Key clinical point: In patients with newly diagnosed rheumatoid arthritis (RA), initial glucocorticoid bridging (GB) led to more rapid clinical improvements than non-bridging, without any apparent risk for increased glucocorticoid use after the intended bridging period.

Major finding: The risk of using glucocorticoids at 12 months was higher in the GB vs non-bridging group, but this risk reduced over time and was not significantly different at 18 and 24 months. The cumulative doses did not differ significantly between groups after the planned bridging schedule. Patients in the GB group showed more rapid improvements in the mean Disease Activity Score of 28 Joints during the first 6 months (P < .001).

Study details: This individual patient data meta-analysis combined data from three randomized clinical trials and included 625 patients with newly diagnosed RA who received conventional synthetic disease-modifying antirheumatic drugs with (n = 252) or without (n = 373) initial GB.

Disclosures: This study did not declare any specific funding source. Some authors declared receiving consultancy or speaker honoraria, fees, or grants from or providing expert advice or testimony for or serving as chair for various sources.

Source: van Ouwerkerk L et al. Initial glucocorticoid bridging in rheumatoid arthritis: Does it affect glucocorticoid use over time? Ann Rheum Dis. 2023 (Aug 22). doi: 10.1136/ard-2023-224270

Key clinical point: In patients with newly diagnosed rheumatoid arthritis (RA), initial glucocorticoid bridging (GB) led to more rapid clinical improvements than non-bridging, without any apparent risk for increased glucocorticoid use after the intended bridging period.

Major finding: The risk of using glucocorticoids at 12 months was higher in the GB vs non-bridging group, but this risk reduced over time and was not significantly different at 18 and 24 months. The cumulative doses did not differ significantly between groups after the planned bridging schedule. Patients in the GB group showed more rapid improvements in the mean Disease Activity Score of 28 Joints during the first 6 months (P < .001).

Study details: This individual patient data meta-analysis combined data from three randomized clinical trials and included 625 patients with newly diagnosed RA who received conventional synthetic disease-modifying antirheumatic drugs with (n = 252) or without (n = 373) initial GB.

Disclosures: This study did not declare any specific funding source. Some authors declared receiving consultancy or speaker honoraria, fees, or grants from or providing expert advice or testimony for or serving as chair for various sources.

Source: van Ouwerkerk L et al. Initial glucocorticoid bridging in rheumatoid arthritis: Does it affect glucocorticoid use over time? Ann Rheum Dis. 2023 (Aug 22). doi: 10.1136/ard-2023-224270

Key clinical point: In patients with newly diagnosed rheumatoid arthritis (RA), initial glucocorticoid bridging (GB) led to more rapid clinical improvements than non-bridging, without any apparent risk for increased glucocorticoid use after the intended bridging period.

Major finding: The risk of using glucocorticoids at 12 months was higher in the GB vs non-bridging group, but this risk reduced over time and was not significantly different at 18 and 24 months. The cumulative doses did not differ significantly between groups after the planned bridging schedule. Patients in the GB group showed more rapid improvements in the mean Disease Activity Score of 28 Joints during the first 6 months (P < .001).

Study details: This individual patient data meta-analysis combined data from three randomized clinical trials and included 625 patients with newly diagnosed RA who received conventional synthetic disease-modifying antirheumatic drugs with (n = 252) or without (n = 373) initial GB.

Disclosures: This study did not declare any specific funding source. Some authors declared receiving consultancy or speaker honoraria, fees, or grants from or providing expert advice or testimony for or serving as chair for various sources.

Source: van Ouwerkerk L et al. Initial glucocorticoid bridging in rheumatoid arthritis: Does it affect glucocorticoid use over time? Ann Rheum Dis. 2023 (Aug 22). doi: 10.1136/ard-2023-224270

Key clinical point: In patients with newly diagnosed rheumatoid arthritis (RA), initial glucocorticoid bridging (GB) led to more rapid clinical improvements than non-bridging, without any apparent risk for increased glucocorticoid use after the intended bridging period.

Major finding: The risk of using glucocorticoids at 12 months was higher in the GB vs non-bridging group, but this risk reduced over time and was not significantly different at 18 and 24 months. The cumulative doses did not differ significantly between groups after the planned bridging schedule. Patients in the GB group showed more rapid improvements in the mean Disease Activity Score of 28 Joints during the first 6 months (P < .001).

Study details: This individual patient data meta-analysis combined data from three randomized clinical trials and included 625 patients with newly diagnosed RA who received conventional synthetic disease-modifying antirheumatic drugs with (n = 252) or without (n = 373) initial GB.

Disclosures: This study did not declare any specific funding source. Some authors declared receiving consultancy or speaker honoraria, fees, or grants from or providing expert advice or testimony for or serving as chair for various sources.

Source: van Ouwerkerk L et al. Initial glucocorticoid bridging in rheumatoid arthritis: Does it affect glucocorticoid use over time? Ann Rheum Dis. 2023 (Aug 22). doi: 10.1136/ard-2023-224270

Key clinical point: In patients with newly diagnosed rheumatoid arthritis (RA), initial glucocorticoid bridging (GB) led to more rapid clinical improvements than non-bridging, without any apparent risk for increased glucocorticoid use after the intended bridging period.

Major finding: The risk of using glucocorticoids at 12 months was higher in the GB vs non-bridging group, but this risk reduced over time and was not significantly different at 18 and 24 months. The cumulative doses did not differ significantly between groups after the planned bridging schedule. Patients in the GB group showed more rapid improvements in the mean Disease Activity Score of 28 Joints during the first 6 months (P < .001).

Study details: This individual patient data meta-analysis combined data from three randomized clinical trials and included 625 patients with newly diagnosed RA who received conventional synthetic disease-modifying antirheumatic drugs with (n = 252) or without (n = 373) initial GB.

Disclosures: This study did not declare any specific funding source. Some authors declared receiving consultancy or speaker honoraria, fees, or grants from or providing expert advice or testimony for or serving as chair for various sources.

Source: van Ouwerkerk L et al. Initial glucocorticoid bridging in rheumatoid arthritis: Does it affect glucocorticoid use over time? Ann Rheum Dis. 2023 (Aug 22). doi: 10.1136/ard-2023-224270

Key clinical point: In patients with newly diagnosed rheumatoid arthritis (RA), initial glucocorticoid bridging (GB) led to more rapid clinical improvements than non-bridging, without any apparent risk for increased glucocorticoid use after the intended bridging period.

Major finding: The risk of using glucocorticoids at 12 months was higher in the GB vs non-bridging group, but this risk reduced over time and was not significantly different at 18 and 24 months. The cumulative doses did not differ significantly between groups after the planned bridging schedule. Patients in the GB group showed more rapid improvements in the mean Disease Activity Score of 28 Joints during the first 6 months (P < .001).

Study details: This individual patient data meta-analysis combined data from three randomized clinical trials and included 625 patients with newly diagnosed RA who received conventional synthetic disease-modifying antirheumatic drugs with (n = 252) or without (n = 373) initial GB.

Disclosures: This study did not declare any specific funding source. Some authors declared receiving consultancy or speaker honoraria, fees, or grants from or providing expert advice or testimony for or serving as chair for various sources.

Source: van Ouwerkerk L et al. Initial glucocorticoid bridging in rheumatoid arthritis: Does it affect glucocorticoid use over time? Ann Rheum Dis. 2023 (Aug 22). doi: 10.1136/ard-2023-224270

Key clinical point: Patients with rheumatoid arthritis (RA) in long-standing remission had a significant risk of experiencing a disease flare if the tumor necrosis factor inhibitor (TNFi) dose is tapered to discontinuation, but most patients regained remission after the original TNFi dose was reinstated.

Major finding: The frequency of disease activity flares during the 12-month follow-up was significantly higher among patients who tapered TNFi to discontinuation vs those who continued with the stable dose (risk difference 58%; P < .0001). However, reinstatement of the initial TNFi dose led to comparable remission rates in both treatment groups.

Study details: Findings are from the phase 4 ARCTIC REWIND trial including 92 patients with RA in sustained remission for ≥ 1 year on stable TNFi therapy and without swollen joints at inclusion, who were randomly assigned to either tapering of their TNFi dose to discontinuation or to a continued stable TNFi dose.

Disclosures: This study was funded by the Research Council of Norway and South-Eastern Norway Regional Health Authority. Some authors declared receiving personal fees or grants from various sources, including the study funders.

Source: Lillegraven S et al. Effect of tapered versus stable treatment with tumour necrosis factor inhibitors on disease flares in patients with rheumatoid arthritis in remission: A randomised, open label, non-inferiority trial. Ann Rheum Dis. 2023 (Aug 22). doi: 10.1136/ard-2023-224476

Key clinical point: Patients with rheumatoid arthritis (RA) in long-standing remission had a significant risk of experiencing a disease flare if the tumor necrosis factor inhibitor (TNFi) dose is tapered to discontinuation, but most patients regained remission after the original TNFi dose was reinstated.

Major finding: The frequency of disease activity flares during the 12-month follow-up was significantly higher among patients who tapered TNFi to discontinuation vs those who continued with the stable dose (risk difference 58%; P < .0001). However, reinstatement of the initial TNFi dose led to comparable remission rates in both treatment groups.

Study details: Findings are from the phase 4 ARCTIC REWIND trial including 92 patients with RA in sustained remission for ≥ 1 year on stable TNFi therapy and without swollen joints at inclusion, who were randomly assigned to either tapering of their TNFi dose to discontinuation or to a continued stable TNFi dose.

Disclosures: This study was funded by the Research Council of Norway and South-Eastern Norway Regional Health Authority. Some authors declared receiving personal fees or grants from various sources, including the study funders.

Source: Lillegraven S et al. Effect of tapered versus stable treatment with tumour necrosis factor inhibitors on disease flares in patients with rheumatoid arthritis in remission: A randomised, open label, non-inferiority trial. Ann Rheum Dis. 2023 (Aug 22). doi: 10.1136/ard-2023-224476

Key clinical point: Patients with rheumatoid arthritis (RA) in long-standing remission had a significant risk of experiencing a disease flare if the tumor necrosis factor inhibitor (TNFi) dose is tapered to discontinuation, but most patients regained remission after the original TNFi dose was reinstated.

Major finding: The frequency of disease activity flares during the 12-month follow-up was significantly higher among patients who tapered TNFi to discontinuation vs those who continued with the stable dose (risk difference 58%; P < .0001). However, reinstatement of the initial TNFi dose led to comparable remission rates in both treatment groups.

Study details: Findings are from the phase 4 ARCTIC REWIND trial including 92 patients with RA in sustained remission for ≥ 1 year on stable TNFi therapy and without swollen joints at inclusion, who were randomly assigned to either tapering of their TNFi dose to discontinuation or to a continued stable TNFi dose.

Disclosures: This study was funded by the Research Council of Norway and South-Eastern Norway Regional Health Authority. Some authors declared receiving personal fees or grants from various sources, including the study funders.

Source: Lillegraven S et al. Effect of tapered versus stable treatment with tumour necrosis factor inhibitors on disease flares in patients with rheumatoid arthritis in remission: A randomised, open label, non-inferiority trial. Ann Rheum Dis. 2023 (Aug 22). doi: 10.1136/ard-2023-224476

Key clinical point: The administration of low-dose glucocorticoids over 2 years resulted in a modest weight gain of ~1 kg but had no effect on blood pressure (BP) in patients with early and established rheumatoid arthritis (RA).

Major finding: After 2 years, participants in both the low-dose glucocorticoid and control groups gained weight, but the low-dose glucocorticoid group gained an additional 1.1 kg of body weight (P < .001), with no significant between-group differences in the mean arterial pressure (P = .187).

Study details: Findings are from a pooled analysis of five randomized controlled trials including 1112 patients with early and established RA who received low-dose glucocorticoids (≤7.5 mg/day of prednisone equivalent; n = 548) or control treatment (n = 564) over at least 2 years.

Disclosures: This study did not receive any specific funding. Some authors declared receiving investigator fees, grants or contracts, consulting fees, payments or honoraria, or support for attending meetings or travel from or owning stocks or options in various sources.

Source: Palmowski A et al. The effect of low-dose glucocorticoids over two years on weight and blood pressure in rheumatoid arthritis: Individual patient data from five randomized trials. Ann Intern Med. 2023 (Aug 15). doi: 10.7326/M23-0192

Key clinical point: The administration of low-dose glucocorticoids over 2 years resulted in a modest weight gain of ~1 kg but had no effect on blood pressure (BP) in patients with early and established rheumatoid arthritis (RA).

Major finding: After 2 years, participants in both the low-dose glucocorticoid and control groups gained weight, but the low-dose glucocorticoid group gained an additional 1.1 kg of body weight (P < .001), with no significant between-group differences in the mean arterial pressure (P = .187).

