapy services in the recovery of these patients,” says John Baratta, MD, of the department of physical medicine and rehabilitation at the University of North Carolina at Chapel Hill.

But the limited number of long COVID clinics can mean some people are unable to get to therapists trained on the needs of patients with lingering COVID symptoms. Educating community physical and occupational therapists is one solution.
 

How long does it take for people with long COVID to recover and get back to 100% if they can?

Specific numbers aren’t really available, Dr. Baratta says.

“But I can tell you the general trend that I see is that a lot of patients have a gradual improvement of symptoms. The slow but steady improvement with time may be the body’s natural healing process, a result of medical interventions, or both.”

It can help to reassure people with long COVID that they will not be discharged from care until they feel they’ve maximized their health, says Sharagim Kemp, DO, medical director of the COVID Recovery Program for Nuvance Health, a health system in New York and Connecticut.

It’s essential to set realistic recovery expectations and tell patients that not everyone will return to 100% of their pre-COVID functioning, she says.

“Once we are able to help them reset their expectations, there’s almost an accelerated recovery because they are not putting that pressure on themselves anymore,” Dr. Kemp says.
 

What are the most common symptoms you’re seeing in long COVID?

It’s helpful to think of long COVID as a very broad umbrella term, Dr. Abramoff says.

Echoing what many others have observed, fatigue, cognitive dysfunction or “brain fog,“ and shortness of breath or troubled breathing appear to be the most common symptoms, he says.

Some reported vague symptoms, Dr. Kemp says.

People may go to the doctor “not even realizing that they had COVID. That’s one of the important points here – to have a high index of suspicion for patients who come in with multiple symptoms,” she says.

For this reason, patients can report symptoms that don’t necessarily fit into any specialty, says Sarah J. Ryan, MD, an internal medicine doctor at Columbia University Irving Medical Center in New York. People say they are “just not themselves” or they are tired after their COVID-19 recovery.
 

Is there a connection between severe COVID cases and severe long COVID?

“It’s not like that at all. I would say that more than 80% of the patients that we see had mild to moderate illness and they were not hospitalized,” Dr. Baratta says.

Long COVID is a bit different in children and teenagers, says Ixsy Ramirez, MD, a pediatric pulmonologist at University of Michigan Health, Ann Arbor. Most patients in the long COVID clinic at the University of Michigan were previously healthy, and not children with asthma or other lung conditions as one might expect. In fact, many are student athletes, or were before they had long COVID.

In this population, shortness of breath is most common, followed by chest pain and fatigue. Unfortunately, the symptoms are so serious for many kids that their performance is limited, even if they can return to competitive play.
 

Are there defined criteria you use to diagnose long COVID? How do you give someone a diagnosis?

That’s an ever-evolving question, Dr. Kemp says. The generally accepted definition centers on persistent or new symptoms 4 weeks or more after the original COVID-19 illness, but there are exceptions.

Researchers are working on lab tests to help confirm the diagnosis. But without a definitive blood biomarker, getting to the diagnosis requires “some thorough detective work,” Dr. Ryan says.
 

Do you bring in mental health providers to help with treatment?

“We focus on mental health quite a bit actually,” says, Dr. Chen, cofounder of his institution’s COVID recovery clinic. Mount Sinai offers one-on-one and group mental health services, for example.

“Personally, I’ve seen patients that I did not expect to have such severe mental health changes” with long COVID.
 

One of the most powerful accounts and testimonies I have seen on what most #LongCovid patients experience when interacting with their doctors.

“I did not fit in a box, so they chose not to see me, even worse they made me feel like it was my fault for not fitting in their box” pic.twitter.com/7GQLBucuO5

— charlos (@loscharlos) February 3, 2022

Examples include severe depression, cases of acute psychosis, hallucinations, and other problems “that are really unexpected after a viral illness.”

Stony Brook University Hospital in New York has a long COVID clinic staffed by multiple primary care doctors who do exams and refer patients to services. A bonus of offering psychological services to all post-COVID patients is doctors get a more complete picture of each person and a better understanding of what they are going through, says Abigail Chua, MD, a pulmonologist at Stony Brook.

Some empathy is essential, Dr. Baratta says. “It’s important to recognize that a lot of these patients present with a sense of grief or loss for their prior life.”
 

What does the future hold?

A simple test to diagnose long COVID, combined with an effective treatment that helps people feel better within a week, would be ideal, Dr. Abramoff says.

“That would be lovely. But you know, we’re just not at that point.”

And it would be helpful to start identifying subtypes of long COVID so diagnosis and treatment can be more targeted, Dr. Abramoff says. Otherwise, “It’s going to be a very challenging approach to try to treat all of our patients with long COVID symptoms the same way.”

