Dr. Jones and Dr. Joans are neurologists in town. I don’t know either one particularly well.

I don’t know their backstory, either, but they seem to have some intense competition going on.

Technically all of us neuros in the area compete with each other, but it’s pretty friendly. There are plenty of patients, and we all get along on the occasions we run into each other at the hospital or Costco or a meeting. Occasionally we call to bounce a case off each other. None of us advertise.

But Jones and Joans have kicked it up a notch. One got an EEG machine, the other got an EEG machine. A few weeks later one got a balance testing gadget, then the other got the same thing. One invested in all kinds of fancy devices to detect concussions, and shortly afterward so did the other one. Within a few months each bought their own Doppler equipment and hired an ultrasound tech. One took out a glossy ad in a local magazine, the next month so had the other. Both point out that they’ve been named on different “best doctor” lists. I assume it’s only a matter of time before each invests in their own MRI.

This kind of thing requires a lot of money to support, so both have jumped into the world of medical liens and hired NPs and PAs to increase patient volume.

I’m sure they both make more money than I ever will, and they can have it.

I don’t need that kind of complexity in my life. I have my own EMG/NCV machine, and beyond that I send all the testing (and complicated EMG/NCVs) to other facilities. I don’t want to figure out how to make payments on all those new gadgets, or hire staff to run them, or learn all the new codes I’d need (I do all my own coding, anyway), or decide if the advertising will pay for itself, or deal with liens.

I’m not even sure I want to be that busy. Obviously, I don’t want to be empty, but I also like having some degree of sanity. Time to review tests, type up notes, return calls ... all the things you have to do on the fly between patients, because if you don’t get them done at the office then you have to do them when you get home. Believe me, I already have enough going on there.

I have no desire to advertise that I’m the best neurologist in town (though I believe I’m the best in my building, since there isn’t another one) or to be the busiest, or to be involved in a game of one-upmanship with the nice group down the street.

If Drs. Jones and Joans want to do that, fine. More power to them.

For me, I’ve chosen simplicity in my practice, and prefer it. Like everyone else I want to earn a living, but I also want to to enjoy my job, and non-job, time as best possible.

I’m willing to trade that for money.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

Dr. Jones and Dr. Joans are neurologists in town. I don’t know either one particularly well.

I don’t know their backstory, either, but they seem to have some intense competition going on.

Technically all of us neuros in the area compete with each other, but it’s pretty friendly. There are plenty of patients, and we all get along on the occasions we run into each other at the hospital or Costco or a meeting. Occasionally we call to bounce a case off each other. None of us advertise.

But Jones and Joans have kicked it up a notch. One got an EEG machine, the other got an EEG machine. A few weeks later one got a balance testing gadget, then the other got the same thing. One invested in all kinds of fancy devices to detect concussions, and shortly afterward so did the other one. Within a few months each bought their own Doppler equipment and hired an ultrasound tech. One took out a glossy ad in a local magazine, the next month so had the other. Both point out that they’ve been named on different “best doctor” lists. I assume it’s only a matter of time before each invests in their own MRI.

This kind of thing requires a lot of money to support, so both have jumped into the world of medical liens and hired NPs and PAs to increase patient volume.

I’m sure they both make more money than I ever will, and they can have it.

I don’t need that kind of complexity in my life. I have my own EMG/NCV machine, and beyond that I send all the testing (and complicated EMG/NCVs) to other facilities. I don’t want to figure out how to make payments on all those new gadgets, or hire staff to run them, or learn all the new codes I’d need (I do all my own coding, anyway), or decide if the advertising will pay for itself, or deal with liens.

I’m not even sure I want to be that busy. Obviously, I don’t want to be empty, but I also like having some degree of sanity. Time to review tests, type up notes, return calls ... all the things you have to do on the fly between patients, because if you don’t get them done at the office then you have to do them when you get home. Believe me, I already have enough going on there.

I have no desire to advertise that I’m the best neurologist in town (though I believe I’m the best in my building, since there isn’t another one) or to be the busiest, or to be involved in a game of one-upmanship with the nice group down the street.

If Drs. Jones and Joans want to do that, fine. More power to them.

For me, I’ve chosen simplicity in my practice, and prefer it. Like everyone else I want to earn a living, but I also want to to enjoy my job, and non-job, time as best possible.

I’m willing to trade that for money.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

Dr. Jones and Dr. Joans are neurologists in town. I don’t know either one particularly well.

I don’t know their backstory, either, but they seem to have some intense competition going on.

Technically all of us neuros in the area compete with each other, but it’s pretty friendly. There are plenty of patients, and we all get along on the occasions we run into each other at the hospital or Costco or a meeting. Occasionally we call to bounce a case off each other. None of us advertise.

But Jones and Joans have kicked it up a notch. One got an EEG machine, the other got an EEG machine. A few weeks later one got a balance testing gadget, then the other got the same thing. One invested in all kinds of fancy devices to detect concussions, and shortly afterward so did the other one. Within a few months each bought their own Doppler equipment and hired an ultrasound tech. One took out a glossy ad in a local magazine, the next month so had the other. Both point out that they’ve been named on different “best doctor” lists. I assume it’s only a matter of time before each invests in their own MRI.

This kind of thing requires a lot of money to support, so both have jumped into the world of medical liens and hired NPs and PAs to increase patient volume.

I’m sure they both make more money than I ever will, and they can have it.

I don’t need that kind of complexity in my life. I have my own EMG/NCV machine, and beyond that I send all the testing (and complicated EMG/NCVs) to other facilities. I don’t want to figure out how to make payments on all those new gadgets, or hire staff to run them, or learn all the new codes I’d need (I do all my own coding, anyway), or decide if the advertising will pay for itself, or deal with liens.