Study details: Findings are from a pooled analysis of five randomized controlled trials including 1112 patients with early and established RA who received low-dose glucocorticoids (≤7.5 mg/day of prednisone equivalent; n = 548) or control treatment (n = 564) over at least 2 years.

Disclosures: This study did not receive any specific funding. Some authors declared receiving investigator fees, grants or contracts, consulting fees, payments or honoraria, or support for attending meetings or travel from or owning stocks or options in various sources.

Source: Palmowski A et al. The effect of low-dose glucocorticoids over two years on weight and blood pressure in rheumatoid arthritis: Individual patient data from five randomized trials. Ann Intern Med. 2023 (Aug 15). doi: 10.7326/M23-0192

Key clinical point: The administration of low-dose glucocorticoids over 2 years resulted in a modest weight gain of ~1 kg but had no effect on blood pressure (BP) in patients with early and established rheumatoid arthritis (RA).

Major finding: After 2 years, participants in both the low-dose glucocorticoid and control groups gained weight, but the low-dose glucocorticoid group gained an additional 1.1 kg of body weight (P < .001), with no significant between-group differences in the mean arterial pressure (P = .187).

Study details: Findings are from a pooled analysis of five randomized controlled trials including 1112 patients with early and established RA who received low-dose glucocorticoids (≤7.5 mg/day of prednisone equivalent; n = 548) or control treatment (n = 564) over at least 2 years.

Disclosures: This study did not receive any specific funding. Some authors declared receiving investigator fees, grants or contracts, consulting fees, payments or honoraria, or support for attending meetings or travel from or owning stocks or options in various sources.

Source: Palmowski A et al. The effect of low-dose glucocorticoids over two years on weight and blood pressure in rheumatoid arthritis: Individual patient data from five randomized trials. Ann Intern Med. 2023 (Aug 15). doi: 10.7326/M23-0192

The remarkable story of cystic fibrosis (CF) – from gene discovery in 1989 to highly effective precision-medicine therapies today – inspires Christine Kim Garcia, MD, PhD, as she searches for rare mutations in genes linked to inherited forms of lung fibrosis, termed familial pulmonary fibrosis (FPF).

“Cystic fibrosis has provided a framework for approaching the genetics of lung fibrosis,” said Dr. Garcia, Frode Jensen Professor of Medicine and chief of the pulmonology, allergy, and critical care medicine division at Columbia University, and director of the Columbia Precision Medicine Initiative, both in New York.

Pulmonary fibrosis is more complicated than CF. “Mutations in more than 10 different genes can lead to the increased heritable risk of pulmonary fibrosis that we find in families. Different mutations exist for each gene. Sometimes the mutations are so rare that they are only found in a single family,” she said. “In addition, different subtypes of fibrotic interstitial lung disease can be linked to the same mutation and found in the same family.”

Despite these complexities, genetic discoveries in PF have illuminated pathophysiologic pathways and are driving the research that Dr. Garcia and other experts hope will lead to helpful prognostic tools and to precision therapies. And already, at institutions like Columbia, genetic discoveries are changing clinical care, driving treatment decisions and spurring family screening.

Thomas Ferkol, MD, whose research focuses on genetic factors that contribute to suppurative airway diseases such as CF and primary ciliary dyskinesia (PCD), similarly regards CF as a road map for genetics research and genetic testing in practice.

“The treatments we’re doing now for CF are increasingly based on the genetics of the individual,” said Dr. Ferkol, professor and division chief for pediatric pulmonology at the University of North Carolina at Chapel Hill, where the UNC Children’s Hospital hosts a rare and genetic lung disease program. For PCD, genetic testing has become a front-line diagnostic tool. But in the future, he hopes, it will also become a determinant for personalized treatment for children with PCD.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene was the first lung disease gene to be discovered using gene-mapping techniques. Since then, and especially in the last 15-20 years, “there’s been a lot of progress in the identification of genes for which mutations and variations cause specific forms of pulmonary disease, many of which can now establish a firm diagnosis, and some of which lead to very directed changes in management. There has also been great progress in the availability of genetic testing,” said Benjamin A. Raby, MD, MPH, director of the Pulmonary Genetics Center at Brigham and Women’s Hospital, Boston, which sees patients with a host of cystic lung diseases, bronchiectasic lung diseases, fibrotic lung diseases, and other conditions, including pulmonary fibrosis and PCD.

Pulmonary fibrosis in adults and PCD in children are two examples of lung diseases for which genetic discoveries have exploded in recent years, with important implications for care now and in the future.
 

Leveraging genetic testing in PF

FPF describes families with two or more members with PF within three degrees of relationship; it is a designation believed to affect 20%-25% of people with PF and occurs predominantly later in the adult years (after 50 years of age), most commonly in autosomal dominant fashion, and amidst a stew of genetic risks, environmental exposures, and other insults.

Dr. Garcia and other researchers have uncovered two main types of genes in which rare variants can give rise to a heritable risk of FP: Genes that contribute to the maintenance of telomere length, and genes involved in surfactant metabolism. [Last year, Dr. Garcia and colleagues reported their discovery of both rare and common variants in a “spindle gene,” KIF15, in patients with IPF, suggesting an additional pathogenic pathway. The gene controls dynamics of cell division. (Am J Respir Crit Care Med. 2022;206[1]:p 56-69.)]

Detection of telomere pathway involvement – most commonly involving the TERT gene – is consequential because patients with telomere-associated gene mutations “tend to progress faster and have a more aggressive disease course than patients without these mutations … regardless of how their scans or biopsies look,” as do patients who have short age-adjusted telomere length, said Dr. Chad Newton, MD, who directs the Interstitial Lung Disease program at the University of Texas Southwestern and researches the genetics of ILD.

Dr. Newton and Dr. Garcia advise patients with PF and a positive family history to undergo panel-based genetic sequencing, along with telomere length measurement. They also advise that undiagnosed first-degree relatives consider what’s called “cascade testing” – genetic sequencing for any pathogenic or likely pathogenic rare variants found in the patient’s investigation. (Dr. Garcia, who cochairs a National Institutes of Health–funded interstitial lung disease curation panel, said she finds evidence of a pathogenic or likely pathogenic variant in about 25% of patients with a family history of PF.)

“We can use this genetic information to consider starting early [antifibrotic] treatment to try to delay progression … just as we would with other forms of pulmonary fibrosis,” Dr. Newton said, “and to expand our reach to others not sitting in our clinics who have the same rare condition or are at risk.”

After cascade testing, Dr. Garcia said, she invites family members with positive results to have baseline CT scans and pulmonary function testing. “And if there’s anything abnormal, we’re inviting them to have regular follow-up testing,” she said, “because we advise starting antifibrotic treatment at the very first sign of disease worsening.”

Such an approach to genetic testing for patients and relatives is described in a statement commissioned by the Pulmonary Fibrosis Foundation and published last year in the journal Chest (2022:162[2]:394-405). The statement, for which Dr. Newton and Dr. Garcia were among the authors, also lists clinical features within patients and families suggestive of a possible genetic pathway, and describes the potential yield for identifying a variant in different clinical scenarios.

Pathogenic variants in telomere genes as well as findings of short telomere length are associated with various extrapulmonary manifestations such as liver dysfunction, bone marrow dysfunction, and head and neck cancers, Dr. Newton said, making surveillance and referrals important. (Rare variants and short telomere length are associated with disease progression across several non-IPF diagnoses as well.)

Moreover, short telomeres may signal the need to avoid long-term immunosuppression. Research published in 2019 from multiple cohorts, and led by Dr. Newton and Dr. Garcia, showed that short telomere length is associated with worse outcomes (faster time to composite death, transplant, FVC decline, and hospitalization) in patients with IPF who received immunosuppression. These adverse outcomes were not found in IPF patients with normal telomere lengths who received similar immunosuppression (Am J Respir Crit Care Med. 2019;200(3):336-347).

Gene sequencing and telomere length measurement are described in the 2020 Chest statement on the role of genetic testing in PF as yielding “different yet complementary information.” Short age-adjusted telomere length (less than the 10th percentile) is common in those with pathogenic variants in telomere genes, but it can also occur in the absence of identifiable rare telomere-related variants, the statement says. Telomere length testing can be helpful, it notes, in determining the significance of a “variant of unknown significance (VUS)” if gene sequencing identifies one.
 

The future of genetic screening for PF

Future genetic screening approaches for PF may cast an even wider net while better stratifying risk for family members. At Brigham and Women’s Hospital, where family screening was a major impetus for the 2008 founding of the Pulmonary Genetics Center, research published several years ago by Dr. Raby and his colleagues found that 31% of 107 asymptomatic first-degree relatives of patients with PF had interstitial lung abnormalities on chest CTs – whether or not a family history was reported – and 18% had clear radiographic or physiological manifestations of fibrosis (Am J Respir Crit Care Med. 2020;201[10]:1240-8).

“That’s more than 10-fold higher than what we thought we’d see, based on prior literature. … And the numbers were pretty much the same whether or not there was a family history of fibrosis reported by the patient,” said Dr. Raby, also the Leila and Irving Perlmutter professor of pediatrics at Harvard Medical School, Boston, and chief of the division of pulmonary medicine at Boston Children’s Hospital. “We used to think we only needed to worry about genetic risk when there was a family history. But now we see that sporadic cases are also driven by genetics.”

Their study also included a 2-year follow-up chest CT, in which the majority of the screened relatives participated. Of those, 65% who had interstitial changes at baseline showed progression. Four percent of those without interstitial abnormalities at baseline developed abnormalities (Am J Respir Crit Care Med. 2023;207[2]:211-4). “The fact that 65% progressed suggests that in the majority of patients what we’re finding is something that’s real and is going to be clinically meaningful for patients,” he said.
 

Genetic signatures

A next phase of research at Brigham & Women’s and Boston Children’s, he said, will address PF’s “complex genetic signature” and test polygenic risk scores for idiopathic PF that take into account not only rare genetic variants that can be solidly linked to disease but many common genetic variants being detected in genome-wide association studies. [By definition, common variants, otherwise known as single-nucleotide polymorphisms (SNPs) occur with greater frequency in the general population (> 5%), generally reside within noncoding regions, and may contribute to disease risk but alone do not cause disease.]

“As technologies and genetic studies improve, we’re seeing we can estimate much better the likelihood of disease than we could 10 years ago,” he said. A “potent” common variant called the MUC5B promoter polymorphism has been shown to confer a 3-fold to 20-fold increased risk for PF, he noted. (Polygenic risk scores are also being developed, he said, for asthma and chronic obstructive pulmonary disease.)

“Every time one sees a patient with PF that is thought to be idiopathic one should start thinking about their at-risk family members, particularly their siblings,” Dr. Raby said. But in doing so, “wouldn’t it be wonderful if we could use polygenic risk scores to assure some [family members] that they’re in the lowest tier of risk and might need pulmonary function studies every 5 years, for example, versus someone we’d want to see more frequently, versus someone [for whom] we’d want to start preventive therapy at the earlier signs of declining lung function?”

Moving forward, he and the others said, the field needs more research to determine how genetic risk factors predict disease progression and prospective clinical trials to test whether long-term outcomes are indeed improved by early institution of antifibrotic therapy and other genetics-driven management decisions. “The data we’re using to inform prognosis and treatment decisions are compelling, but a lot of it is based on cohort studies and retrospective research,” Dr. Newton said.

Multi-institutional transomics studies and other research projects are underway, meanwhile, to build upon gene identifications and learn more about the pathobiology of PF. “We know about two big genetic pathways … but we need to sort it all out,” he said. For instance, “are there intermediate pathways? And where does it actually start? What kind of cell?”
 

Genetics’ impact on PCD

About 20 years ago, only two genes were linked to PCD, a largely autosomal recessive disorder that results from abnormalities in the cilia and subsequently improper airway clearance. Today, said Dr. Ferkol, there are over 50 known genes that, if defective, can lead to PCD.

“Based on our latest estimates, I’d say we can diagnose people using genetics about 70%, maybe 80%, of the time,” Dr. Ferkol said. Genetic testing has become a first-line diagnostic tool for PCD in North America – a significant development given that a definitive diagnosis has long been challenging, he said.

A genetics-based diagnosis of PCD is sometimes challenged by the finding of variants of unknown significance (VUSs) on genetic testing (often missense mutations) “because some of the genes involved are huge,” noted Dr. Ferkol, who coleads the NIH-funded Genetic Disorders of Mucociliary Clearance Consortium. “But many times, it’s straightforward.”

Children with PCD have repeated or persistent upper respiratory tract infections beginning early in life – like chronic rhinosinusitis or suppurative otitis media – and chronic bronchitis, leading to bronchiectasis. About half of patients have a spectrum of laterality defects, where organs are malpositioned in a mirror image of normal. Some individuals also have cardiac defects, and subfertility in both males and females can frequently occur.