Good clinical trials likewise are needed to address all the subtleties of long COVID.

A number of long COVID centers are collaborating on research to find out more, Dr. Chen says. Actions include setting up a bank of tissue samples from people with long COVID so researchers can continue to figure out the condition.

One goal, Dr. Chen says, would be the ability to treat long COVID rather than just its symptoms.

Long COVID emphasizes the need to prevent people from getting COVID in the first place, Dr. Ramirez says. This will continue to be important, particularly when some people dismiss the seriousness of COVID, comparing it to a cold if they get it. That attitude discounts the large number of people who unfortunately go on to develop long-term, often debilitating, symptoms.

A version of this article first appeared on WebMD.com.

Long COVID continues to be a moving target – continuously evolving and still surprising doctors and patients who have sometimes incapacitating long-term symptoms.

Little about the disorder seems predictable at this point. People can have long COVID after asymptomatic, mild, or severe COVID-19, for example. And when a person gets long COVID – also known as long-haul COVID – symptoms can vary widely.

To address all the uncertainty, the New York State Department of Health gathered experts in primary care, pediatrics, physical medicine, rehabilitation, and pulmonology to answer some pressing questions.

New York in 2020 was the first epicenter of the pandemic in the United States, making it also the center of the long COVID epidemic, says Emily Lutterloh, MD, director of the Division of Epidemiology at the New York State Department of Health.
 

What do you do when you’re seeing a patient with long COVID for the first time?

The first exam varies because there are so many different ways long COVID presents itself, says Benjamin Abramoff, MD, a physical medicine and rehabilitation specialist at Penn Medicine in Philadelphia.

I’ve now been seriously ill with #LongCovid for 11 months. I was never hospitalized. I didn’t even have a “mild” covid case. Instead, I developed Long Covid from an asymptomatic infection.

I’m far from unique. Up to 1/5 of asymptomatic patients go on to have long-term symptoms.

— Ravi Veriah Jacques (@RaviHVJ) February 3, 2022

Assessing their previous and current care also helps to direct their ongoing management, says Zijian Chen, MD, medical director of the Center for Post-COVID Care at Mount Sinai Health System in New York.
 

Can vaccination help people with long COVID?

Anything that we can do to help prevent people from being critically ill or being hospitalized with COVID-19 is helpful to prevent long COVID, says Dr. Abramoff, who is also director of the long COVID clinic at the University of Pennsylvania, Philadelphia.

“So that’s something I always discuss with patients. In some research, sometimes patients do feel better after the vaccine,” he says.
 

What kind of therapies do you find helpful for your patients?

Rehabilitation is a key part of recovery from long COVID, Dr. Abramoff says. “It is very important to make this very patient-specific.”

“We have patients that are working. They’re already going to the gym in some cases but don’t feel like they have the same endurance,” he says. “And then we have patients who are so crippled by their fatigue that they can’t get out of bed.”
 

1/ What is #LongCOVID?!

A disabling malady from ongoing inflammation, autoimmunity, & potential viral reservoirs (GI, brain?)

NEW DATA: The Lungs “light up” on special MRI Scans 3 to 9 months later in patients never hospitalized for COVID.https://t.co/I2kyZ4cK5F pic.twitter.com/dL1P67L2DK

— WesElyMD (@WesElyMD) February 2, 2022

An exercise program can help people who have long COVID.

“There’s a big role for therapy services in the recovery of these patients,” says John Baratta, MD, of the department of physical medicine and rehabilitation at the University of North Carolina at Chapel Hill.

But the limited number of long COVID clinics can mean some people are unable to get to therapists trained on the needs of patients with lingering COVID symptoms. Educating community physical and occupational therapists is one solution.
 

How long does it take for people with long COVID to recover and get back to 100% if they can?

Specific numbers aren’t really available, Dr. Baratta says.

“But I can tell you the general trend that I see is that a lot of patients have a gradual improvement of symptoms. The slow but steady improvement with time may be the body’s natural healing process, a result of medical interventions, or both.”

It can help to reassure people with long COVID that they will not be discharged from care until they feel they’ve maximized their health, says Sharagim Kemp, DO, medical director of the COVID Recovery Program for Nuvance Health, a health system in New York and Connecticut.

It’s essential to set realistic recovery expectations and tell patients that not everyone will return to 100% of their pre-COVID functioning, she says.

“Once we are able to help them reset their expectations, there’s almost an accelerated recovery because they are not putting that pressure on themselves anymore,” Dr. Kemp says.
 

What are the most common symptoms you’re seeing in long COVID?