I’m not even sure I want to be that busy. Obviously, I don’t want to be empty, but I also like having some degree of sanity. Time to review tests, type up notes, return calls ... all the things you have to do on the fly between patients, because if you don’t get them done at the office then you have to do them when you get home. Believe me, I already have enough going on there.

I have no desire to advertise that I’m the best neurologist in town (though I believe I’m the best in my building, since there isn’t another one) or to be the busiest, or to be involved in a game of one-upmanship with the nice group down the street.

If Drs. Jones and Joans want to do that, fine. More power to them.

For me, I’ve chosen simplicity in my practice, and prefer it. Like everyone else I want to earn a living, but I also want to to enjoy my job, and non-job, time as best possible.

I’m willing to trade that for money.
 

Dr. Block has a solo neurology practice in Scottsdale, Arizona.

TOPLINE:

Roflumilast cream 0.15% was well tolerated and significantly improved symptoms in adults and children with mild to moderate atopic dermatitis (AD) in two phase 3 trials.

METHODOLOGY:

• Two randomized, parallel-group, double-blind, vehicle-controlled phase 3 trials, INTEGUMENT-1 (n = 654) and INTEGUMENT-2 (n = 683), enrolled patients aged ≥ 6 years with mild to moderate AD who were randomly assigned in a 2:1 ratio to roflumilast cream 0.15%, a phosphodiesterase 4 inhibitor, or vehicle cream once daily for 4 weeks.
• The primary efficacy endpoint was the Validated Investigator Global Assessment for AD (vIGA-AD) success at week 4, defined as a score of 0 (clear) or 1 (almost clear) plus improvement of at least two grades from baseline.
• Secondary endpoints included vIGA-AD success at week 4 in patients with a baseline score of 3, at least a four-point reduction in the Worst Itch Numeric Rating Scale (WI-NRS), and at least a 75% reduction in the Eczema Area and Severity Index (EASI-75) at weeks 1, 2, and 4.

TAKEAWAY:

• Significantly more patients receiving roflumilast achieved vIGA-AD success at week 4 vs those in the vehicle group in INTEGUMENT-1 (32.0% vs 15.2%; P < .001) and INTEGUMENT-2 (28.9% vs 12.0%; P < .001), which was consistent across all age groups and in those with a baseline score of 3.
• Similarly, a greater proportion of patients treated with roflumilast vs vehicle achieved at least a four-point reduction in WI-NRS at weeks 1, 2, and 4, with improvements noted as early as 24 hours after the first application (P < .05 at all subsequent timepoints).
• The number of patients achieving EASI-75 and vIGA-AD scores of 0 or 1 was significantly higher with roflumilast than with vehicle at weeks 1, 2, and 4.
• Most treatment-emergent adverse events (TEAEs) were mild to moderate, with only 0.9% of the patients experiencing serious TEAEs in each trial. More than 95% of the patients showed no signs of irritation, and over 90% reported no or mild sensation at the application site.

IN PRACTICE:

The two phase 3 randomized clinical trials of patients with AD treated with roflumilast cream 0.15% “demonstrated improvement across multiple efficacy endpoints, including reducing pruritus within 24 hours after application, with favorable safety and tolerability,” the authors wrote. “Additional research, including subgroup analyses, will provide more data regarding the efficacy and safety of roflumilast cream 0.15%, in patients with AD,” they added.

SOURCE:

The study was led by Eric L. Simpson, MD, of the Department of Dermatology, Oregon Health & Science University, Portland, Oregon, and was published online on September 18 in JAMA Dermatology.

LIMITATIONS:

A short duration, a minimum age limit of 6 years, and the lack of an active comparator may influence the interpretation and generalizability of the results.

DISCLOSURES:

The study was sponsored by Arcutis Biotherapeutics. Simpson received grants and personal fees from Arcutis during this study. Three authors reported being employees and/or stockholders of Arcutis, two other authors reported patents for Arcutis, and several authors declared having various ties with various sources, including Arcutis.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Roflumilast cream 0.15% was well tolerated and significantly improved symptoms in adults and children with mild to moderate atopic dermatitis (AD) in two phase 3 trials.

METHODOLOGY:

• Two randomized, parallel-group, double-blind, vehicle-controlled phase 3 trials, INTEGUMENT-1 (n = 654) and INTEGUMENT-2 (n = 683), enrolled patients aged ≥ 6 years with mild to moderate AD who were randomly assigned in a 2:1 ratio to roflumilast cream 0.15%, a phosphodiesterase 4 inhibitor, or vehicle cream once daily for 4 weeks.
• The primary efficacy endpoint was the Validated Investigator Global Assessment for AD (vIGA-AD) success at week 4, defined as a score of 0 (clear) or 1 (almost clear) plus improvement of at least two grades from baseline.
• Secondary endpoints included vIGA-AD success at week 4 in patients with a baseline score of 3, at least a four-point reduction in the Worst Itch Numeric Rating Scale (WI-NRS), and at least a 75% reduction in the Eczema Area and Severity Index (EASI-75) at weeks 1, 2, and 4.

TAKEAWAY:

• Significantly more patients receiving roflumilast achieved vIGA-AD success at week 4 vs those in the vehicle group in INTEGUMENT-1 (32.0% vs 15.2%; P < .001) and INTEGUMENT-2 (28.9% vs 12.0%; P < .001), which was consistent across all age groups and in those with a baseline score of 3.
• Similarly, a greater proportion of patients treated with roflumilast vs vehicle achieved at least a four-point reduction in WI-NRS at weeks 1, 2, and 4, with improvements noted as early as 24 hours after the first application (P < .05 at all subsequent timepoints).
• The number of patients achieving EASI-75 and vIGA-AD scores of 0 or 1 was significantly higher with roflumilast than with vehicle at weeks 1, 2, and 4.
• Most treatment-emergent adverse events (TEAEs) were mild to moderate, with only 0.9% of the patients experiencing serious TEAEs in each trial. More than 95% of the patients showed no signs of irritation, and over 90% reported no or mild sensation at the application site.