Just as it has become increasingly clear that CF exists as a continuum, with milder and variant forms having been recognized since the advent of genetic testing, “we’re finding genotype-phenotype relationships in PCD,” Dr. Ferkol said. “Certain individuals have more rapid pulmonary decline, which is related in part to their genetics.”

With PCD, “I’m convinced this is a continuum. Some patients have unmistakable, clear-cut PCD, but I’m sure we’re going to find individuals who have milder variants in these PCD-associated genes that lead to milder disease,” he said.

There are no specific treatments that will correct cilia dysfunction, and current therapy options are borrowed from other diseases such as asthma and CF. However, newer treatments targeting specific genetic defects are in early clinical studies. Will the gene discoveries and more research open up new avenues for treating PCD, as happened in CF? Dr. Ferkol hopes so.

Approximately 2,000 genetic variants have been identified in the CFTR gene, though not all are pathogenic. “The newer, highly effective modulators used in CF target a particular CFTR mutation class, so some drugs will work for some people with the disease, but not all,” Dr. Ferkol said. “It’s personalized medicine.”

Modulator therapies designed to correct the malfunctioning proteins made by the CFTR gene have profoundly changed the lives of many with CF, improving lung function and everyday symptoms for patients, allowing them to lead near-normal lives. “It’s astonishing,” he said.

Dr. Garcia reported consulting for Rejuvenation Technologies and Rejuveron Telomere Therapeutics; in addition, her laboratory has received support from Boehringer Ingelheim and Astrazeneca for investigator-initiated research. Dr. Newton reported he has performed consulting for Boehringer Ingelheim. Dr. Ferkol reported involvement in a longitudinal study defining endpoints for future clinical PCD trials funded by ReCode Therapeutics and leadership of an international clinical trial for PCD supported by Parion Sciences. He has received honoraria from the Cystic Fibrosis Foundation and serves as a member of the ReCode Therapeutics PCD Clinical Steering Committee. Dr. Raby reported no relevant disclosures.

The remarkable story of cystic fibrosis (CF) – from gene discovery in 1989 to highly effective precision-medicine therapies today – inspires Christine Kim Garcia, MD, PhD, as she searches for rare mutations in genes linked to inherited forms of lung fibrosis, termed familial pulmonary fibrosis (FPF).

“Cystic fibrosis has provided a framework for approaching the genetics of lung fibrosis,” said Dr. Garcia, Frode Jensen Professor of Medicine and chief of the pulmonology, allergy, and critical care medicine division at Columbia University, and director of the Columbia Precision Medicine Initiative, both in New York.

Pulmonary fibrosis is more complicated than CF. “Mutations in more than 10 different genes can lead to the increased heritable risk of pulmonary fibrosis that we find in families. Different mutations exist for each gene. Sometimes the mutations are so rare that they are only found in a single family,” she said. “In addition, different subtypes of fibrotic interstitial lung disease can be linked to the same mutation and found in the same family.”

Despite these complexities, genetic discoveries in PF have illuminated pathophysiologic pathways and are driving the research that Dr. Garcia and other experts hope will lead to helpful prognostic tools and to precision therapies. And already, at institutions like Columbia, genetic discoveries are changing clinical care, driving treatment decisions and spurring family screening.

Thomas Ferkol, MD, whose research focuses on genetic factors that contribute to suppurative airway diseases such as CF and primary ciliary dyskinesia (PCD), similarly regards CF as a road map for genetics research and genetic testing in practice.

“The treatments we’re doing now for CF are increasingly based on the genetics of the individual,” said Dr. Ferkol, professor and division chief for pediatric pulmonology at the University of North Carolina at Chapel Hill, where the UNC Children’s Hospital hosts a rare and genetic lung disease program. For PCD, genetic testing has become a front-line diagnostic tool. But in the future, he hopes, it will also become a determinant for personalized treatment for children with PCD.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene was the first lung disease gene to be discovered using gene-mapping techniques. Since then, and especially in the last 15-20 years, “there’s been a lot of progress in the identification of genes for which mutations and variations cause specific forms of pulmonary disease, many of which can now establish a firm diagnosis, and some of which lead to very directed changes in management. There has also been great progress in the availability of genetic testing,” said Benjamin A. Raby, MD, MPH, director of the Pulmonary Genetics Center at Brigham and Women’s Hospital, Boston, which sees patients with a host of cystic lung diseases, bronchiectasic lung diseases, fibrotic lung diseases, and other conditions, including pulmonary fibrosis and PCD.

Pulmonary fibrosis in adults and PCD in children are two examples of lung diseases for which genetic discoveries have exploded in recent years, with important implications for care now and in the future.
 

Leveraging genetic testing in PF

FPF describes families with two or more members with PF within three degrees of relationship; it is a designation believed to affect 20%-25% of people with PF and occurs predominantly later in the adult years (after 50 years of age), most commonly in autosomal dominant fashion, and amidst a stew of genetic risks, environmental exposures, and other insults.

Dr. Garcia and other researchers have uncovered two main types of genes in which rare variants can give rise to a heritable risk of FP: Genes that contribute to the maintenance of telomere length, and genes involved in surfactant metabolism. [Last year, Dr. Garcia and colleagues reported their discovery of both rare and common variants in a “spindle gene,” KIF15, in patients with IPF, suggesting an additional pathogenic pathway. The gene controls dynamics of cell division. (Am J Respir Crit Care Med. 2022;206[1]:p 56-69.)]

Detection of telomere pathway involvement – most commonly involving the TERT gene – is consequential because patients with telomere-associated gene mutations “tend to progress faster and have a more aggressive disease course than patients without these mutations … regardless of how their scans or biopsies look,” as do patients who have short age-adjusted telomere length, said Dr. Chad Newton, MD, who directs the Interstitial Lung Disease program at the University of Texas Southwestern and researches the genetics of ILD.

Dr. Newton and Dr. Garcia advise patients with PF and a positive family history to undergo panel-based genetic sequencing, along with telomere length measurement. They also advise that undiagnosed first-degree relatives consider what’s called “cascade testing” – genetic sequencing for any pathogenic or likely pathogenic rare variants found in the patient’s investigation. (Dr. Garcia, who cochairs a National Institutes of Health–funded interstitial lung disease curation panel, said she finds evidence of a pathogenic or likely pathogenic variant in about 25% of patients with a family history of PF.)

“We can use this genetic information to consider starting early [antifibrotic] treatment to try to delay progression … just as we would with other forms of pulmonary fibrosis,” Dr. Newton said, “and to expand our reach to others not sitting in our clinics who have the same rare condition or are at risk.”

After cascade testing, Dr. Garcia said, she invites family members with positive results to have baseline CT scans and pulmonary function testing. “And if there’s anything abnormal, we’re inviting them to have regular follow-up testing,” she said, “because we advise starting antifibrotic treatment at the very first sign of disease worsening.”

Such an approach to genetic testing for patients and relatives is described in a statement commissioned by the Pulmonary Fibrosis Foundation and published last year in the journal Chest (2022:162[2]:394-405). The statement, for which Dr. Newton and Dr. Garcia were among the authors, also lists clinical features within patients and families suggestive of a possible genetic pathway, and describes the potential yield for identifying a variant in different clinical scenarios.

Pathogenic variants in telomere genes as well as findings of short telomere length are associated with various extrapulmonary manifestations such as liver dysfunction, bone marrow dysfunction, and head and neck cancers, Dr. Newton said, making surveillance and referrals important. (Rare variants and short telomere length are associated with disease progression across several non-IPF diagnoses as well.)

Moreover, short telomeres may signal the need to avoid long-term immunosuppression. Research published in 2019 from multiple cohorts, and led by Dr. Newton and Dr. Garcia, showed that short telomere length is associated with worse outcomes (faster time to composite death, transplant, FVC decline, and hospitalization) in patients with IPF who received immunosuppression. These adverse outcomes were not found in IPF patients with normal telomere lengths who received similar immunosuppression (Am J Respir Crit Care Med. 2019;200(3):336-347).

Gene sequencing and telomere length measurement are described in the 2020 Chest statement on the role of genetic testing in PF as yielding “different yet complementary information.” Short age-adjusted telomere length (less than the 10th percentile) is common in those with pathogenic variants in telomere genes, but it can also occur in the absence of identifiable rare telomere-related variants, the statement says. Telomere length testing can be helpful, it notes, in determining the significance of a “variant of unknown significance (VUS)” if gene sequencing identifies one.
 

The future of genetic screening for PF

Future genetic screening approaches for PF may cast an even wider net while better stratifying risk for family members. At Brigham and Women’s Hospital, where family screening was a major impetus for the 2008 founding of the Pulmonary Genetics Center, research published several years ago by Dr. Raby and his colleagues found that 31% of 107 asymptomatic first-degree relatives of patients with PF had interstitial lung abnormalities on chest CTs – whether or not a family history was reported – and 18% had clear radiographic or physiological manifestations of fibrosis (Am J Respir Crit Care Med. 2020;201[10]:1240-8).

“That’s more than 10-fold higher than what we thought we’d see, based on prior literature. … And the numbers were pretty much the same whether or not there was a family history of fibrosis reported by the patient,” said Dr. Raby, also the Leila and Irving Perlmutter professor of pediatrics at Harvard Medical School, Boston, and chief of the division of pulmonary medicine at Boston Children’s Hospital. “We used to think we only needed to worry about genetic risk when there was a family history. But now we see that sporadic cases are also driven by genetics.”

Their study also included a 2-year follow-up chest CT, in which the majority of the screened relatives participated. Of those, 65% who had interstitial changes at baseline showed progression. Four percent of those without interstitial abnormalities at baseline developed abnormalities (Am J Respir Crit Care Med. 2023;207[2]:211-4). “The fact that 65% progressed suggests that in the majority of patients what we’re finding is something that’s real and is going to be clinically meaningful for patients,” he said.
 

Genetic signatures

A next phase of research at Brigham & Women’s and Boston Children’s, he said, will address PF’s “complex genetic signature” and test polygenic risk scores for idiopathic PF that take into account not only rare genetic variants that can be solidly linked to disease but many common genetic variants being detected in genome-wide association studies. [By definition, common variants, otherwise known as single-nucleotide polymorphisms (SNPs) occur with greater frequency in the general population (> 5%), generally reside within noncoding regions, and may contribute to disease risk but alone do not cause disease.]

“As technologies and genetic studies improve, we’re seeing we can estimate much better the likelihood of disease than we could 10 years ago,” he said. A “potent” common variant called the MUC5B promoter polymorphism has been shown to confer a 3-fold to 20-fold increased risk for PF, he noted. (Polygenic risk scores are also being developed, he said, for asthma and chronic obstructive pulmonary disease.)

“Every time one sees a patient with PF that is thought to be idiopathic one should start thinking about their at-risk family members, particularly their siblings,” Dr. Raby said. But in doing so, “wouldn’t it be wonderful if we could use polygenic risk scores to assure some [family members] that they’re in the lowest tier of risk and might need pulmonary function studies every 5 years, for example, versus someone we’d want to see more frequently, versus someone [for whom] we’d want to start preventive therapy at the earlier signs of declining lung function?”

Moving forward, he and the others said, the field needs more research to determine how genetic risk factors predict disease progression and prospective clinical trials to test whether long-term outcomes are indeed improved by early institution of antifibrotic therapy and other genetics-driven management decisions. “The data we’re using to inform prognosis and treatment decisions are compelling, but a lot of it is based on cohort studies and retrospective research,” Dr. Newton said.

Multi-institutional transomics studies and other research projects are underway, meanwhile, to build upon gene identifications and learn more about the pathobiology of PF. “We know about two big genetic pathways … but we need to sort it all out,” he said. For instance, “are there intermediate pathways? And where does it actually start? What kind of cell?”
 

Genetics’ impact on PCD

About 20 years ago, only two genes were linked to PCD, a largely autosomal recessive disorder that results from abnormalities in the cilia and subsequently improper airway clearance. Today, said Dr. Ferkol, there are over 50 known genes that, if defective, can lead to PCD.

“Based on our latest estimates, I’d say we can diagnose people using genetics about 70%, maybe 80%, of the time,” Dr. Ferkol said. Genetic testing has become a first-line diagnostic tool for PCD in North America – a significant development given that a definitive diagnosis has long been challenging, he said.

A genetics-based diagnosis of PCD is sometimes challenged by the finding of variants of unknown significance (VUSs) on genetic testing (often missense mutations) “because some of the genes involved are huge,” noted Dr. Ferkol, who coleads the NIH-funded Genetic Disorders of Mucociliary Clearance Consortium. “But many times, it’s straightforward.”