It’s helpful to think of long COVID as a very broad umbrella term, Dr. Abramoff says.

Echoing what many others have observed, fatigue, cognitive dysfunction or “brain fog,“ and shortness of breath or troubled breathing appear to be the most common symptoms, he says.

Some reported vague symptoms, Dr. Kemp says.

People may go to the doctor “not even realizing that they had COVID. That’s one of the important points here – to have a high index of suspicion for patients who come in with multiple symptoms,” she says.

For this reason, patients can report symptoms that don’t necessarily fit into any specialty, says Sarah J. Ryan, MD, an internal medicine doctor at Columbia University Irving Medical Center in New York. People say they are “just not themselves” or they are tired after their COVID-19 recovery.
 

Is there a connection between severe COVID cases and severe long COVID?

“It’s not like that at all. I would say that more than 80% of the patients that we see had mild to moderate illness and they were not hospitalized,” Dr. Baratta says.

Long COVID is a bit different in children and teenagers, says Ixsy Ramirez, MD, a pediatric pulmonologist at University of Michigan Health, Ann Arbor. Most patients in the long COVID clinic at the University of Michigan were previously healthy, and not children with asthma or other lung conditions as one might expect. In fact, many are student athletes, or were before they had long COVID.

In this population, shortness of breath is most common, followed by chest pain and fatigue. Unfortunately, the symptoms are so serious for many kids that their performance is limited, even if they can return to competitive play.
 

Are there defined criteria you use to diagnose long COVID? How do you give someone a diagnosis?

That’s an ever-evolving question, Dr. Kemp says. The generally accepted definition centers on persistent or new symptoms 4 weeks or more after the original COVID-19 illness, but there are exceptions.

Researchers are working on lab tests to help confirm the diagnosis. But without a definitive blood biomarker, getting to the diagnosis requires “some thorough detective work,” Dr. Ryan says.
 

Do you bring in mental health providers to help with treatment?

“We focus on mental health quite a bit actually,” says, Dr. Chen, cofounder of his institution’s COVID recovery clinic. Mount Sinai offers one-on-one and group mental health services, for example.

“Personally, I’ve seen patients that I did not expect to have such severe mental health changes” with long COVID.
 

One of the most powerful accounts and testimonies I have seen on what most #LongCovid patients experience when interacting with their doctors.

“I did not fit in a box, so they chose not to see me, even worse they made me feel like it was my fault for not fitting in their box” pic.twitter.com/7GQLBucuO5

— charlos (@loscharlos) February 3, 2022

Examples include severe depression, cases of acute psychosis, hallucinations, and other problems “that are really unexpected after a viral illness.”

Stony Brook University Hospital in New York has a long COVID clinic staffed by multiple primary care doctors who do exams and refer patients to services. A bonus of offering psychological services to all post-COVID patients is doctors get a more complete picture of each person and a better understanding of what they are going through, says Abigail Chua, MD, a pulmonologist at Stony Brook.

Some empathy is essential, Dr. Baratta says. “It’s important to recognize that a lot of these patients present with a sense of grief or loss for their prior life.”
 

What does the future hold?

A simple test to diagnose long COVID, combined with an effective treatment that helps people feel better within a week, would be ideal, Dr. Abramoff says.

“That would be lovely. But you know, we’re just not at that point.”

And it would be helpful to start identifying subtypes of long COVID so diagnosis and treatment can be more targeted, Dr. Abramoff says. Otherwise, “It’s going to be a very challenging approach to try to treat all of our patients with long COVID symptoms the same way.”

Good clinical trials likewise are needed to address all the subtleties of long COVID.

A number of long COVID centers are collaborating on research to find out more, Dr. Chen says. Actions include setting up a bank of tissue samples from people with long COVID so researchers can continue to figure out the condition.

One goal, Dr. Chen says, would be the ability to treat long COVID rather than just its symptoms.

Long COVID emphasizes the need to prevent people from getting COVID in the first place, Dr. Ramirez says. This will continue to be important, particularly when some people dismiss the seriousness of COVID, comparing it to a cold if they get it. That attitude discounts the large number of people who unfortunately go on to develop long-term, often debilitating, symptoms.

A version of this article first appeared on WebMD.com.

Two illicit drugs are contributing to a sharp rise in fentanyl-related deaths, a new study from the Centers for Disease Control and Prevention shows.

Para-fluorofentanyl, a schedule I substance often found in heroin packets and counterfeit pills, is making a comeback on the illicit drug market, Jordan Trecki, PhD, and associates reported in the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report (2022 Jan 28;71[4]:153-5). U.S. medical examiner reports and national law enforcement seizure data point to a rise in encounters of this drug along with metonitazene, a benzimidazole-opioid, in combination with fentanyl.