IN PRACTICE:

The two phase 3 randomized clinical trials of patients with AD treated with roflumilast cream 0.15% “demonstrated improvement across multiple efficacy endpoints, including reducing pruritus within 24 hours after application, with favorable safety and tolerability,” the authors wrote. “Additional research, including subgroup analyses, will provide more data regarding the efficacy and safety of roflumilast cream 0.15%, in patients with AD,” they added.

SOURCE:

The study was led by Eric L. Simpson, MD, of the Department of Dermatology, Oregon Health & Science University, Portland, Oregon, and was published online on September 18 in JAMA Dermatology.

LIMITATIONS:

A short duration, a minimum age limit of 6 years, and the lack of an active comparator may influence the interpretation and generalizability of the results.

DISCLOSURES:

The study was sponsored by Arcutis Biotherapeutics. Simpson received grants and personal fees from Arcutis during this study. Three authors reported being employees and/or stockholders of Arcutis, two other authors reported patents for Arcutis, and several authors declared having various ties with various sources, including Arcutis.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Roflumilast cream 0.15% was well tolerated and significantly improved symptoms in adults and children with mild to moderate atopic dermatitis (AD) in two phase 3 trials.

METHODOLOGY:

• Two randomized, parallel-group, double-blind, vehicle-controlled phase 3 trials, INTEGUMENT-1 (n = 654) and INTEGUMENT-2 (n = 683), enrolled patients aged ≥ 6 years with mild to moderate AD who were randomly assigned in a 2:1 ratio to roflumilast cream 0.15%, a phosphodiesterase 4 inhibitor, or vehicle cream once daily for 4 weeks.
• The primary efficacy endpoint was the Validated Investigator Global Assessment for AD (vIGA-AD) success at week 4, defined as a score of 0 (clear) or 1 (almost clear) plus improvement of at least two grades from baseline.
• Secondary endpoints included vIGA-AD success at week 4 in patients with a baseline score of 3, at least a four-point reduction in the Worst Itch Numeric Rating Scale (WI-NRS), and at least a 75% reduction in the Eczema Area and Severity Index (EASI-75) at weeks 1, 2, and 4.

TAKEAWAY:

• Significantly more patients receiving roflumilast achieved vIGA-AD success at week 4 vs those in the vehicle group in INTEGUMENT-1 (32.0% vs 15.2%; P < .001) and INTEGUMENT-2 (28.9% vs 12.0%; P < .001), which was consistent across all age groups and in those with a baseline score of 3.
• Similarly, a greater proportion of patients treated with roflumilast vs vehicle achieved at least a four-point reduction in WI-NRS at weeks 1, 2, and 4, with improvements noted as early as 24 hours after the first application (P < .05 at all subsequent timepoints).
• The number of patients achieving EASI-75 and vIGA-AD scores of 0 or 1 was significantly higher with roflumilast than with vehicle at weeks 1, 2, and 4.
• Most treatment-emergent adverse events (TEAEs) were mild to moderate, with only 0.9% of the patients experiencing serious TEAEs in each trial. More than 95% of the patients showed no signs of irritation, and over 90% reported no or mild sensation at the application site.

IN PRACTICE:

The two phase 3 randomized clinical trials of patients with AD treated with roflumilast cream 0.15% “demonstrated improvement across multiple efficacy endpoints, including reducing pruritus within 24 hours after application, with favorable safety and tolerability,” the authors wrote. “Additional research, including subgroup analyses, will provide more data regarding the efficacy and safety of roflumilast cream 0.15%, in patients with AD,” they added.

SOURCE:

The study was led by Eric L. Simpson, MD, of the Department of Dermatology, Oregon Health & Science University, Portland, Oregon, and was published online on September 18 in JAMA Dermatology.

LIMITATIONS:

A short duration, a minimum age limit of 6 years, and the lack of an active comparator may influence the interpretation and generalizability of the results.

DISCLOSURES:

The study was sponsored by Arcutis Biotherapeutics. Simpson received grants and personal fees from Arcutis during this study. Three authors reported being employees and/or stockholders of Arcutis, two other authors reported patents for Arcutis, and several authors declared having various ties with various sources, including Arcutis.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Presented at the European Association for the Study of Diabetes (EASD) 2024 congress in Madrid, the QWINT-2 study established that once-weekly dosing of insulin efsitora was as effective as once-daily dosing of insulin degludec for reducing A1c in patients with type 2 diabetes (T2D) who had not previously received insulin. Study participants were, however, receiving noninsulin glucose-lowering agents, including glucagon-like peptide 1 (GLP-1) receptor agonists. 

Slightly higher rates of mild to moderate hypoglycemia were noted with efsitora compared with degludec, but no significant differences in severe hypoglycemia were observed. Nor was there any difference in weight gain between groups, and adverse events were balanced between study arms. 

This study positions insulin efsitora alongside once-weekly insulin icodec as a novel long-acting insulin therapy. In the ONWARDS 3 trial, icodec was noninferior to once-daily degludec, in terms of A1c reduction. It also had an adverse effect profile like that of efsitora with respect to hypoglycemia and weight change.

So, what are the implications of a once-weekly insulin for primary care?

“Game-changer” is an overused term, but from the perspective of primary care, it applies to once-weekly insulin.

I initiate basal insulin much less frequently these days, given the multitude of noninsulin options now available to me in primary care, particularly the GLP-1 receptor agonists and the dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonists. The American Diabetes Association/EASD 2022 consensus report also reminds me that GLP-1 receptor agonists should be considered in all individuals with T2D before insulin, unless they are contraindicated. GLP-1 receptor agonists are insulin-sparing agents with a lower injection burden and a lower risk for hypoglycemia. They also promote significant weight loss compared with basal insulin.