Children with PCD have repeated or persistent upper respiratory tract infections beginning early in life – like chronic rhinosinusitis or suppurative otitis media – and chronic bronchitis, leading to bronchiectasis. About half of patients have a spectrum of laterality defects, where organs are malpositioned in a mirror image of normal. Some individuals also have cardiac defects, and subfertility in both males and females can frequently occur.

Just as it has become increasingly clear that CF exists as a continuum, with milder and variant forms having been recognized since the advent of genetic testing, “we’re finding genotype-phenotype relationships in PCD,” Dr. Ferkol said. “Certain individuals have more rapid pulmonary decline, which is related in part to their genetics.”

With PCD, “I’m convinced this is a continuum. Some patients have unmistakable, clear-cut PCD, but I’m sure we’re going to find individuals who have milder variants in these PCD-associated genes that lead to milder disease,” he said.

There are no specific treatments that will correct cilia dysfunction, and current therapy options are borrowed from other diseases such as asthma and CF. However, newer treatments targeting specific genetic defects are in early clinical studies. Will the gene discoveries and more research open up new avenues for treating PCD, as happened in CF? Dr. Ferkol hopes so.

Approximately 2,000 genetic variants have been identified in the CFTR gene, though not all are pathogenic. “The newer, highly effective modulators used in CF target a particular CFTR mutation class, so some drugs will work for some people with the disease, but not all,” Dr. Ferkol said. “It’s personalized medicine.”

Modulator therapies designed to correct the malfunctioning proteins made by the CFTR gene have profoundly changed the lives of many with CF, improving lung function and everyday symptoms for patients, allowing them to lead near-normal lives. “It’s astonishing,” he said.

Dr. Garcia reported consulting for Rejuvenation Technologies and Rejuveron Telomere Therapeutics; in addition, her laboratory has received support from Boehringer Ingelheim and Astrazeneca for investigator-initiated research. Dr. Newton reported he has performed consulting for Boehringer Ingelheim. Dr. Ferkol reported involvement in a longitudinal study defining endpoints for future clinical PCD trials funded by ReCode Therapeutics and leadership of an international clinical trial for PCD supported by Parion Sciences. He has received honoraria from the Cystic Fibrosis Foundation and serves as a member of the ReCode Therapeutics PCD Clinical Steering Committee. Dr. Raby reported no relevant disclosures.

The remarkable story of cystic fibrosis (CF) – from gene discovery in 1989 to highly effective precision-medicine therapies today – inspires Christine Kim Garcia, MD, PhD, as she searches for rare mutations in genes linked to inherited forms of lung fibrosis, termed familial pulmonary fibrosis (FPF).

“Cystic fibrosis has provided a framework for approaching the genetics of lung fibrosis,” said Dr. Garcia, Frode Jensen Professor of Medicine and chief of the pulmonology, allergy, and critical care medicine division at Columbia University, and director of the Columbia Precision Medicine Initiative, both in New York.

Pulmonary fibrosis is more complicated than CF. “Mutations in more than 10 different genes can lead to the increased heritable risk of pulmonary fibrosis that we find in families. Different mutations exist for each gene. Sometimes the mutations are so rare that they are only found in a single family,” she said. “In addition, different subtypes of fibrotic interstitial lung disease can be linked to the same mutation and found in the same family.”

Despite these complexities, genetic discoveries in PF have illuminated pathophysiologic pathways and are driving the research that Dr. Garcia and other experts hope will lead to helpful prognostic tools and to precision therapies. And already, at institutions like Columbia, genetic discoveries are changing clinical care, driving treatment decisions and spurring family screening.

Thomas Ferkol, MD, whose research focuses on genetic factors that contribute to suppurative airway diseases such as CF and primary ciliary dyskinesia (PCD), similarly regards CF as a road map for genetics research and genetic testing in practice.

“The treatments we’re doing now for CF are increasingly based on the genetics of the individual,” said Dr. Ferkol, professor and division chief for pediatric pulmonology at the University of North Carolina at Chapel Hill, where the UNC Children’s Hospital hosts a rare and genetic lung disease program. For PCD, genetic testing has become a front-line diagnostic tool. But in the future, he hopes, it will also become a determinant for personalized treatment for children with PCD.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene was the first lung disease gene to be discovered using gene-mapping techniques. Since then, and especially in the last 15-20 years, “there’s been a lot of progress in the identification of genes for which mutations and variations cause specific forms of pulmonary disease, many of which can now establish a firm diagnosis, and some of which lead to very directed changes in management. There has also been great progress in the availability of genetic testing,” said Benjamin A. Raby, MD, MPH, director of the Pulmonary Genetics Center at Brigham and Women’s Hospital, Boston, which sees patients with a host of cystic lung diseases, bronchiectasic lung diseases, fibrotic lung diseases, and other conditions, including pulmonary fibrosis and PCD.

Pulmonary fibrosis in adults and PCD in children are two examples of lung diseases for which genetic discoveries have exploded in recent years, with important implications for care now and in the future.
 

Leveraging genetic testing in PF

FPF describes families with two or more members with PF within three degrees of relationship; it is a designation believed to affect 20%-25% of people with PF and occurs predominantly later in the adult years (after 50 years of age), most commonly in autosomal dominant fashion, and amidst a stew of genetic risks, environmental exposures, and other insults.

Dr. Garcia and other researchers have uncovered two main types of genes in which rare variants can give rise to a heritable risk of FP: Genes that contribute to the maintenance of telomere length, and genes involved in surfactant metabolism. [Last year, Dr. Garcia and colleagues reported their discovery of both rare and common variants in a “spindle gene,” KIF15, in patients with IPF, suggesting an additional pathogenic pathway. The gene controls dynamics of cell division. (Am J Respir Crit Care Med. 2022;206[1]:p 56-69.)]

Detection of telomere pathway involvement – most commonly involving the TERT gene – is consequential because patients with telomere-associated gene mutations “tend to progress faster and have a more aggressive disease course than patients without these mutations … regardless of how their scans or biopsies look,” as do patients who have short age-adjusted telomere length, said Dr. Chad Newton, MD, who directs the Interstitial Lung Disease program at the University of Texas Southwestern and researches the genetics of ILD.

Dr. Newton and Dr. Garcia advise patients with PF and a positive family history to undergo panel-based genetic sequencing, along with telomere length measurement. They also advise that undiagnosed first-degree relatives consider what’s called “cascade testing” – genetic sequencing for any pathogenic or likely pathogenic rare variants found in the patient’s investigation. (Dr. Garcia, who cochairs a National Institutes of Health–funded interstitial lung disease curation panel, said she finds evidence of a pathogenic or likely pathogenic variant in about 25% of patients with a family history of PF.)

“We can use this genetic information to consider starting early [antifibrotic] treatment to try to delay progression … just as we would with other forms of pulmonary fibrosis,” Dr. Newton said, “and to expand our reach to others not sitting in our clinics who have the same rare condition or are at risk.”

After cascade testing, Dr. Garcia said, she invites family members with positive results to have baseline CT scans and pulmonary function testing. “And if there’s anything abnormal, we’re inviting them to have regular follow-up testing,” she said, “because we advise starting antifibrotic treatment at the very first sign of disease worsening.”

Such an approach to genetic testing for patients and relatives is described in a statement commissioned by the Pulmonary Fibrosis Foundation and published last year in the journal Chest (2022:162[2]:394-405). The statement, for which Dr. Newton and Dr. Garcia were among the authors, also lists clinical features within patients and families suggestive of a possible genetic pathway, and describes the potential yield for identifying a variant in different clinical scenarios.

Pathogenic variants in telomere genes as well as findings of short telomere length are associated with various extrapulmonary manifestations such as liver dysfunction, bone marrow dysfunction, and head and neck cancers, Dr. Newton said, making surveillance and referrals important. (Rare variants and short telomere length are associated with disease progression across several non-IPF diagnoses as well.)

Moreover, short telomeres may signal the need to avoid long-term immunosuppression. Research published in 2019 from multiple cohorts, and led by Dr. Newton and Dr. Garcia, showed that short telomere length is associated with worse outcomes (faster time to composite death, transplant, FVC decline, and hospitalization) in patients with IPF who received immunosuppression. These adverse outcomes were not found in IPF patients with normal telomere lengths who received similar immunosuppression (Am J Respir Crit Care Med. 2019;200(3):336-347).

Gene sequencing and telomere length measurement are described in the 2020 Chest statement on the role of genetic testing in PF as yielding “different yet complementary information.” Short age-adjusted telomere length (less than the 10th percentile) is common in those with pathogenic variants in telomere genes, but it can also occur in the absence of identifiable rare telomere-related variants, the statement says. Telomere length testing can be helpful, it notes, in determining the significance of a “variant of unknown significance (VUS)” if gene sequencing identifies one.
 

The future of genetic screening for PF

Future genetic screening approaches for PF may cast an even wider net while better stratifying risk for family members. At Brigham and Women’s Hospital, where family screening was a major impetus for the 2008 founding of the Pulmonary Genetics Center, research published several years ago by Dr. Raby and his colleagues found that 31% of 107 asymptomatic first-degree relatives of patients with PF had interstitial lung abnormalities on chest CTs – whether or not a family history was reported – and 18% had clear radiographic or physiological manifestations of fibrosis (Am J Respir Crit Care Med. 2020;201[10]:1240-8).

“That’s more than 10-fold higher than what we thought we’d see, based on prior literature. … And the numbers were pretty much the same whether or not there was a family history of fibrosis reported by the patient,” said Dr. Raby, also the Leila and Irving Perlmutter professor of pediatrics at Harvard Medical School, Boston, and chief of the division of pulmonary medicine at Boston Children’s Hospital. “We used to think we only needed to worry about genetic risk when there was a family history. But now we see that sporadic cases are also driven by genetics.”

Their study also included a 2-year follow-up chest CT, in which the majority of the screened relatives participated. Of those, 65% who had interstitial changes at baseline showed progression. Four percent of those without interstitial abnormalities at baseline developed abnormalities (Am J Respir Crit Care Med. 2023;207[2]:211-4). “The fact that 65% progressed suggests that in the majority of patients what we’re finding is something that’s real and is going to be clinically meaningful for patients,” he said.
 

Genetic signatures

A next phase of research at Brigham & Women’s and Boston Children’s, he said, will address PF’s “complex genetic signature” and test polygenic risk scores for idiopathic PF that take into account not only rare genetic variants that can be solidly linked to disease but many common genetic variants being detected in genome-wide association studies. [By definition, common variants, otherwise known as single-nucleotide polymorphisms (SNPs) occur with greater frequency in the general population (> 5%), generally reside within noncoding regions, and may contribute to disease risk but alone do not cause disease.]

“As technologies and genetic studies improve, we’re seeing we can estimate much better the likelihood of disease than we could 10 years ago,” he said. A “potent” common variant called the MUC5B promoter polymorphism has been shown to confer a 3-fold to 20-fold increased risk for PF, he noted. (Polygenic risk scores are also being developed, he said, for asthma and chronic obstructive pulmonary disease.)

“Every time one sees a patient with PF that is thought to be idiopathic one should start thinking about their at-risk family members, particularly their siblings,” Dr. Raby said. But in doing so, “wouldn’t it be wonderful if we could use polygenic risk scores to assure some [family members] that they’re in the lowest tier of risk and might need pulmonary function studies every 5 years, for example, versus someone we’d want to see more frequently, versus someone [for whom] we’d want to start preventive therapy at the earlier signs of declining lung function?”

Moving forward, he and the others said, the field needs more research to determine how genetic risk factors predict disease progression and prospective clinical trials to test whether long-term outcomes are indeed improved by early institution of antifibrotic therapy and other genetics-driven management decisions. “The data we’re using to inform prognosis and treatment decisions are compelling, but a lot of it is based on cohort studies and retrospective research,” Dr. Newton said.

Multi-institutional transomics studies and other research projects are underway, meanwhile, to build upon gene identifications and learn more about the pathobiology of PF. “We know about two big genetic pathways … but we need to sort it all out,” he said. For instance, “are there intermediate pathways? And where does it actually start? What kind of cell?”
 

Genetics’ impact on PCD

About 20 years ago, only two genes were linked to PCD, a largely autosomal recessive disorder that results from abnormalities in the cilia and subsequently improper airway clearance. Today, said Dr. Ferkol, there are over 50 known genes that, if defective, can lead to PCD.

“Based on our latest estimates, I’d say we can diagnose people using genetics about 70%, maybe 80%, of the time,” Dr. Ferkol said. Genetic testing has become a first-line diagnostic tool for PCD in North America – a significant development given that a definitive diagnosis has long been challenging, he said.