On their own, para-fluorofentanyl and metonitazene can kill the user through respiratory depression. Combinations of these substances and other opioids, including fentanyl-related compounds or adulterants, “pose an even greater potential harm to the patient than previously observed,” reported Dr. Trecki, a pharmacologist affiliated with the Drug Enforcement Administration, and colleagues.

Opioids contribute to about 75% of all U.S. drug overdose deaths, which rose by 28.5% during 2020-2021, according to the National Center for Health Statistics. And fentanyl is replacing heroin as the primary drug of use, said addiction specialist Brian Fuehrlein, MD, PhD, in an interview.

“For patients with stimulant use disorder and even cannabis use disorder, fentanyl is becoming more and more common as an adulterant in those substances, often resulting in inadvertent use. Hence, fentanyl and fentanyl-like drugs and fentanyl analogues are becoming increasingly common and important,” said Dr. Fuehrlein, director of the psychiatric emergency room at the VA Connecticut Healthcare System. He was not involved with the MMWR study.
 

Tennessee data reflect national problem

Recent data from a medical examiner in Knoxville, Tenn., illustrate what might be happening nationwide with those two emerging substances.

Over the last 2 years, the Knox County Regional Forensic Center has identified para-fluorofentanyl in the toxicology results of drug overdose victims, and metonitazene – either on its own or in combination with fentanyl and para-fluorofentanyl. Fentanyl appeared in 562 or 73% of 770 unintentional drug overdose deaths from November 2020 to August 2021. Forty-eight of these cases involved para-fluorofentanyl, and 26 involved metonitazene.

“Although the percentage of law enforcement encounters with these substances in Tennessee decreased relative to the national total percentage within this time frame, the increase in encounters both within Tennessee and nationally reflect an increased distribution of para-fluorofentanyl and metonitazene throughout the United States,” the authors reported.
 

How to identify substances, manage overdoses

The authors encouraged physicians, labs, and medical examiners to be on the lookout for these two substances either in the emergency department or when identifying the cause of drug overdose deaths.

They also advised that stronger opioids, such as fentanyl, para-fluorofentanyl, metonitazene, or other benzimidazoles may warrant additional doses of the opioid-reversal drug naloxone.

While he hasn’t personally seen any of these drugs in his practice, “I would assume that these are on the rise due to inexpensive cost to manufacture and potency of effect,” said Dr. Fuehrlein, also an associate professor of psychiatry at Yale University, New Haven, Conn.

The need for additional naloxone to manage acute overdoses is a key takeaway of the MMWR paper, he added. Clinicians should also educate patients about harm reduction strategies to avoid overdose death when using potentially powerful and unknown drugs. “Things like start low and go slow, buy from the same supplier, do not use opioids with alcohol or benzos, have Narcan available, do not use alone, etc.”

Dr. Fuehrlein had no disclosures.

Two illicit drugs are contributing to a sharp rise in fentanyl-related deaths, a new study from the Centers for Disease Control and Prevention shows.

Para-fluorofentanyl, a schedule I substance often found in heroin packets and counterfeit pills, is making a comeback on the illicit drug market, Jordan Trecki, PhD, and associates reported in the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report (2022 Jan 28;71[4]:153-5). U.S. medical examiner reports and national law enforcement seizure data point to a rise in encounters of this drug along with metonitazene, a benzimidazole-opioid, in combination with fentanyl.

On their own, para-fluorofentanyl and metonitazene can kill the user through respiratory depression. Combinations of these substances and other opioids, including fentanyl-related compounds or adulterants, “pose an even greater potential harm to the patient than previously observed,” reported Dr. Trecki, a pharmacologist affiliated with the Drug Enforcement Administration, and colleagues.

Opioids contribute to about 75% of all U.S. drug overdose deaths, which rose by 28.5% during 2020-2021, according to the National Center for Health Statistics. And fentanyl is replacing heroin as the primary drug of use, said addiction specialist Brian Fuehrlein, MD, PhD, in an interview.

“For patients with stimulant use disorder and even cannabis use disorder, fentanyl is becoming more and more common as an adulterant in those substances, often resulting in inadvertent use. Hence, fentanyl and fentanyl-like drugs and fentanyl analogues are becoming increasingly common and important,” said Dr. Fuehrlein, director of the psychiatric emergency room at the VA Connecticut Healthcare System. He was not involved with the MMWR study.
 

Tennessee data reflect national problem

Recent data from a medical examiner in Knoxville, Tenn., illustrate what might be happening nationwide with those two emerging substances.