But progressive beta-cell decline and insulin deficiency are among the key pathophysiologic abnormalities in T2D. Eventually, many patients with T2D, despite lifestyle interventions and medication adherence, do require insulin. 

Understandably, many of my patients have reservations about commencing insulin. Significant stigma about starting insulin persists, because others often perceive insulin use as a failure to manage T2D. Patients frequently fear injections, and many are worried about how insulin therapy, specifically the risk for hypoglycemia, will affect their daily activities such as driving. 

Clinicians often experience therapeutic inertia, hesitating to escalate therapy to insulin because of a lack of confidence and competence, which often results from inadequate education. Lengthy referral-to-treatment waiting times are common in the United Kingdom, and there is concern about the workload implications associated with insulin initiation.

Workload is a particular concern for my community nursing colleagues, who must visit some of my more frail and functionally dependent patients daily to administer their insulin. 

In addition, the delivery of high-quality diabetes care in nursing homes, particularly for patients requiring insulin, has been a perennial challenge in the UK, again because of a lack of confidence and competence due to an absence of education for nursing and ancillary staff. 

Moreover, it is not appropriate to switch many of these frail patients to noninsulin therapies because of their insulinopenia, as well as the significant weight (and sometimes muscle) loss associated with GLP-1 receptor agonists. Also, sodium-glucose cotransporter 2 inhibitors are associated with a risk for volume depletion and diabetic ketoacidosis.

I believe that the availability of a once-weekly insulin will help overcome many of the above barriers.

From a patient’s viewpoint, simplification of insulin therapy with once-weekly insulin will substantially reduce the number of injections required (from 365 to 52 over 1 year). This change will improve compliance and concordance even in patients with injection anxiety. These results will hopefully translate into improved glycemic control and a lower risk for the complications of T2D. Real-world evidence for these outcomes is not yet available, however. Also, the reduced amount of insulin consumables that once-weekly dosing requires will also help improve the environmental footprint of insulin therapy.

From a clinician’s viewpoint, once-weekly insulin may seem less daunting and could reduce therapeutic inertia, thus facilitating earlier initiation of insulin therapy and reducing the risk for complications of T2D. Although education remains pivotal, this ease of dosing may be more acceptable to many clinicians because it has less of an effect on workload. This dosing could even save time because it requires less intensive follow-up than daily basal insulin does.

My community nurse colleagues were ecstatic when I mentioned that once-weekly basal insulin was on the horizon. This formulation could reduce the number of weekly home visits from 7 to just 1, thus freeing up considerable healthcare resources. And if once-weekly insulin is coupled with continuous glucose monitoring, then remote review of glucose data can further streamline and optimize the management of T2D in frail older patients. I am sure that my nursing-home colleagues will be equally enthusiastic about simplifying insulin regimens and monitoring.

Finally, an unanswered question is how I manage “sick days” for patients on weekly insulin dosing. Of course, the golden rule of never stopping insulin during intercurrent illness must be followed, but is any dose titration required for once-weekly insulin? I suspect not, but do I need to consider adding a once-daily basal insulin or rapid-acting insulin to mitigate the glucose counterregulatory hormone response during acute illness? Initially, I will be asking specialist diabetes teams for further advice on managing sick days.

In conclusion, once-weekly dosing of insulin is a game-changer for primary care and could finally be the driver to quash therapeutic inertia and address common patient barriers when escalation to insulin is required.

Dr. Fernando, general practitioner partner, North Berwick Health Centre, North Berwick, Scotland, disclosed ties with Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Dexcom, Daiichi Sankyo, Lilly, Menarini, Novartis, Novo Nordisk, Roche Diagnostics, Embecta, Roche Diabetes Care, and Sanofi.

A version of this article appeared on Medscape.com.

Presented at the European Association for the Study of Diabetes (EASD) 2024 congress in Madrid, the QWINT-2 study established that once-weekly dosing of insulin efsitora was as effective as once-daily dosing of insulin degludec for reducing A1c in patients with type 2 diabetes (T2D) who had not previously received insulin. Study participants were, however, receiving noninsulin glucose-lowering agents, including glucagon-like peptide 1 (GLP-1) receptor agonists. 

Slightly higher rates of mild to moderate hypoglycemia were noted with efsitora compared with degludec, but no significant differences in severe hypoglycemia were observed. Nor was there any difference in weight gain between groups, and adverse events were balanced between study arms. 

This study positions insulin efsitora alongside once-weekly insulin icodec as a novel long-acting insulin therapy. In the ONWARDS 3 trial, icodec was noninferior to once-daily degludec, in terms of A1c reduction. It also had an adverse effect profile like that of efsitora with respect to hypoglycemia and weight change.

So, what are the implications of a once-weekly insulin for primary care?

“Game-changer” is an overused term, but from the perspective of primary care, it applies to once-weekly insulin.

I initiate basal insulin much less frequently these days, given the multitude of noninsulin options now available to me in primary care, particularly the GLP-1 receptor agonists and the dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonists. The American Diabetes Association/EASD 2022 consensus report also reminds me that GLP-1 receptor agonists should be considered in all individuals with T2D before insulin, unless they are contraindicated. GLP-1 receptor agonists are insulin-sparing agents with a lower injection burden and a lower risk for hypoglycemia. They also promote significant weight loss compared with basal insulin.

But progressive beta-cell decline and insulin deficiency are among the key pathophysiologic abnormalities in T2D. Eventually, many patients with T2D, despite lifestyle interventions and medication adherence, do require insulin. 

Understandably, many of my patients have reservations about commencing insulin. Significant stigma about starting insulin persists, because others often perceive insulin use as a failure to manage T2D. Patients frequently fear injections, and many are worried about how insulin therapy, specifically the risk for hypoglycemia, will affect their daily activities such as driving. 