A genetics-based diagnosis of PCD is sometimes challenged by the finding of variants of unknown significance (VUSs) on genetic testing (often missense mutations) “because some of the genes involved are huge,” noted Dr. Ferkol, who coleads the NIH-funded Genetic Disorders of Mucociliary Clearance Consortium. “But many times, it’s straightforward.”

Children with PCD have repeated or persistent upper respiratory tract infections beginning early in life – like chronic rhinosinusitis or suppurative otitis media – and chronic bronchitis, leading to bronchiectasis. About half of patients have a spectrum of laterality defects, where organs are malpositioned in a mirror image of normal. Some individuals also have cardiac defects, and subfertility in both males and females can frequently occur.

Just as it has become increasingly clear that CF exists as a continuum, with milder and variant forms having been recognized since the advent of genetic testing, “we’re finding genotype-phenotype relationships in PCD,” Dr. Ferkol said. “Certain individuals have more rapid pulmonary decline, which is related in part to their genetics.”

With PCD, “I’m convinced this is a continuum. Some patients have unmistakable, clear-cut PCD, but I’m sure we’re going to find individuals who have milder variants in these PCD-associated genes that lead to milder disease,” he said.

There are no specific treatments that will correct cilia dysfunction, and current therapy options are borrowed from other diseases such as asthma and CF. However, newer treatments targeting specific genetic defects are in early clinical studies. Will the gene discoveries and more research open up new avenues for treating PCD, as happened in CF? Dr. Ferkol hopes so.

Approximately 2,000 genetic variants have been identified in the CFTR gene, though not all are pathogenic. “The newer, highly effective modulators used in CF target a particular CFTR mutation class, so some drugs will work for some people with the disease, but not all,” Dr. Ferkol said. “It’s personalized medicine.”

Modulator therapies designed to correct the malfunctioning proteins made by the CFTR gene have profoundly changed the lives of many with CF, improving lung function and everyday symptoms for patients, allowing them to lead near-normal lives. “It’s astonishing,” he said.

Dr. Garcia reported consulting for Rejuvenation Technologies and Rejuveron Telomere Therapeutics; in addition, her laboratory has received support from Boehringer Ingelheim and Astrazeneca for investigator-initiated research. Dr. Newton reported he has performed consulting for Boehringer Ingelheim. Dr. Ferkol reported involvement in a longitudinal study defining endpoints for future clinical PCD trials funded by ReCode Therapeutics and leadership of an international clinical trial for PCD supported by Parion Sciences. He has received honoraria from the Cystic Fibrosis Foundation and serves as a member of the ReCode Therapeutics PCD Clinical Steering Committee. Dr. Raby reported no relevant disclosures.

SAN DIEGO – Injecting a scar with intralesional steroids is a popular way to reduce its size and soften the surrounding tissue, but proper technique matters, according to Victor Ross, MD.

“A lot of lip service is paid to how to inject the steroid,” Dr. Ross, director of laser and cosmetic dermatology at the Scripps Clinic in San Diego, said at the annual Masters of Aesthetics Symposium. “The most important part is the amount and the fastidiousness that you have injecting. You should see the tip of the needle and be very slow. Use a 1 cc syringe.” He used to inject scars with triamcinolone acetate 40 mg/mL, but now he almost always injects 10-20 mg/mL to avoid inducing white streak-like atrophy or hypopigmentation around the treated area.

“When you treat a scar, you treat the features of the scar that make it stand out,” Dr. Ross continued. “If it’s red, you address the hyperemia. If it’s brown, you address the pigment. You want to have a reasonable pathophysiological basis for what you’re doing. Understand how the scar got there and have a reasonable algorithm.” When he counsels patients about clinical outcomes to expect, he emphasizes rehabilitation instead of blemish-free perfection. “It’s not making the scar go away,” he said. “It’s not restoring completely normal skin form and function; it’s a restorative effort to get toward normality. That’s what it’s all about.”

Besides injecting scars with triamcinolone acetate, other scar treatment options include intralesional 5-fluorouracil, oral antihistamines, COX-2 inhibitors, hydrogel sheeting, compression, acoustic wave therapy, photodynamic therapy, radiofrequency, and lasers. “I’m not a big fan of low-level light; it probably does something [to scars], but I’m skeptical,” Dr. Ross said.

In his clinical opinion, most scars respond best to treatments with ablative and nonablative fractional lasers tuned to gentle settings such as an energy level of 20 millijoules at a density of 5%-10%. “Every scar deserves a chance for laser remediation and rehabilitation,” he said. “With radiation scars you want to be particularly gentle. If you have a Mohs scar that has been subsequently treated with radiation, I would lower my settings by half, because I’ve had some scars worsen with settings for red scars after radiation therapy.”

He often uses fractional lasers for stubborn acne scarring. “The hyperemic component you can treat with a vascular laser, then come back [and treat the scarring] with a nonablative fractional laser, or you could use radiofrequency microneedling as well,” Dr. Ross said.

New or innovative scar treatments coming down the pike, he said, include the following: mitomycin C (applied topically, he said that this has worked well for postoperative keloids), tamoxifen, oral methotrexate, imiquimod (which has mixed results to date), platelet-rich plasma, and retinoids.

Dr. Ross disclosed having research and financial ties to numerous pharmaceutical and device companies.

SAN DIEGO – Injecting a scar with intralesional steroids is a popular way to reduce its size and soften the surrounding tissue, but proper technique matters, according to Victor Ross, MD.

“A lot of lip service is paid to how to inject the steroid,” Dr. Ross, director of laser and cosmetic dermatology at the Scripps Clinic in San Diego, said at the annual Masters of Aesthetics Symposium. “The most important part is the amount and the fastidiousness that you have injecting. You should see the tip of the needle and be very slow. Use a 1 cc syringe.” He used to inject scars with triamcinolone acetate 40 mg/mL, but now he almost always injects 10-20 mg/mL to avoid inducing white streak-like atrophy or hypopigmentation around the treated area.

“When you treat a scar, you treat the features of the scar that make it stand out,” Dr. Ross continued. “If it’s red, you address the hyperemia. If it’s brown, you address the pigment. You want to have a reasonable pathophysiological basis for what you’re doing. Understand how the scar got there and have a reasonable algorithm.” When he counsels patients about clinical outcomes to expect, he emphasizes rehabilitation instead of blemish-free perfection. “It’s not making the scar go away,” he said. “It’s not restoring completely normal skin form and function; it’s a restorative effort to get toward normality. That’s what it’s all about.”

Besides injecting scars with triamcinolone acetate, other scar treatment options include intralesional 5-fluorouracil, oral antihistamines, COX-2 inhibitors, hydrogel sheeting, compression, acoustic wave therapy, photodynamic therapy, radiofrequency, and lasers. “I’m not a big fan of low-level light; it probably does something [to scars], but I’m skeptical,” Dr. Ross said.

In his clinical opinion, most scars respond best to treatments with ablative and nonablative fractional lasers tuned to gentle settings such as an energy level of 20 millijoules at a density of 5%-10%. “Every scar deserves a chance for laser remediation and rehabilitation,” he said. “With radiation scars you want to be particularly gentle. If you have a Mohs scar that has been subsequently treated with radiation, I would lower my settings by half, because I’ve had some scars worsen with settings for red scars after radiation therapy.”

He often uses fractional lasers for stubborn acne scarring. “The hyperemic component you can treat with a vascular laser, then come back [and treat the scarring] with a nonablative fractional laser, or you could use radiofrequency microneedling as well,” Dr. Ross said.

New or innovative scar treatments coming down the pike, he said, include the following: mitomycin C (applied topically, he said that this has worked well for postoperative keloids), tamoxifen, oral methotrexate, imiquimod (which has mixed results to date), platelet-rich plasma, and retinoids.

Dr. Ross disclosed having research and financial ties to numerous pharmaceutical and device companies.

SAN DIEGO – Injecting a scar with intralesional steroids is a popular way to reduce its size and soften the surrounding tissue, but proper technique matters, according to Victor Ross, MD.

“A lot of lip service is paid to how to inject the steroid,” Dr. Ross, director of laser and cosmetic dermatology at the Scripps Clinic in San Diego, said at the annual Masters of Aesthetics Symposium. “The most important part is the amount and the fastidiousness that you have injecting. You should see the tip of the needle and be very slow. Use a 1 cc syringe.” He used to inject scars with triamcinolone acetate 40 mg/mL, but now he almost always injects 10-20 mg/mL to avoid inducing white streak-like atrophy or hypopigmentation around the treated area.

“When you treat a scar, you treat the features of the scar that make it stand out,” Dr. Ross continued. “If it’s red, you address the hyperemia. If it’s brown, you address the pigment. You want to have a reasonable pathophysiological basis for what you’re doing. Understand how the scar got there and have a reasonable algorithm.” When he counsels patients about clinical outcomes to expect, he emphasizes rehabilitation instead of blemish-free perfection. “It’s not making the scar go away,” he said. “It’s not restoring completely normal skin form and function; it’s a restorative effort to get toward normality. That’s what it’s all about.”

Besides injecting scars with triamcinolone acetate, other scar treatment options include intralesional 5-fluorouracil, oral antihistamines, COX-2 inhibitors, hydrogel sheeting, compression, acoustic wave therapy, photodynamic therapy, radiofrequency, and lasers. “I’m not a big fan of low-level light; it probably does something [to scars], but I’m skeptical,” Dr. Ross said.

In his clinical opinion, most scars respond best to treatments with ablative and nonablative fractional lasers tuned to gentle settings such as an energy level of 20 millijoules at a density of 5%-10%. “Every scar deserves a chance for laser remediation and rehabilitation,” he said. “With radiation scars you want to be particularly gentle. If you have a Mohs scar that has been subsequently treated with radiation, I would lower my settings by half, because I’ve had some scars worsen with settings for red scars after radiation therapy.”

He often uses fractional lasers for stubborn acne scarring. “The hyperemic component you can treat with a vascular laser, then come back [and treat the scarring] with a nonablative fractional laser, or you could use radiofrequency microneedling as well,” Dr. Ross said.

New or innovative scar treatments coming down the pike, he said, include the following: mitomycin C (applied topically, he said that this has worked well for postoperative keloids), tamoxifen, oral methotrexate, imiquimod (which has mixed results to date), platelet-rich plasma, and retinoids.

Dr. Ross disclosed having research and financial ties to numerous pharmaceutical and device companies.

In utero exposure to selective serotonin reuptake inhibitors (SSRIs) has been tied to reduced brain volume in children, results of a large population-based study show.

However, the investigators, led by Henning Tiemeier, MD, PhD, professor of social and behavioral sciences at Harvard School of Public Health in Boston, note that the findings should be interpreted cautiously because the size of the study population who received brain MRI was relatively small.

Dr. Tiemeier said in an interview that the associations detected were small and could not show causality between prenatal SSRI use and a decrease in gray and white matter across certain areas of the brain.

“Women who are pregnant and on maintenance therapy should consult their therapist if preventive therapy is still needed and if there are alternatives. This choice must be carefully considered, and women should be carefully advised,” he said.

The study was published online in JAMA Psychiatry.
 

An important decision

The investigators note that the decision to prescribe antidepressants, particularly SSRIs, during pregnancy is challenging. Though SSRI use during pregnancy is generally considered safe, some previous research suggests an association with negative outcomes in offspring, including adverse effects on neurodevelopment.

However, the researchers also note that it’s possible that pregnant women who use SSRIs may have other factors, including more severe depressive symptoms, which may be independently associated with adverse outcomes in offspring.

To investigate the link between intrauterine SSRI exposure and brain development, the researchers conducted a prospective, population-based study that included 3,198 pregnant individuals with an expected delivery date between April 2002 and January 2006. Study participants were divided into five groups: 41 who used SSRIs during pregnancy, 257 who did not use the medications but had depressive symptoms during pregnancy, 77 who used SSRIs prenatally, 74 who developed depressive symptoms after giving birth, and 2,749 controls with no SSRI use or depressive symptoms. Participants had a mean age of 31 years, and all identified as women.

Of those who took SSRIs during pregnancy, 20 used them during the first trimester only, and 21 used them the first or in one or two additional trimesters. The SSRIs used included paroxetine, fluoxetine, sertraline, fluvoxamine, and citalopram.

Offspring of the women enrolled in the study received MRIs at three different times between the ages 7 and 15 years.

The 41 children born to the women who took SSRIs prenatally had 80 scans in total, the 257 with mothers who did not use SSRIs yet had depressive symptoms while pregnant had 477 MRIs, the 77 children born to the mothers who took SSRIs before pregnancy had 126 MRIs, the 74 born to mothers with postnatal depression only had 128 MRIs, and the 2,749 children born to the mothers with no SSRI use or depression had 4,813 MRIs.

The study’s primary outcome was brain morphometry in offspring including global and cortical brain volumes, measured by three MRI assessments from ages 7 to 15 years.
 