Over the last 2 years, the Knox County Regional Forensic Center has identified para-fluorofentanyl in the toxicology results of drug overdose victims, and metonitazene – either on its own or in combination with fentanyl and para-fluorofentanyl. Fentanyl appeared in 562 or 73% of 770 unintentional drug overdose deaths from November 2020 to August 2021. Forty-eight of these cases involved para-fluorofentanyl, and 26 involved metonitazene.

“Although the percentage of law enforcement encounters with these substances in Tennessee decreased relative to the national total percentage within this time frame, the increase in encounters both within Tennessee and nationally reflect an increased distribution of para-fluorofentanyl and metonitazene throughout the United States,” the authors reported.
 

How to identify substances, manage overdoses

The authors encouraged physicians, labs, and medical examiners to be on the lookout for these two substances either in the emergency department or when identifying the cause of drug overdose deaths.

They also advised that stronger opioids, such as fentanyl, para-fluorofentanyl, metonitazene, or other benzimidazoles may warrant additional doses of the opioid-reversal drug naloxone.

While he hasn’t personally seen any of these drugs in his practice, “I would assume that these are on the rise due to inexpensive cost to manufacture and potency of effect,” said Dr. Fuehrlein, also an associate professor of psychiatry at Yale University, New Haven, Conn.

The need for additional naloxone to manage acute overdoses is a key takeaway of the MMWR paper, he added. Clinicians should also educate patients about harm reduction strategies to avoid overdose death when using potentially powerful and unknown drugs. “Things like start low and go slow, buy from the same supplier, do not use opioids with alcohol or benzos, have Narcan available, do not use alone, etc.”

Dr. Fuehrlein had no disclosures.

Two illicit drugs are contributing to a sharp rise in fentanyl-related deaths, a new study from the Centers for Disease Control and Prevention shows.

Para-fluorofentanyl, a schedule I substance often found in heroin packets and counterfeit pills, is making a comeback on the illicit drug market, Jordan Trecki, PhD, and associates reported in the Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report (2022 Jan 28;71[4]:153-5). U.S. medical examiner reports and national law enforcement seizure data point to a rise in encounters of this drug along with metonitazene, a benzimidazole-opioid, in combination with fentanyl.

On their own, para-fluorofentanyl and metonitazene can kill the user through respiratory depression. Combinations of these substances and other opioids, including fentanyl-related compounds or adulterants, “pose an even greater potential harm to the patient than previously observed,” reported Dr. Trecki, a pharmacologist affiliated with the Drug Enforcement Administration, and colleagues.

Opioids contribute to about 75% of all U.S. drug overdose deaths, which rose by 28.5% during 2020-2021, according to the National Center for Health Statistics. And fentanyl is replacing heroin as the primary drug of use, said addiction specialist Brian Fuehrlein, MD, PhD, in an interview.

“For patients with stimulant use disorder and even cannabis use disorder, fentanyl is becoming more and more common as an adulterant in those substances, often resulting in inadvertent use. Hence, fentanyl and fentanyl-like drugs and fentanyl analogues are becoming increasingly common and important,” said Dr. Fuehrlein, director of the psychiatric emergency room at the VA Connecticut Healthcare System. He was not involved with the MMWR study.
 

Tennessee data reflect national problem

Recent data from a medical examiner in Knoxville, Tenn., illustrate what might be happening nationwide with those two emerging substances.

Over the last 2 years, the Knox County Regional Forensic Center has identified para-fluorofentanyl in the toxicology results of drug overdose victims, and metonitazene – either on its own or in combination with fentanyl and para-fluorofentanyl. Fentanyl appeared in 562 or 73% of 770 unintentional drug overdose deaths from November 2020 to August 2021. Forty-eight of these cases involved para-fluorofentanyl, and 26 involved metonitazene.

“Although the percentage of law enforcement encounters with these substances in Tennessee decreased relative to the national total percentage within this time frame, the increase in encounters both within Tennessee and nationally reflect an increased distribution of para-fluorofentanyl and metonitazene throughout the United States,” the authors reported.
 

How to identify substances, manage overdoses

The authors encouraged physicians, labs, and medical examiners to be on the lookout for these two substances either in the emergency department or when identifying the cause of drug overdose deaths.

They also advised that stronger opioids, such as fentanyl, para-fluorofentanyl, metonitazene, or other benzimidazoles may warrant additional doses of the opioid-reversal drug naloxone.

While he hasn’t personally seen any of these drugs in his practice, “I would assume that these are on the rise due to inexpensive cost to manufacture and potency of effect,” said Dr. Fuehrlein, also an associate professor of psychiatry at Yale University, New Haven, Conn.