Clinicians often experience therapeutic inertia, hesitating to escalate therapy to insulin because of a lack of confidence and competence, which often results from inadequate education. Lengthy referral-to-treatment waiting times are common in the United Kingdom, and there is concern about the workload implications associated with insulin initiation.

Workload is a particular concern for my community nursing colleagues, who must visit some of my more frail and functionally dependent patients daily to administer their insulin. 

In addition, the delivery of high-quality diabetes care in nursing homes, particularly for patients requiring insulin, has been a perennial challenge in the UK, again because of a lack of confidence and competence due to an absence of education for nursing and ancillary staff. 

Moreover, it is not appropriate to switch many of these frail patients to noninsulin therapies because of their insulinopenia, as well as the significant weight (and sometimes muscle) loss associated with GLP-1 receptor agonists. Also, sodium-glucose cotransporter 2 inhibitors are associated with a risk for volume depletion and diabetic ketoacidosis.

I believe that the availability of a once-weekly insulin will help overcome many of the above barriers.

From a patient’s viewpoint, simplification of insulin therapy with once-weekly insulin will substantially reduce the number of injections required (from 365 to 52 over 1 year). This change will improve compliance and concordance even in patients with injection anxiety. These results will hopefully translate into improved glycemic control and a lower risk for the complications of T2D. Real-world evidence for these outcomes is not yet available, however. Also, the reduced amount of insulin consumables that once-weekly dosing requires will also help improve the environmental footprint of insulin therapy.

From a clinician’s viewpoint, once-weekly insulin may seem less daunting and could reduce therapeutic inertia, thus facilitating earlier initiation of insulin therapy and reducing the risk for complications of T2D. Although education remains pivotal, this ease of dosing may be more acceptable to many clinicians because it has less of an effect on workload. This dosing could even save time because it requires less intensive follow-up than daily basal insulin does.

My community nurse colleagues were ecstatic when I mentioned that once-weekly basal insulin was on the horizon. This formulation could reduce the number of weekly home visits from 7 to just 1, thus freeing up considerable healthcare resources. And if once-weekly insulin is coupled with continuous glucose monitoring, then remote review of glucose data can further streamline and optimize the management of T2D in frail older patients. I am sure that my nursing-home colleagues will be equally enthusiastic about simplifying insulin regimens and monitoring.

Finally, an unanswered question is how I manage “sick days” for patients on weekly insulin dosing. Of course, the golden rule of never stopping insulin during intercurrent illness must be followed, but is any dose titration required for once-weekly insulin? I suspect not, but do I need to consider adding a once-daily basal insulin or rapid-acting insulin to mitigate the glucose counterregulatory hormone response during acute illness? Initially, I will be asking specialist diabetes teams for further advice on managing sick days.

In conclusion, once-weekly dosing of insulin is a game-changer for primary care and could finally be the driver to quash therapeutic inertia and address common patient barriers when escalation to insulin is required.

Dr. Fernando, general practitioner partner, North Berwick Health Centre, North Berwick, Scotland, disclosed ties with Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Dexcom, Daiichi Sankyo, Lilly, Menarini, Novartis, Novo Nordisk, Roche Diagnostics, Embecta, Roche Diabetes Care, and Sanofi.

A version of this article appeared on Medscape.com.

Presented at the European Association for the Study of Diabetes (EASD) 2024 congress in Madrid, the QWINT-2 study established that once-weekly dosing of insulin efsitora was as effective as once-daily dosing of insulin degludec for reducing A1c in patients with type 2 diabetes (T2D) who had not previously received insulin. Study participants were, however, receiving noninsulin glucose-lowering agents, including glucagon-like peptide 1 (GLP-1) receptor agonists. 

Slightly higher rates of mild to moderate hypoglycemia were noted with efsitora compared with degludec, but no significant differences in severe hypoglycemia were observed. Nor was there any difference in weight gain between groups, and adverse events were balanced between study arms. 

This study positions insulin efsitora alongside once-weekly insulin icodec as a novel long-acting insulin therapy. In the ONWARDS 3 trial, icodec was noninferior to once-daily degludec, in terms of A1c reduction. It also had an adverse effect profile like that of efsitora with respect to hypoglycemia and weight change.

So, what are the implications of a once-weekly insulin for primary care?

“Game-changer” is an overused term, but from the perspective of primary care, it applies to once-weekly insulin.

I initiate basal insulin much less frequently these days, given the multitude of noninsulin options now available to me in primary care, particularly the GLP-1 receptor agonists and the dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonists. The American Diabetes Association/EASD 2022 consensus report also reminds me that GLP-1 receptor agonists should be considered in all individuals with T2D before insulin, unless they are contraindicated. GLP-1 receptor agonists are insulin-sparing agents with a lower injection burden and a lower risk for hypoglycemia. They also promote significant weight loss compared with basal insulin.

But progressive beta-cell decline and insulin deficiency are among the key pathophysiologic abnormalities in T2D. Eventually, many patients with T2D, despite lifestyle interventions and medication adherence, do require insulin. 

Understandably, many of my patients have reservations about commencing insulin. Significant stigma about starting insulin persists, because others often perceive insulin use as a failure to manage T2D. Patients frequently fear injections, and many are worried about how insulin therapy, specifically the risk for hypoglycemia, will affect their daily activities such as driving. 

Clinicians often experience therapeutic inertia, hesitating to escalate therapy to insulin because of a lack of confidence and competence, which often results from inadequate education. Lengthy referral-to-treatment waiting times are common in the United Kingdom, and there is concern about the workload implications associated with insulin initiation.

Workload is a particular concern for my community nursing colleagues, who must visit some of my more frail and functionally dependent patients daily to administer their insulin. 

In addition, the delivery of high-quality diabetes care in nursing homes, particularly for patients requiring insulin, has been a perennial challenge in the UK, again because of a lack of confidence and competence due to an absence of education for nursing and ancillary staff. 