Reduced brain volume

Compared with children with no in utero SSRI exposure, those who were exposed had reduced gray and white matter volume that persisted up to 15 years of age (P = .006), particularly in the corticolimbic circuit.

Investigators observed a “persistent association between prenatal SSRI exposure and less cortical volumes across the 10-year follow-up period, including in the superior frontal cortex, medial orbitofrontal cortex, parahippocampal gyrus, rostral anterior cingulate cortex, and posterior cingulate.”

Investigators noted that prenatal SSRI exposure was consistently associated with 5%-10% lower brain volume in the frontal, cingulate, and temporal cortex throughout the age range studied.

In a couple of areas of the brain, however, the brain volume gradually increased back to levels seen in non-SSRI exposed children. For instance, smaller amygdala volumes had increased by age 15 years, so children who were exposed to SSRIs were not any different from control children.

Among the group of women with postnatal depression using an SSRI before or during pregnancy who had depressive symptoms post natally, neonates had a reduced fusiform gyrus (P = .002)

Dr. Tiemeier could not speculate on the effects of the volume differences on children’s development, although the parts of the brain found to be reduced are primarily responsible for emotion regulation.

Investigators noted there was limited ability to investigate trimester-specific outcomes of SSRI use and assess associations with specific SSRIs due to low prevalence of SSRI use.

In addition, research on the long-term behavioral and psychological outcomes associated with demonstrated brain changes is needed, investigators noted.
 

Clinical significance ‘unclear’

In an accompanying editorial, Ardesheer Talati, PhD, Columbia University, New York, noted that though the research enhances understanding of how brain development through adolescence may be associated with SSRI exposure, “the clinical significance was unclear, especially as key limbic regions, including the amygdala, normalized over time.”

If future evidence links brain anomalies to adverse youth outcomes, Dr. Talati writes, this will need to be “calibrated into the risk-benefit profile.” Until then, he said, the findings must not be overinterpreted “to either promote or discourage antidepressant medication use during the critical period of pregnancy.”

The study was funded by the Netherlands Organization for Scientific Research, European Union’s Horizon Research and Innovation Program, the Netherlands Organization for Health Research and Development, the Sophia Foundation for Neuroimaging, and the European Union’s Horizon Research and Innovation 5 Program. Dr. Talati reported receiving grants from the National Institutes of Health outside of the submitted work.

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

In utero exposure to selective serotonin reuptake inhibitors (SSRIs) has been tied to reduced brain volume in children, results of a large population-based study show.

However, the investigators, led by Henning Tiemeier, MD, PhD, professor of social and behavioral sciences at Harvard School of Public Health in Boston, note that the findings should be interpreted cautiously because the size of the study population who received brain MRI was relatively small.

Dr. Tiemeier said in an interview that the associations detected were small and could not show causality between prenatal SSRI use and a decrease in gray and white matter across certain areas of the brain.

“Women who are pregnant and on maintenance therapy should consult their therapist if preventive therapy is still needed and if there are alternatives. This choice must be carefully considered, and women should be carefully advised,” he said.

The study was published online in JAMA Psychiatry.
 

An important decision

The investigators note that the decision to prescribe antidepressants, particularly SSRIs, during pregnancy is challenging. Though SSRI use during pregnancy is generally considered safe, some previous research suggests an association with negative outcomes in offspring, including adverse effects on neurodevelopment.

However, the researchers also note that it’s possible that pregnant women who use SSRIs may have other factors, including more severe depressive symptoms, which may be independently associated with adverse outcomes in offspring.

To investigate the link between intrauterine SSRI exposure and brain development, the researchers conducted a prospective, population-based study that included 3,198 pregnant individuals with an expected delivery date between April 2002 and January 2006. Study participants were divided into five groups: 41 who used SSRIs during pregnancy, 257 who did not use the medications but had depressive symptoms during pregnancy, 77 who used SSRIs prenatally, 74 who developed depressive symptoms after giving birth, and 2,749 controls with no SSRI use or depressive symptoms. Participants had a mean age of 31 years, and all identified as women.

Of those who took SSRIs during pregnancy, 20 used them during the first trimester only, and 21 used them the first or in one or two additional trimesters. The SSRIs used included paroxetine, fluoxetine, sertraline, fluvoxamine, and citalopram.

Offspring of the women enrolled in the study received MRIs at three different times between the ages 7 and 15 years.

The 41 children born to the women who took SSRIs prenatally had 80 scans in total, the 257 with mothers who did not use SSRIs yet had depressive symptoms while pregnant had 477 MRIs, the 77 children born to the mothers who took SSRIs before pregnancy had 126 MRIs, the 74 born to mothers with postnatal depression only had 128 MRIs, and the 2,749 children born to the mothers with no SSRI use or depression had 4,813 MRIs.

The study’s primary outcome was brain morphometry in offspring including global and cortical brain volumes, measured by three MRI assessments from ages 7 to 15 years.
 

Reduced brain volume

Compared with children with no in utero SSRI exposure, those who were exposed had reduced gray and white matter volume that persisted up to 15 years of age (P = .006), particularly in the corticolimbic circuit.

Investigators observed a “persistent association between prenatal SSRI exposure and less cortical volumes across the 10-year follow-up period, including in the superior frontal cortex, medial orbitofrontal cortex, parahippocampal gyrus, rostral anterior cingulate cortex, and posterior cingulate.”

Investigators noted that prenatal SSRI exposure was consistently associated with 5%-10% lower brain volume in the frontal, cingulate, and temporal cortex throughout the age range studied.

In a couple of areas of the brain, however, the brain volume gradually increased back to levels seen in non-SSRI exposed children. For instance, smaller amygdala volumes had increased by age 15 years, so children who were exposed to SSRIs were not any different from control children.

Among the group of women with postnatal depression using an SSRI before or during pregnancy who had depressive symptoms post natally, neonates had a reduced fusiform gyrus (P = .002)

Dr. Tiemeier could not speculate on the effects of the volume differences on children’s development, although the parts of the brain found to be reduced are primarily responsible for emotion regulation.

Investigators noted there was limited ability to investigate trimester-specific outcomes of SSRI use and assess associations with specific SSRIs due to low prevalence of SSRI use.

In addition, research on the long-term behavioral and psychological outcomes associated with demonstrated brain changes is needed, investigators noted.
 

Clinical significance ‘unclear’

In an accompanying editorial, Ardesheer Talati, PhD, Columbia University, New York, noted that though the research enhances understanding of how brain development through adolescence may be associated with SSRI exposure, “the clinical significance was unclear, especially as key limbic regions, including the amygdala, normalized over time.”

If future evidence links brain anomalies to adverse youth outcomes, Dr. Talati writes, this will need to be “calibrated into the risk-benefit profile.” Until then, he said, the findings must not be overinterpreted “to either promote or discourage antidepressant medication use during the critical period of pregnancy.”

The study was funded by the Netherlands Organization for Scientific Research, European Union’s Horizon Research and Innovation Program, the Netherlands Organization for Health Research and Development, the Sophia Foundation for Neuroimaging, and the European Union’s Horizon Research and Innovation 5 Program. Dr. Talati reported receiving grants from the National Institutes of Health outside of the submitted work.

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

In utero exposure to selective serotonin reuptake inhibitors (SSRIs) has been tied to reduced brain volume in children, results of a large population-based study show.

However, the investigators, led by Henning Tiemeier, MD, PhD, professor of social and behavioral sciences at Harvard School of Public Health in Boston, note that the findings should be interpreted cautiously because the size of the study population who received brain MRI was relatively small.

Dr. Tiemeier said in an interview that the associations detected were small and could not show causality between prenatal SSRI use and a decrease in gray and white matter across certain areas of the brain.

“Women who are pregnant and on maintenance therapy should consult their therapist if preventive therapy is still needed and if there are alternatives. This choice must be carefully considered, and women should be carefully advised,” he said.

The study was published online in JAMA Psychiatry.
 

An important decision

The investigators note that the decision to prescribe antidepressants, particularly SSRIs, during pregnancy is challenging. Though SSRI use during pregnancy is generally considered safe, some previous research suggests an association with negative outcomes in offspring, including adverse effects on neurodevelopment.

However, the researchers also note that it’s possible that pregnant women who use SSRIs may have other factors, including more severe depressive symptoms, which may be independently associated with adverse outcomes in offspring.

To investigate the link between intrauterine SSRI exposure and brain development, the researchers conducted a prospective, population-based study that included 3,198 pregnant individuals with an expected delivery date between April 2002 and January 2006. Study participants were divided into five groups: 41 who used SSRIs during pregnancy, 257 who did not use the medications but had depressive symptoms during pregnancy, 77 who used SSRIs prenatally, 74 who developed depressive symptoms after giving birth, and 2,749 controls with no SSRI use or depressive symptoms. Participants had a mean age of 31 years, and all identified as women.

Of those who took SSRIs during pregnancy, 20 used them during the first trimester only, and 21 used them the first or in one or two additional trimesters. The SSRIs used included paroxetine, fluoxetine, sertraline, fluvoxamine, and citalopram.

Offspring of the women enrolled in the study received MRIs at three different times between the ages 7 and 15 years.

The 41 children born to the women who took SSRIs prenatally had 80 scans in total, the 257 with mothers who did not use SSRIs yet had depressive symptoms while pregnant had 477 MRIs, the 77 children born to the mothers who took SSRIs before pregnancy had 126 MRIs, the 74 born to mothers with postnatal depression only had 128 MRIs, and the 2,749 children born to the mothers with no SSRI use or depression had 4,813 MRIs.

The study’s primary outcome was brain morphometry in offspring including global and cortical brain volumes, measured by three MRI assessments from ages 7 to 15 years.
 

Reduced brain volume

Compared with children with no in utero SSRI exposure, those who were exposed had reduced gray and white matter volume that persisted up to 15 years of age (P = .006), particularly in the corticolimbic circuit.

Investigators observed a “persistent association between prenatal SSRI exposure and less cortical volumes across the 10-year follow-up period, including in the superior frontal cortex, medial orbitofrontal cortex, parahippocampal gyrus, rostral anterior cingulate cortex, and posterior cingulate.”

Investigators noted that prenatal SSRI exposure was consistently associated with 5%-10% lower brain volume in the frontal, cingulate, and temporal cortex throughout the age range studied.

In a couple of areas of the brain, however, the brain volume gradually increased back to levels seen in non-SSRI exposed children. For instance, smaller amygdala volumes had increased by age 15 years, so children who were exposed to SSRIs were not any different from control children.

Among the group of women with postnatal depression using an SSRI before or during pregnancy who had depressive symptoms post natally, neonates had a reduced fusiform gyrus (P = .002)

Dr. Tiemeier could not speculate on the effects of the volume differences on children’s development, although the parts of the brain found to be reduced are primarily responsible for emotion regulation.

Investigators noted there was limited ability to investigate trimester-specific outcomes of SSRI use and assess associations with specific SSRIs due to low prevalence of SSRI use.

In addition, research on the long-term behavioral and psychological outcomes associated with demonstrated brain changes is needed, investigators noted.
 

Clinical significance ‘unclear’

In an accompanying editorial, Ardesheer Talati, PhD, Columbia University, New York, noted that though the research enhances understanding of how brain development through adolescence may be associated with SSRI exposure, “the clinical significance was unclear, especially as key limbic regions, including the amygdala, normalized over time.”

If future evidence links brain anomalies to adverse youth outcomes, Dr. Talati writes, this will need to be “calibrated into the risk-benefit profile.” Until then, he said, the findings must not be overinterpreted “to either promote or discourage antidepressant medication use during the critical period of pregnancy.”

The study was funded by the Netherlands Organization for Scientific Research, European Union’s Horizon Research and Innovation Program, the Netherlands Organization for Health Research and Development, the Sophia Foundation for Neuroimaging, and the European Union’s Horizon Research and Innovation 5 Program. Dr. Talati reported receiving grants from the National Institutes of Health outside of the submitted work.

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

A recent study found a significant association between lower sexual frequency and greater all-cause mortality in young and middle-aged people with hypertension. Should primary care physicians be offering a pleasure prescription to the 6 in 10 Americans living with chronic illness? How can we help these patients access their capacity for sexual pleasure, a critical and life-affirming component of the human experience?

Ask, don’t tell

First, we need to ask routinely about sexual well-being and pleasure. Without asking patients their views, we do not know the relevance of sex for their quality of life. Unless we ask, we do not know what specific kinds of sexual play are important for a person’s pleasure, nor can we assume how they prioritize their sexual functioning in the context of their medical care. When I began asking my primary care patients about sexual well-being, many more than I expected were quietly holding on to distressing issues. Now, as a sexual medicine specialist, in each sexual function evaluation, I ask three key questions: What are your goals? What does sex mean to you? What kinds of sexual play are important for your (and your partner’s) pleasure?