The need for additional naloxone to manage acute overdoses is a key takeaway of the MMWR paper, he added. Clinicians should also educate patients about harm reduction strategies to avoid overdose death when using potentially powerful and unknown drugs. “Things like start low and go slow, buy from the same supplier, do not use opioids with alcohol or benzos, have Narcan available, do not use alone, etc.”

Dr. Fuehrlein had no disclosures.

As rheumatologists contend with vaccine hesitancy among certain subsets of patients, the American College of Rheumatology has released updated clinical guidelines on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases (RMDs), including new recommendations on supplemental and booster doses.

The revised guidance from this fifth version of the ACR guidelines includes strongly recommending that all RMD patients receive a booster after their primary vaccine series, regardless of whether they have been naturally infected with COVID-19. In addition, they strongly recommend third supplemental doses for patients with autoimmune inflammatory rheumatic diseases (AIIRDs) who likely mounted an inadequate vaccine response, which would then be followed by a fourth booster dose as advised by the Centers for Disease Control and Prevention for immunocompromised individuals.

South_agency/Getty Images

Other recommendations include pre-exposure prophylaxis monoclonal antibody treatment for high-risk AIIRD patients, defined as those with moderate to severely compromised immune systems who may not mount an adequate immune response to COVID-19 vaccination, when it is available and authorized for emergency use by the Food and Drug Administration, as well as monoclonal antibody therapy for postexposure prophylaxis of asymptomatic, recently exposed high-risk AIIRD patients or as treatment for newly symptomatic, high-risk AIIRD patients. The ACR guidance notes that, currently, neither the monoclonal antibodies bamlanivimab and etesevimab (administered together) nor casirivimab and imdevimab (REGEN-COV), are licensed or available under an emergency use authorization given their lack of activity against the Omicron variant, the dominant strain of SARS-CoV-2 circulating in the United States.

Finally, the guidance clarified that the timing of intravenous immunoglobulin doses does not need to be modified around the administration of COVID vaccine doses, based on moderate consensus among task force members.

Vaccine hesitancy in community rheumatology practices

The revised guidelines were released just as Arthritis & Rheumatology published a new study that assessed vaccine hesitancy among rheumatology patients on immunomodulatory therapies. A three-item electronic survey was conducted at 101 offices within a community practice–based rheumatology research network and ultimately collected responses from 58,529 patients, 20,987 of whom had an AIIRD and were receiving targeted therapies like biologics or Janus kinase inhibitors.

Of the total respondents, 77% (n = 43,675) had been vaccinated, 16.9% were not vaccinated and did not plan to be, and 6.1% were not vaccinated but planned to be. However, AIIRD patients were 16% less likely to be vaccinated, compared with the other patients, such as those with osteoarthritis or osteoporosis who were not receiving disease-modifying antirheumatic drugs (76.9% vs. 87%; odds ratio, 0.84; 95% confidence interval, 0.77-0.92; P < .001). Multivariable analysis also found that older patients (OR, 1.49 per 10 years) and Asians (OR, 2.42; 95% CI, 1.77-3.33) were more likely to be vaccinated.

Courtesy UAB Photo

“Rheumatologists need to be asking their patients more than just: ‘Are you vaccinated?’ ” Jeffrey Curtis, MD, MPH, head of the ACR COVID-19 vaccine task force and a coauthor of the vaccine hesitancy study, said in an interview. “A year ago, that was a fine approach, but now they need to be asking whether you’ve been vaccinated, and with what, and how many times, and how recently. There are a whole lot of subtleties there; ‘vaccinated: yes or no’ is just the tip of the iceberg.”

His research into the vaccine hesitant includes recent anecdotal data from thousands of patients treated in local rheumatology community practices, many of whom cited long-term safety data and potential side effects as reasons why they were unwilling to get vaccinated. But despite their on-paper responses, he cautioned rheumatologists to think critically when determining which patients may truly be open to vaccination.

“If you’re designing strategies to affect vaccine hesitancy, you may be wasting your time with some people,” said Dr. Curtis, professor of medicine at the University of Alabama at Birmingham. “A critical need is to figure out who are the patients who may be amendable to more information or an intervention or a little bit more time and care, and who are the people where you know, this is a lost cause: You don’t get a flu shot, you haven’t been vaccinated for shingles, [and] you’re not going to get this one either.

“In terms of a research agenda, how do we develop efficient, simple, short screening tools?” he added. “Something with a few helpful questions, on a patient portal or an iPad, that will do a good job identifying your patients at risk who haven’t had vaccination but that you might be able to spend time with, intervene, and actually change their mind. If you spend gobs of time with everyone, you’ll help some people, but clinicians don’t have an infinite amount of time.”