Moreover, it is not appropriate to switch many of these frail patients to noninsulin therapies because of their insulinopenia, as well as the significant weight (and sometimes muscle) loss associated with GLP-1 receptor agonists. Also, sodium-glucose cotransporter 2 inhibitors are associated with a risk for volume depletion and diabetic ketoacidosis.

I believe that the availability of a once-weekly insulin will help overcome many of the above barriers.

From a patient’s viewpoint, simplification of insulin therapy with once-weekly insulin will substantially reduce the number of injections required (from 365 to 52 over 1 year). This change will improve compliance and concordance even in patients with injection anxiety. These results will hopefully translate into improved glycemic control and a lower risk for the complications of T2D. Real-world evidence for these outcomes is not yet available, however. Also, the reduced amount of insulin consumables that once-weekly dosing requires will also help improve the environmental footprint of insulin therapy.

From a clinician’s viewpoint, once-weekly insulin may seem less daunting and could reduce therapeutic inertia, thus facilitating earlier initiation of insulin therapy and reducing the risk for complications of T2D. Although education remains pivotal, this ease of dosing may be more acceptable to many clinicians because it has less of an effect on workload. This dosing could even save time because it requires less intensive follow-up than daily basal insulin does.

My community nurse colleagues were ecstatic when I mentioned that once-weekly basal insulin was on the horizon. This formulation could reduce the number of weekly home visits from 7 to just 1, thus freeing up considerable healthcare resources. And if once-weekly insulin is coupled with continuous glucose monitoring, then remote review of glucose data can further streamline and optimize the management of T2D in frail older patients. I am sure that my nursing-home colleagues will be equally enthusiastic about simplifying insulin regimens and monitoring.

Finally, an unanswered question is how I manage “sick days” for patients on weekly insulin dosing. Of course, the golden rule of never stopping insulin during intercurrent illness must be followed, but is any dose titration required for once-weekly insulin? I suspect not, but do I need to consider adding a once-daily basal insulin or rapid-acting insulin to mitigate the glucose counterregulatory hormone response during acute illness? Initially, I will be asking specialist diabetes teams for further advice on managing sick days.

In conclusion, once-weekly dosing of insulin is a game-changer for primary care and could finally be the driver to quash therapeutic inertia and address common patient barriers when escalation to insulin is required.

Dr. Fernando, general practitioner partner, North Berwick Health Centre, North Berwick, Scotland, disclosed ties with Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Dexcom, Daiichi Sankyo, Lilly, Menarini, Novartis, Novo Nordisk, Roche Diagnostics, Embecta, Roche Diabetes Care, and Sanofi.

A version of this article appeared on Medscape.com.

TOPLINE:

The prevalence of diabetes in the United States increased by 18.6% from 2012 to 2022, with notably higher rates among racial and ethnic minorities, men, older adults, and socioeconomically disadvantaged populations.

METHODOLOGY:

• Over 37 million people in the United States have diabetes, and its prevalence is only expected to increase in the coming years, making identifying high-risk demographic groups particularly crucial.
• To assess recent national trends and disparities in diabetes prevalence among US adults, researchers conducted an observational study using data from the Behavioral Risk Factor Surveillance System and included 5,312,827 observations from 2012 to 2022.
• Diabetes was defined on the basis of a previous self-reported diagnosis using standardized questionnaires.
• The sociodemographic factors of age, sex, race, education, physical activity, income, and body mass index were used to establish the risk indicators for diabetes diagnosis.
• Age-standardized diabetes prevalence and the association between risk factors and diabetes were assessed both overall and across various sociodemographic groups.

TAKEAWAY:

• The overall prevalence of diabetes increased by 18.6% (P < .001) from 2012 to 2022, with the highest prevalence observed among non-Hispanic Black individuals (15.8%) and people aged ≥ 65 years (23.86%).
• The likelihood of being diagnosed with diabetes was 1.15 times higher in men than in women, 5.16 times higher in adults aged 45-64 years than in those aged 18-24 years, and 3.64 times higher in those with obesity than in those with normal weight.
• The risk for being diagnosed with diabetes was 1.60 times higher among Hispanic individuals, 1.67 times higher among non-Hispanic Asian individuals, and 2.10 times higher among non-Hispanic Black individuals than among non-Hispanic White individuals.
• Individuals with a college education and higher income level were 24% and 41% less likely, respectively, to be diagnosed with diabetes.

IN PRACTICE:

“Improving access to quality care, implementing diabetes prevention programs focusing on high-risk groups, and addressing social determinants through multilevel interventions may help curb the diabetes epidemic in the United States,” the authors wrote.

SOURCE:

The study, led by Sulakshan Neupane, MS, Department of Agricultural and Applied Economics, University of Georgia, Athens, Georgia, was published online in Diabetes, Obesity, and Metabolism.

LIMITATIONS:

The self-reported diagnoses and lack of clinical data may have introduced bias. Diabetes prevalence could not be analyzed in South-East Asian and South Asian populations owing to limitations in the data collection process.

DISCLOSURES:

The study was not supported by any funding, and no potential author disclosures or conflicts were identified.
 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

The prevalence of diabetes in the United States increased by 18.6% from 2012 to 2022, with notably higher rates among racial and ethnic minorities, men, older adults, and socioeconomically disadvantaged populations.

METHODOLOGY:

• Over 37 million people in the United States have diabetes, and its prevalence is only expected to increase in the coming years, making identifying high-risk demographic groups particularly crucial.
• To assess recent national trends and disparities in diabetes prevalence among US adults, researchers conducted an observational study using data from the Behavioral Risk Factor Surveillance System and included 5,312,827 observations from 2012 to 2022.
• Diabetes was defined on the basis of a previous self-reported diagnosis using standardized questionnaires.
• The sociodemographic factors of age, sex, race, education, physical activity, income, and body mass index were used to establish the risk indicators for diabetes diagnosis.
• Age-standardized diabetes prevalence and the association between risk factors and diabetes were assessed both overall and across various sociodemographic groups.