Chronic disease – with physical symptoms as well as psychological, relational, and cultural components – affects both general and genital physiology. Any disease process that alters vascular, neuroendocrine, or musculoskeletal function is likely to influence sexual function, either directly through the disease process or indirectly through complications or the effect on identity and well-being. In addition, a host of iatrogenic changes to sexual function may accompany effects of treatments.

Managing the effects of chronic illness on sexuality requires resilience and flexibility. A serious injury may require a massive adjustment to sexuality, but progressive disease may require continuous accommodations to sexual changes. The life stage at which the disease occurs also matters. People facing disease early in life encounter challenges (finding willing sexual partners and limited medical guidance regarding their sexual functioning) as well as benefits (they may integrate their disease as part of their sexual life). Those who experience sexual changes related to their illness later in life may face a loss of “normal” sexual function and well-being.

Meanwhile, the partner who is not ill may have their own sexual needs, fears, and worries. Both patients and partners may experience disenfranchised grief – a sense of loss about something one is not culturally permitted to mourn (“I/my partner is alive in the face of this terrible illness; who am I to worry about our/my sexual pleasure?”).

Positive marital relationships influence health through improved survival, improved medical adherence, better quality of life for the patient, and improved life satisfaction. Sexual satisfaction is an important factor in relational satisfaction. Helping our patients with these changes therefore may improve not only sexual health but overall health.

How, then, should we address sexual pleasure in chronic illness care? Here are a few tips:

Focus on pleasure. “Performance” is foul language when it comes to sex. Full attention to sensation and enjoyment, the only sexual “skill” anyone needs, is impossible while trying to perform.

Encourage flexibility and recognize that sex encompasses a wide and varied menu of experiences that change over a lifetime. Sex is everything from kissing and cuddling to the wildest things a mind can imagine. We can help both patients and partners think about the wide variety of ways to meet sexual needs. Balancing acceptance of sexual changes with motivation for improvement also is part of our role.

Address the effects of illness on the patient’s relationship with their body. Illness may alter not only bodily function but also self-esteem and body image. A reorganization of self-concept may occur (“I am no longer a sexual person; I’m a sexually dysfunctional asthmatic/diabetic/etc. and should avoid sexual intimacy”). Examining these self-constructs allows shifts in thoughts and behaviors, leading to improved psychological and sexual well-being. Encourage patients to explore what feels good in this body now. When possible, we can help with referral for corrective surgeries or direction to resources like stoma covers, wigs, scarves, and tattoos.

We offer suggestions for “sleep hygiene”; how about pleasure hygiene?

• Encourage open communication with partner(s) and offer resources to develop communication skills.
• Consider needs for physical and emotional preparation for sexual play: adequate rest, preparing the environment for body fluids, pillows for comfort or aides for positioning, and plenty of lubricant at hand.
• Allow adequate time for sexual play and encourage the ability to adjust or stop and start over – with humor and self-compassion.
• Use sexual aides to enhance pleasure.
• Seek out sexual medicine and sex therapy colleagues when things become tricky.

All bodies, no matter their health or illness state, are capable of pleasure. Hey, pleasure might even save lives!

Dr. Kranz is an clinical assistant professor of obstetrics/gynecology and family medicine, University of Rochester (N.Y.) Medical Center. She reported no conflicts of interest.

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

A recent study found a significant association between lower sexual frequency and greater all-cause mortality in young and middle-aged people with hypertension. Should primary care physicians be offering a pleasure prescription to the 6 in 10 Americans living with chronic illness? How can we help these patients access their capacity for sexual pleasure, a critical and life-affirming component of the human experience?

Ask, don’t tell

First, we need to ask routinely about sexual well-being and pleasure. Without asking patients their views, we do not know the relevance of sex for their quality of life. Unless we ask, we do not know what specific kinds of sexual play are important for a person’s pleasure, nor can we assume how they prioritize their sexual functioning in the context of their medical care. When I began asking my primary care patients about sexual well-being, many more than I expected were quietly holding on to distressing issues. Now, as a sexual medicine specialist, in each sexual function evaluation, I ask three key questions: What are your goals? What does sex mean to you? What kinds of sexual play are important for your (and your partner’s) pleasure?

Chronic disease – with physical symptoms as well as psychological, relational, and cultural components – affects both general and genital physiology. Any disease process that alters vascular, neuroendocrine, or musculoskeletal function is likely to influence sexual function, either directly through the disease process or indirectly through complications or the effect on identity and well-being. In addition, a host of iatrogenic changes to sexual function may accompany effects of treatments.

Managing the effects of chronic illness on sexuality requires resilience and flexibility. A serious injury may require a massive adjustment to sexuality, but progressive disease may require continuous accommodations to sexual changes. The life stage at which the disease occurs also matters. People facing disease early in life encounter challenges (finding willing sexual partners and limited medical guidance regarding their sexual functioning) as well as benefits (they may integrate their disease as part of their sexual life). Those who experience sexual changes related to their illness later in life may face a loss of “normal” sexual function and well-being.

Meanwhile, the partner who is not ill may have their own sexual needs, fears, and worries. Both patients and partners may experience disenfranchised grief – a sense of loss about something one is not culturally permitted to mourn (“I/my partner is alive in the face of this terrible illness; who am I to worry about our/my sexual pleasure?”).

Positive marital relationships influence health through improved survival, improved medical adherence, better quality of life for the patient, and improved life satisfaction. Sexual satisfaction is an important factor in relational satisfaction. Helping our patients with these changes therefore may improve not only sexual health but overall health.

How, then, should we address sexual pleasure in chronic illness care? Here are a few tips:

Focus on pleasure. “Performance” is foul language when it comes to sex. Full attention to sensation and enjoyment, the only sexual “skill” anyone needs, is impossible while trying to perform.

Encourage flexibility and recognize that sex encompasses a wide and varied menu of experiences that change over a lifetime. Sex is everything from kissing and cuddling to the wildest things a mind can imagine. We can help both patients and partners think about the wide variety of ways to meet sexual needs. Balancing acceptance of sexual changes with motivation for improvement also is part of our role.

Address the effects of illness on the patient’s relationship with their body. Illness may alter not only bodily function but also self-esteem and body image. A reorganization of self-concept may occur (“I am no longer a sexual person; I’m a sexually dysfunctional asthmatic/diabetic/etc. and should avoid sexual intimacy”). Examining these self-constructs allows shifts in thoughts and behaviors, leading to improved psychological and sexual well-being. Encourage patients to explore what feels good in this body now. When possible, we can help with referral for corrective surgeries or direction to resources like stoma covers, wigs, scarves, and tattoos.

We offer suggestions for “sleep hygiene”; how about pleasure hygiene?

• Encourage open communication with partner(s) and offer resources to develop communication skills.
• Consider needs for physical and emotional preparation for sexual play: adequate rest, preparing the environment for body fluids, pillows for comfort or aides for positioning, and plenty of lubricant at hand.
• Allow adequate time for sexual play and encourage the ability to adjust or stop and start over – with humor and self-compassion.
• Use sexual aides to enhance pleasure.
• Seek out sexual medicine and sex therapy colleagues when things become tricky.

All bodies, no matter their health or illness state, are capable of pleasure. Hey, pleasure might even save lives!

Dr. Kranz is an clinical assistant professor of obstetrics/gynecology and family medicine, University of Rochester (N.Y.) Medical Center. She reported no conflicts of interest.

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

A recent study found a significant association between lower sexual frequency and greater all-cause mortality in young and middle-aged people with hypertension. Should primary care physicians be offering a pleasure prescription to the 6 in 10 Americans living with chronic illness? How can we help these patients access their capacity for sexual pleasure, a critical and life-affirming component of the human experience?

Ask, don’t tell

First, we need to ask routinely about sexual well-being and pleasure. Without asking patients their views, we do not know the relevance of sex for their quality of life. Unless we ask, we do not know what specific kinds of sexual play are important for a person’s pleasure, nor can we assume how they prioritize their sexual functioning in the context of their medical care. When I began asking my primary care patients about sexual well-being, many more than I expected were quietly holding on to distressing issues. Now, as a sexual medicine specialist, in each sexual function evaluation, I ask three key questions: What are your goals? What does sex mean to you? What kinds of sexual play are important for your (and your partner’s) pleasure?

Chronic disease – with physical symptoms as well as psychological, relational, and cultural components – affects both general and genital physiology. Any disease process that alters vascular, neuroendocrine, or musculoskeletal function is likely to influence sexual function, either directly through the disease process or indirectly through complications or the effect on identity and well-being. In addition, a host of iatrogenic changes to sexual function may accompany effects of treatments.

Managing the effects of chronic illness on sexuality requires resilience and flexibility. A serious injury may require a massive adjustment to sexuality, but progressive disease may require continuous accommodations to sexual changes. The life stage at which the disease occurs also matters. People facing disease early in life encounter challenges (finding willing sexual partners and limited medical guidance regarding their sexual functioning) as well as benefits (they may integrate their disease as part of their sexual life). Those who experience sexual changes related to their illness later in life may face a loss of “normal” sexual function and well-being.

Meanwhile, the partner who is not ill may have their own sexual needs, fears, and worries. Both patients and partners may experience disenfranchised grief – a sense of loss about something one is not culturally permitted to mourn (“I/my partner is alive in the face of this terrible illness; who am I to worry about our/my sexual pleasure?”).

Positive marital relationships influence health through improved survival, improved medical adherence, better quality of life for the patient, and improved life satisfaction. Sexual satisfaction is an important factor in relational satisfaction. Helping our patients with these changes therefore may improve not only sexual health but overall health.

How, then, should we address sexual pleasure in chronic illness care? Here are a few tips:

Focus on pleasure. “Performance” is foul language when it comes to sex. Full attention to sensation and enjoyment, the only sexual “skill” anyone needs, is impossible while trying to perform.

Encourage flexibility and recognize that sex encompasses a wide and varied menu of experiences that change over a lifetime. Sex is everything from kissing and cuddling to the wildest things a mind can imagine. We can help both patients and partners think about the wide variety of ways to meet sexual needs. Balancing acceptance of sexual changes with motivation for improvement also is part of our role.

Address the effects of illness on the patient’s relationship with their body. Illness may alter not only bodily function but also self-esteem and body image. A reorganization of self-concept may occur (“I am no longer a sexual person; I’m a sexually dysfunctional asthmatic/diabetic/etc. and should avoid sexual intimacy”). Examining these self-constructs allows shifts in thoughts and behaviors, leading to improved psychological and sexual well-being. Encourage patients to explore what feels good in this body now. When possible, we can help with referral for corrective surgeries or direction to resources like stoma covers, wigs, scarves, and tattoos.

We offer suggestions for “sleep hygiene”; how about pleasure hygiene?

• Encourage open communication with partner(s) and offer resources to develop communication skills.
• Consider needs for physical and emotional preparation for sexual play: adequate rest, preparing the environment for body fluids, pillows for comfort or aides for positioning, and plenty of lubricant at hand.
• Allow adequate time for sexual play and encourage the ability to adjust or stop and start over – with humor and self-compassion.
• Use sexual aides to enhance pleasure.
• Seek out sexual medicine and sex therapy colleagues when things become tricky.

All bodies, no matter their health or illness state, are capable of pleasure. Hey, pleasure might even save lives!

Dr. Kranz is an clinical assistant professor of obstetrics/gynecology and family medicine, University of Rochester (N.Y.) Medical Center. She reported no conflicts of interest.

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

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended marketing authorization of lebrikizumab for the treatment of adult and adolescent patients with moderate to severe atopic dermatitis (AD) who are candidates for systemic therapy.

Lebrikizumab is an investigational, monoclonal antibody that binds to cytokine interleukin (IL)-13, which has been implicated in driving the type-2 inflammatory loop in the skin, leading to skin barrier dysfunction, itch, skin thickening, and infection. The biologic is being developed by Almirall and is designed to be administered once per month. Lebrikizumab is not yet available in the United States.

According to a press release from Almirall, the CHMP opinion was based on three pivotal phase 3 studies that showed long-term response in skin clearance and itch control. ADvocate 1 and ADvocate 2 evaluated lebrikizumab as monotherapy, while ADhere assessed lebrikizumab in combination with topical corticosteroids (TCS) in adult and adolescent patients with moderate to severe AD. At week 16, more than 50% of patients with moderate to severe AD experienced at least a 75% reduction in disease severity (EASI-75) when receiving lebrikizumab monotherapy in the ADvocate studies and nearly 70% of patients receiving lebrikizumab combined with standard-of-care TCS achieved EASI-75 in the ADhere trial.

Most adverse events across the studies were mild or moderate. The most common reactions were conjunctivitis, injection site reactions, allergic conjunctivitis, and dry eye.