One of the authors of the vaccine hesitancy study acknowledged being employed by the rheumatology research network that hosted the survey. Several others, including Dr. Curtis, reported receiving grants and consulting fees from various pharmaceutical companies.

As rheumatologists contend with vaccine hesitancy among certain subsets of patients, the American College of Rheumatology has released updated clinical guidelines on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases (RMDs), including new recommendations on supplemental and booster doses.

The revised guidance from this fifth version of the ACR guidelines includes strongly recommending that all RMD patients receive a booster after their primary vaccine series, regardless of whether they have been naturally infected with COVID-19. In addition, they strongly recommend third supplemental doses for patients with autoimmune inflammatory rheumatic diseases (AIIRDs) who likely mounted an inadequate vaccine response, which would then be followed by a fourth booster dose as advised by the Centers for Disease Control and Prevention for immunocompromised individuals.

South_agency/Getty Images

Other recommendations include pre-exposure prophylaxis monoclonal antibody treatment for high-risk AIIRD patients, defined as those with moderate to severely compromised immune systems who may not mount an adequate immune response to COVID-19 vaccination, when it is available and authorized for emergency use by the Food and Drug Administration, as well as monoclonal antibody therapy for postexposure prophylaxis of asymptomatic, recently exposed high-risk AIIRD patients or as treatment for newly symptomatic, high-risk AIIRD patients. The ACR guidance notes that, currently, neither the monoclonal antibodies bamlanivimab and etesevimab (administered together) nor casirivimab and imdevimab (REGEN-COV), are licensed or available under an emergency use authorization given their lack of activity against the Omicron variant, the dominant strain of SARS-CoV-2 circulating in the United States.

Finally, the guidance clarified that the timing of intravenous immunoglobulin doses does not need to be modified around the administration of COVID vaccine doses, based on moderate consensus among task force members.

Vaccine hesitancy in community rheumatology practices

The revised guidelines were released just as Arthritis & Rheumatology published a new study that assessed vaccine hesitancy among rheumatology patients on immunomodulatory therapies. A three-item electronic survey was conducted at 101 offices within a community practice–based rheumatology research network and ultimately collected responses from 58,529 patients, 20,987 of whom had an AIIRD and were receiving targeted therapies like biologics or Janus kinase inhibitors.

Of the total respondents, 77% (n = 43,675) had been vaccinated, 16.9% were not vaccinated and did not plan to be, and 6.1% were not vaccinated but planned to be. However, AIIRD patients were 16% less likely to be vaccinated, compared with the other patients, such as those with osteoarthritis or osteoporosis who were not receiving disease-modifying antirheumatic drugs (76.9% vs. 87%; odds ratio, 0.84; 95% confidence interval, 0.77-0.92; P < .001). Multivariable analysis also found that older patients (OR, 1.49 per 10 years) and Asians (OR, 2.42; 95% CI, 1.77-3.33) were more likely to be vaccinated.

Courtesy UAB Photo

“Rheumatologists need to be asking their patients more than just: ‘Are you vaccinated?’ ” Jeffrey Curtis, MD, MPH, head of the ACR COVID-19 vaccine task force and a coauthor of the vaccine hesitancy study, said in an interview. “A year ago, that was a fine approach, but now they need to be asking whether you’ve been vaccinated, and with what, and how many times, and how recently. There are a whole lot of subtleties there; ‘vaccinated: yes or no’ is just the tip of the iceberg.”

His research into the vaccine hesitant includes recent anecdotal data from thousands of patients treated in local rheumatology community practices, many of whom cited long-term safety data and potential side effects as reasons why they were unwilling to get vaccinated. But despite their on-paper responses, he cautioned rheumatologists to think critically when determining which patients may truly be open to vaccination.

“If you’re designing strategies to affect vaccine hesitancy, you may be wasting your time with some people,” said Dr. Curtis, professor of medicine at the University of Alabama at Birmingham. “A critical need is to figure out who are the patients who may be amendable to more information or an intervention or a little bit more time and care, and who are the people where you know, this is a lost cause: You don’t get a flu shot, you haven’t been vaccinated for shingles, [and] you’re not going to get this one either.

“In terms of a research agenda, how do we develop efficient, simple, short screening tools?” he added. “Something with a few helpful questions, on a patient portal or an iPad, that will do a good job identifying your patients at risk who haven’t had vaccination but that you might be able to spend time with, intervene, and actually change their mind. If you spend gobs of time with everyone, you’ll help some people, but clinicians don’t have an infinite amount of time.”

One of the authors of the vaccine hesitancy study acknowledged being employed by the rheumatology research network that hosted the survey. Several others, including Dr. Curtis, reported receiving grants and consulting fees from various pharmaceutical companies.