TAKEAWAY:

• The overall prevalence of diabetes increased by 18.6% (P < .001) from 2012 to 2022, with the highest prevalence observed among non-Hispanic Black individuals (15.8%) and people aged ≥ 65 years (23.86%).
• The likelihood of being diagnosed with diabetes was 1.15 times higher in men than in women, 5.16 times higher in adults aged 45-64 years than in those aged 18-24 years, and 3.64 times higher in those with obesity than in those with normal weight.
• The risk for being diagnosed with diabetes was 1.60 times higher among Hispanic individuals, 1.67 times higher among non-Hispanic Asian individuals, and 2.10 times higher among non-Hispanic Black individuals than among non-Hispanic White individuals.
• Individuals with a college education and higher income level were 24% and 41% less likely, respectively, to be diagnosed with diabetes.

IN PRACTICE:

“Improving access to quality care, implementing diabetes prevention programs focusing on high-risk groups, and addressing social determinants through multilevel interventions may help curb the diabetes epidemic in the United States,” the authors wrote.

SOURCE:

The study, led by Sulakshan Neupane, MS, Department of Agricultural and Applied Economics, University of Georgia, Athens, Georgia, was published online in Diabetes, Obesity, and Metabolism.

LIMITATIONS:

The self-reported diagnoses and lack of clinical data may have introduced bias. Diabetes prevalence could not be analyzed in South-East Asian and South Asian populations owing to limitations in the data collection process.

DISCLOSURES:

The study was not supported by any funding, and no potential author disclosures or conflicts were identified.
 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

The prevalence of diabetes in the United States increased by 18.6% from 2012 to 2022, with notably higher rates among racial and ethnic minorities, men, older adults, and socioeconomically disadvantaged populations.

METHODOLOGY:

• Over 37 million people in the United States have diabetes, and its prevalence is only expected to increase in the coming years, making identifying high-risk demographic groups particularly crucial.
• To assess recent national trends and disparities in diabetes prevalence among US adults, researchers conducted an observational study using data from the Behavioral Risk Factor Surveillance System and included 5,312,827 observations from 2012 to 2022.
• Diabetes was defined on the basis of a previous self-reported diagnosis using standardized questionnaires.
• The sociodemographic factors of age, sex, race, education, physical activity, income, and body mass index were used to establish the risk indicators for diabetes diagnosis.
• Age-standardized diabetes prevalence and the association between risk factors and diabetes were assessed both overall and across various sociodemographic groups.

TAKEAWAY:

• The overall prevalence of diabetes increased by 18.6% (P < .001) from 2012 to 2022, with the highest prevalence observed among non-Hispanic Black individuals (15.8%) and people aged ≥ 65 years (23.86%).
• The likelihood of being diagnosed with diabetes was 1.15 times higher in men than in women, 5.16 times higher in adults aged 45-64 years than in those aged 18-24 years, and 3.64 times higher in those with obesity than in those with normal weight.
• The risk for being diagnosed with diabetes was 1.60 times higher among Hispanic individuals, 1.67 times higher among non-Hispanic Asian individuals, and 2.10 times higher among non-Hispanic Black individuals than among non-Hispanic White individuals.
• Individuals with a college education and higher income level were 24% and 41% less likely, respectively, to be diagnosed with diabetes.

IN PRACTICE:

“Improving access to quality care, implementing diabetes prevention programs focusing on high-risk groups, and addressing social determinants through multilevel interventions may help curb the diabetes epidemic in the United States,” the authors wrote.

SOURCE:

The study, led by Sulakshan Neupane, MS, Department of Agricultural and Applied Economics, University of Georgia, Athens, Georgia, was published online in Diabetes, Obesity, and Metabolism.

LIMITATIONS:

The self-reported diagnoses and lack of clinical data may have introduced bias. Diabetes prevalence could not be analyzed in South-East Asian and South Asian populations owing to limitations in the data collection process.

DISCLOSURES:

The study was not supported by any funding, and no potential author disclosures or conflicts were identified.
 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

If you’re like most primary care clinicians, your email inbox is flooded with messages from patients with questions about lab results. A common query: Should I be worried about an abnormal value on a test of thyroid-stimulating hormone (TSH)?

For guidance, this news organization spoke with Angela Leung, MD, associate professor of medicine in the Division of Endocrinology, Diabetes & Metabolism at the UCLA David Geffen School of Medicine and an endocrinologist at UCLA and the VA Greater Los Angeles Healthcare System, and Karen Tsai, MD, assistant clinical professor of endocrinology at City of Hope Comprehensive Cancer Center in Duarte, California. The following interview has been edited for length and clarity.

Question: Why do you usually start by measuring TSH levels?

Dr. Leung: We need to measure the thyroid status in a way that integrates more information about the long-term thyroid status and not small changes in thyroid hormone levels. TSH is made by the pituitary gland in the brain, which integrates information about the signals of high and low levels from each of the different thyroid hormones.

Now we can measure the actual thyroid hormones — primarily we’re talking about T3 and T4 — but if we do that, we are relying on a single snapshot in the bloodstream at that moment. The levels might change throughout the day in response to ongoing metabolism and outside stresses. So we usually start by measuring the TSH level, which is a good representation of the compilation of all those things over the past 30 days or so.

Question: How do you describe a low TSH result to patients?

Dr. Leung: Whenever we encounter a low TSH level, we want to repeat the test because it is a dynamic test, and it can change in response to several factors. If it is indeed low, we’re thinking that perhaps there’s a little bit of extra thyroid hormone in the body. It can be either temporary or more chronic, but that higher amount of thyroid hormone is telling the pituitary gland in the brain to start making less. So TSH levels go low when we need less thyroid hormone.

Question: What are some of the reasons for a low TSH level?