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended marketing authorization of lebrikizumab for the treatment of adult and adolescent patients with moderate to severe atopic dermatitis (AD) who are candidates for systemic therapy.

Lebrikizumab is an investigational, monoclonal antibody that binds to cytokine interleukin (IL)-13, which has been implicated in driving the type-2 inflammatory loop in the skin, leading to skin barrier dysfunction, itch, skin thickening, and infection. The biologic is being developed by Almirall and is designed to be administered once per month. Lebrikizumab is not yet available in the United States.

According to a press release from Almirall, the CHMP opinion was based on three pivotal phase 3 studies that showed long-term response in skin clearance and itch control. ADvocate 1 and ADvocate 2 evaluated lebrikizumab as monotherapy, while ADhere assessed lebrikizumab in combination with topical corticosteroids (TCS) in adult and adolescent patients with moderate to severe AD. At week 16, more than 50% of patients with moderate to severe AD experienced at least a 75% reduction in disease severity (EASI-75) when receiving lebrikizumab monotherapy in the ADvocate studies and nearly 70% of patients receiving lebrikizumab combined with standard-of-care TCS achieved EASI-75 in the ADhere trial.

Most adverse events across the studies were mild or moderate. The most common reactions were conjunctivitis, injection site reactions, allergic conjunctivitis, and dry eye.

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended marketing authorization of lebrikizumab for the treatment of adult and adolescent patients with moderate to severe atopic dermatitis (AD) who are candidates for systemic therapy.

Lebrikizumab is an investigational, monoclonal antibody that binds to cytokine interleukin (IL)-13, which has been implicated in driving the type-2 inflammatory loop in the skin, leading to skin barrier dysfunction, itch, skin thickening, and infection. The biologic is being developed by Almirall and is designed to be administered once per month. Lebrikizumab is not yet available in the United States.

According to a press release from Almirall, the CHMP opinion was based on three pivotal phase 3 studies that showed long-term response in skin clearance and itch control. ADvocate 1 and ADvocate 2 evaluated lebrikizumab as monotherapy, while ADhere assessed lebrikizumab in combination with topical corticosteroids (TCS) in adult and adolescent patients with moderate to severe AD. At week 16, more than 50% of patients with moderate to severe AD experienced at least a 75% reduction in disease severity (EASI-75) when receiving lebrikizumab monotherapy in the ADvocate studies and nearly 70% of patients receiving lebrikizumab combined with standard-of-care TCS achieved EASI-75 in the ADhere trial.

Most adverse events across the studies were mild or moderate. The most common reactions were conjunctivitis, injection site reactions, allergic conjunctivitis, and dry eye.

TOPLINE:

The disease-modifying treatment (DMT) delays conversion to clinical multiple sclerosis (MS) for patients with radiologically isolated syndrome (RIS) and has a reassuring long-term safety profile, new research shows.

METHODOLOGY:

Early use of DMTs is typically recommended for patients with established MS, but mounting evidence, including the ARISE trial, which assessed Tecfidera, suggests these agents benefit patients with RIS, the earliest detectable preclinical MS stage.

The new study, known as Teriflunomide in Radiologically Isolated Syndrome (TERIS), included 89 adult patients with RIS (mean age, 37.8 years) from centers in France, Switzerland, and Turkey. Participants were randomly assigned to receive placebo or teriflunomide 14 mg daily. Teriflunomide is an oral immunomodulator approved for treating relapsing remitting MS.

Investigators performed MRI at baseline and at weeks 48, 96, and 144 and at any time during the study if warranted.

Researchers adjusted for potential confounders, including sex, age at RIS diagnosis, MS family history, brain T2-weighted hyperintense lesion volume, and presence of Gd+/− lesions.

The primary outcome was time to a first acute or progressive neurologic event resulting from central nervous system demyelination, expressed as a rate of conversion to clinical MS.
 

TAKEAWAY:

Eighteen participants – nine in each group – discontinued the study, resulting in a dropout rate of 20%.

The risk of a first clinical event was significantly reduced in the teriflunomide arm (mean time to event, 128.2 weeks) with 8 clinical events (6 acute, 2 progressive) in comparison with the placebo arm (mean time to event, 109.6 weeks) with 20 clinical events (18 acute, 2 progressive) and an adjusted hazard ratio of 0.28 (95% CI, 0.11-0.71; P = .007).

All secondary MRI measures, including the cumulative number of new and/or newly enlarging T2 lesions and the cumulative number of Gd+ lesions, did not reach statistical significance, although these were numerically lower in the teriflunomide arm, possibly because participants with early events switched to the treatment arm.

The most common adverse events that occurred more often in patients treated with teriflunomide were gastrointestinal disorders (11.4%), dysmenorrhea (9.1%), benign respiratory infections (6.8%), general disorders/conditions (6.8%), and transient increase of transaminases (4.5%).
 

IN PRACTICE:

“These results suggest that for the first time, we may have an opportunity to better identify those at risk for a primary progressive clinical course at this preclinical stage and prevent or delay clinical progression from the onset, which is a clear unmet need in MS clinical practice,” wrote the authors.

SOURCE:

The study was carried out by Christine Lebrun-Frénay MD, PhD, head of the inflammatory neurological disorders clinical research unit and MS center at the University of Nice (France). It was published online in JAMA Neurology.

LIMITATIONS:

The investigators could not stratify at-risk subgroups according to risk factors for developing MS, mainly because of power issues. The study was prematurely discontinued by its financial sponsor (Sanofi), owing primarily to slow enrollment that resulted from national regulations on activating recruitment sites and the impact of the COVID-19 pandemic. Another challenge for the study was that some individuals with RIS had already been exposed to a DMT or hesitated to participate in a clinical trial. The financial sponsor, which provided the study drug and placebo tablets, terminated their availability, given the anticipated release of generic teriflunomide.

DISCLOSURES:

The study was supported by Sanofi, the University Hospital of Nice, University Cote d’Azur, and the Radiologically Isolated Syndrome Consortium. Lebrun-Frénay has no relevant conflicts of interest.

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

TOPLINE:

The disease-modifying treatment (DMT) delays conversion to clinical multiple sclerosis (MS) for patients with radiologically isolated syndrome (RIS) and has a reassuring long-term safety profile, new research shows.

METHODOLOGY:

Early use of DMTs is typically recommended for patients with established MS, but mounting evidence, including the ARISE trial, which assessed Tecfidera, suggests these agents benefit patients with RIS, the earliest detectable preclinical MS stage.

The new study, known as Teriflunomide in Radiologically Isolated Syndrome (TERIS), included 89 adult patients with RIS (mean age, 37.8 years) from centers in France, Switzerland, and Turkey. Participants were randomly assigned to receive placebo or teriflunomide 14 mg daily. Teriflunomide is an oral immunomodulator approved for treating relapsing remitting MS.

Investigators performed MRI at baseline and at weeks 48, 96, and 144 and at any time during the study if warranted.

Researchers adjusted for potential confounders, including sex, age at RIS diagnosis, MS family history, brain T2-weighted hyperintense lesion volume, and presence of Gd+/− lesions.

The primary outcome was time to a first acute or progressive neurologic event resulting from central nervous system demyelination, expressed as a rate of conversion to clinical MS.
 

TAKEAWAY:

Eighteen participants – nine in each group – discontinued the study, resulting in a dropout rate of 20%.

The risk of a first clinical event was significantly reduced in the teriflunomide arm (mean time to event, 128.2 weeks) with 8 clinical events (6 acute, 2 progressive) in comparison with the placebo arm (mean time to event, 109.6 weeks) with 20 clinical events (18 acute, 2 progressive) and an adjusted hazard ratio of 0.28 (95% CI, 0.11-0.71; P = .007).

All secondary MRI measures, including the cumulative number of new and/or newly enlarging T2 lesions and the cumulative number of Gd+ lesions, did not reach statistical significance, although these were numerically lower in the teriflunomide arm, possibly because participants with early events switched to the treatment arm.

The most common adverse events that occurred more often in patients treated with teriflunomide were gastrointestinal disorders (11.4%), dysmenorrhea (9.1%), benign respiratory infections (6.8%), general disorders/conditions (6.8%), and transient increase of transaminases (4.5%).
 

IN PRACTICE:

“These results suggest that for the first time, we may have an opportunity to better identify those at risk for a primary progressive clinical course at this preclinical stage and prevent or delay clinical progression from the onset, which is a clear unmet need in MS clinical practice,” wrote the authors.

SOURCE:

The study was carried out by Christine Lebrun-Frénay MD, PhD, head of the inflammatory neurological disorders clinical research unit and MS center at the University of Nice (France). It was published online in JAMA Neurology.

LIMITATIONS:

The investigators could not stratify at-risk subgroups according to risk factors for developing MS, mainly because of power issues. The study was prematurely discontinued by its financial sponsor (Sanofi), owing primarily to slow enrollment that resulted from national regulations on activating recruitment sites and the impact of the COVID-19 pandemic. Another challenge for the study was that some individuals with RIS had already been exposed to a DMT or hesitated to participate in a clinical trial. The financial sponsor, which provided the study drug and placebo tablets, terminated their availability, given the anticipated release of generic teriflunomide.

DISCLOSURES:

The study was supported by Sanofi, the University Hospital of Nice, University Cote d’Azur, and the Radiologically Isolated Syndrome Consortium. Lebrun-Frénay has no relevant conflicts of interest.

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

TOPLINE:

The disease-modifying treatment (DMT) delays conversion to clinical multiple sclerosis (MS) for patients with radiologically isolated syndrome (RIS) and has a reassuring long-term safety profile, new research shows.

METHODOLOGY:

Early use of DMTs is typically recommended for patients with established MS, but mounting evidence, including the ARISE trial, which assessed Tecfidera, suggests these agents benefit patients with RIS, the earliest detectable preclinical MS stage.

The new study, known as Teriflunomide in Radiologically Isolated Syndrome (TERIS), included 89 adult patients with RIS (mean age, 37.8 years) from centers in France, Switzerland, and Turkey. Participants were randomly assigned to receive placebo or teriflunomide 14 mg daily. Teriflunomide is an oral immunomodulator approved for treating relapsing remitting MS.

Investigators performed MRI at baseline and at weeks 48, 96, and 144 and at any time during the study if warranted.

Researchers adjusted for potential confounders, including sex, age at RIS diagnosis, MS family history, brain T2-weighted hyperintense lesion volume, and presence of Gd+/− lesions.

The primary outcome was time to a first acute or progressive neurologic event resulting from central nervous system demyelination, expressed as a rate of conversion to clinical MS.
 

TAKEAWAY:

Eighteen participants – nine in each group – discontinued the study, resulting in a dropout rate of 20%.

The risk of a first clinical event was significantly reduced in the teriflunomide arm (mean time to event, 128.2 weeks) with 8 clinical events (6 acute, 2 progressive) in comparison with the placebo arm (mean time to event, 109.6 weeks) with 20 clinical events (18 acute, 2 progressive) and an adjusted hazard ratio of 0.28 (95% CI, 0.11-0.71; P = .007).

All secondary MRI measures, including the cumulative number of new and/or newly enlarging T2 lesions and the cumulative number of Gd+ lesions, did not reach statistical significance, although these were numerically lower in the teriflunomide arm, possibly because participants with early events switched to the treatment arm.

The most common adverse events that occurred more often in patients treated with teriflunomide were gastrointestinal disorders (11.4%), dysmenorrhea (9.1%), benign respiratory infections (6.8%), general disorders/conditions (6.8%), and transient increase of transaminases (4.5%).
 

IN PRACTICE:

“These results suggest that for the first time, we may have an opportunity to better identify those at risk for a primary progressive clinical course at this preclinical stage and prevent or delay clinical progression from the onset, which is a clear unmet need in MS clinical practice,” wrote the authors.

SOURCE:

The study was carried out by Christine Lebrun-Frénay MD, PhD, head of the inflammatory neurological disorders clinical research unit and MS center at the University of Nice (France). It was published online in JAMA Neurology.

LIMITATIONS:

The investigators could not stratify at-risk subgroups according to risk factors for developing MS, mainly because of power issues. The study was prematurely discontinued by its financial sponsor (Sanofi), owing primarily to slow enrollment that resulted from national regulations on activating recruitment sites and the impact of the COVID-19 pandemic. Another challenge for the study was that some individuals with RIS had already been exposed to a DMT or hesitated to participate in a clinical trial. The financial sponsor, which provided the study drug and placebo tablets, terminated their availability, given the anticipated release of generic teriflunomide.

DISCLOSURES:

The study was supported by Sanofi, the University Hospital of Nice, University Cote d’Azur, and the Radiologically Isolated Syndrome Consortium. Lebrun-Frénay has no relevant conflicts of interest.

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