As rheumatologists contend with vaccine hesitancy among certain subsets of patients, the American College of Rheumatology has released updated clinical guidelines on COVID-19 vaccination for patients with rheumatic and musculoskeletal diseases (RMDs), including new recommendations on supplemental and booster doses.

The revised guidance from this fifth version of the ACR guidelines includes strongly recommending that all RMD patients receive a booster after their primary vaccine series, regardless of whether they have been naturally infected with COVID-19. In addition, they strongly recommend third supplemental doses for patients with autoimmune inflammatory rheumatic diseases (AIIRDs) who likely mounted an inadequate vaccine response, which would then be followed by a fourth booster dose as advised by the Centers for Disease Control and Prevention for immunocompromised individuals.

South_agency/Getty Images

Other recommendations include pre-exposure prophylaxis monoclonal antibody treatment for high-risk AIIRD patients, defined as those with moderate to severely compromised immune systems who may not mount an adequate immune response to COVID-19 vaccination, when it is available and authorized for emergency use by the Food and Drug Administration, as well as monoclonal antibody therapy for postexposure prophylaxis of asymptomatic, recently exposed high-risk AIIRD patients or as treatment for newly symptomatic, high-risk AIIRD patients. The ACR guidance notes that, currently, neither the monoclonal antibodies bamlanivimab and etesevimab (administered together) nor casirivimab and imdevimab (REGEN-COV), are licensed or available under an emergency use authorization given their lack of activity against the Omicron variant, the dominant strain of SARS-CoV-2 circulating in the United States.

Finally, the guidance clarified that the timing of intravenous immunoglobulin doses does not need to be modified around the administration of COVID vaccine doses, based on moderate consensus among task force members.

Vaccine hesitancy in community rheumatology practices

The revised guidelines were released just as Arthritis & Rheumatology published a new study that assessed vaccine hesitancy among rheumatology patients on immunomodulatory therapies. A three-item electronic survey was conducted at 101 offices within a community practice–based rheumatology research network and ultimately collected responses from 58,529 patients, 20,987 of whom had an AIIRD and were receiving targeted therapies like biologics or Janus kinase inhibitors.

Of the total respondents, 77% (n = 43,675) had been vaccinated, 16.9% were not vaccinated and did not plan to be, and 6.1% were not vaccinated but planned to be. However, AIIRD patients were 16% less likely to be vaccinated, compared with the other patients, such as those with osteoarthritis or osteoporosis who were not receiving disease-modifying antirheumatic drugs (76.9% vs. 87%; odds ratio, 0.84; 95% confidence interval, 0.77-0.92; P < .001). Multivariable analysis also found that older patients (OR, 1.49 per 10 years) and Asians (OR, 2.42; 95% CI, 1.77-3.33) were more likely to be vaccinated.

Courtesy UAB Photo

“Rheumatologists need to be asking their patients more than just: ‘Are you vaccinated?’ ” Jeffrey Curtis, MD, MPH, head of the ACR COVID-19 vaccine task force and a coauthor of the vaccine hesitancy study, said in an interview. “A year ago, that was a fine approach, but now they need to be asking whether you’ve been vaccinated, and with what, and how many times, and how recently. There are a whole lot of subtleties there; ‘vaccinated: yes or no’ is just the tip of the iceberg.”

His research into the vaccine hesitant includes recent anecdotal data from thousands of patients treated in local rheumatology community practices, many of whom cited long-term safety data and potential side effects as reasons why they were unwilling to get vaccinated. But despite their on-paper responses, he cautioned rheumatologists to think critically when determining which patients may truly be open to vaccination.

“If you’re designing strategies to affect vaccine hesitancy, you may be wasting your time with some people,” said Dr. Curtis, professor of medicine at the University of Alabama at Birmingham. “A critical need is to figure out who are the patients who may be amendable to more information or an intervention or a little bit more time and care, and who are the people where you know, this is a lost cause: You don’t get a flu shot, you haven’t been vaccinated for shingles, [and] you’re not going to get this one either.

“In terms of a research agenda, how do we develop efficient, simple, short screening tools?” he added. “Something with a few helpful questions, on a patient portal or an iPad, that will do a good job identifying your patients at risk who haven’t had vaccination but that you might be able to spend time with, intervene, and actually change their mind. If you spend gobs of time with everyone, you’ll help some people, but clinicians don’t have an infinite amount of time.”

One of the authors of the vaccine hesitancy study acknowledged being employed by the rheumatology research network that hosted the survey. Several others, including Dr. Curtis, reported receiving grants and consulting fees from various pharmaceutical companies.