Dr. Leung: One of the most common situations for a temporarily low TSH level I see is what we call nonthyroidal illness, like a common cold or just being under the weather. Other things that can artifactually lower the TSH level could be the use of steroids, such as prednisone for asthma or some sort of a rheumatologic condition. Also, the TSH level could be low if a person has been recently exposed to very high amounts of iodine, such as iodinated contrast needed for a CT scan.

If the TSH level remains persistently low, usually in the presence of high thyroid hormone (T3 and/or T4) levels, the most common reason for hyperthyroidism is Graves disease, in which there are autoantibodies — measurable in the blood — that can stimulate the thyroid gland in the neck to make extra thyroid hormone.

Question: And what does an elevated TSH level mean?

Dr. Leung: Again, we want to confirm that it is elevated. We need at least two tests to confirm a high TSH level. A persistently elevated TSH level is a signal there might be low thyroid hormone levels in the body, which could be transient or more longer lasting.

Question: What are some of the most common causes of an elevated TSH level?

Dr. Leung: If the TSH level is confirmed high and the thyroid hormone levels are low, the most common cause of hypothyroidism here in the United States is Hashimoto thyroiditis.

Globally, iodine deficiency is the most common reason for hypothyroidism and may be a problem in parts of the globe where there are endemically low iodine levels in soil, crops, and the food supply like not having enough iodized salt. The thyroid is reliant on having enough iodine as a micronutrient to make thyroid hormone. If it doesn’t, the thyroid really can’t make thyroid hormone. It’s important to also remember, though, that having too much iodine can result in hypo- or hyperthyroidism.

Dr. Tsai: I take a glance at their medication list. Some of the patients are on methimazole or levothyroxine, and those medications should be adjusted first to normalize the TSH level. Other medications like lithium and amiodarone can also cause elevated TSH levels. We are also seeing a lot of patients on cancer therapies, such as tyrosine kinase inhibitors or immunotherapy, that can cause an elevated TSH level.

Question: If the repeat TSH test shows that TSH levels are still elevated, what comes next in your workup?

Dr. Tsai: If there’s not a real clear-cut diagnosis, I’ll order the thyroid peroxidase antibody and the thyroglobulin antibody, although thyroid peroxidase antibody, which is indicative of autoimmune thyroid disease, alone is usually sufficient to make that diagnosis.

Question: Should clinicians follow thyroid antibodies over time?

Dr. Tsai: I usually don’t repeat the antibody tests. In those circumstances where patients who were diagnosed 50-60 years ago and perhaps it is unknown if they had the thyroid antibodies measured at the time and now they’re saying, “Do I actually have Hashimoto’s?” or “Do I really need to continue this for the rest of my life?” I do repeat antibody tests to help gauge if the patient’s levothyroxine can be stopped.

Question: How important is it to follow T4 or T3 levels?

Dr. Tsai: T4 and T3 levels can help differentiate overt thyroid dysfunction — where T3 and/or T4 levels will be abnormal — from subclinical thyroid dysfunction — where T3 and T4 levels would be normal. In general, although we do not fully appreciate the best metric to monitor hypo- or hyperthyroidism, because some patients with a normal TSH level still may have symptoms of thyroid dysfunction, these peripheral thyroid hormone levels are usually the most helpful at the time of initial diagnosis.

Question: What are your criteria for initiating treatment for hypothyroidism?

Dr. Tsai: If the TSH level > 10 mIU/L, I recommend levothyroxine hormone replacement. A lot of published data support clinical benefit in this group.

There is a gray area in those patients who have a TSH level higher than the upper limit of the reference range but less than 10. If the patient doesn’t have overt hypothyroid symptoms, I discuss the findings with the patient but don’t really feel eager to treat. I recommend checking the levels again in 6 months to see where that TSH goes, and if it worsens or becomes greater than 10 mIU/L, I then recommend levothyroxine hormone replacement.

It is also important to note that a TSH level of 5-7 may be an acceptable range for older patients, and they do not require levothyroxine.

The other category is patients whose TSH level is greater than the upper limit of the normal reference range but less than 10 and with overt hypothyroid symptoms such as fatigue, unintentional weight gain, constipation, or cold intolerance. In these patients, it is worthwhile to try a low dose of levothyroxine (25-50 mcg/d) and repeat TSH and free T4 tests in 6-8 weeks and see if the TSH level normalizes.

Dr. Leung: When you look at subclinical hypothyroidism, the situation of an isolated high TSH level in the setting of normal T4 levels, if the TSH level is mildly elevated in the 5-7 mIU/L range, there’s a 60% chance that it will normalize within 6 months.

Going back to Karen’s point, a lot of people are started and maintained on low doses of thyroid hormone forever and ever. A recent study on levothyroxine use found half of the prescriptions were unnecessary.

Question: In an era where many patients obtain much of their health information from TikTok, what’s your approach with patients with a normal TSH level who feel that they should have more testing or start treatment?

Dr. Tsai: Fatigue is one of the common referrals we get into our endocrinology practice, and everyone is convinced that their thyroid is the culprit. It is important to note, however, that fatigue can be due to different diseases such as anemia, depression, sleep disorders, or a recent viral illness.

TSH tests are readily available and cheap. I don’t mind ordering the lab test again if it helps give the patient some reassurance. I also find that patients are relieved once they hear from their endocrinologist that their thyroid is unlikely to be the cause of their fatigue.

Some other endocrine causes we may consider additionally working up include adrenal insufficiency, vitamin D deficiency, and diabetes. A comprehensive metabolic panel and complete blood count is part of my workup to rule out any gross electrolyte abnormalities or any new diagnosis of anemia, liver disease, or chronic kidney disease.

Question: What are your criteria for recommending that someone see an endocrinologist?

Dr. Tsai: Our primary care colleagues can do a workup and interpretation of thyroid function tests in most cases. In the situations where the thyroid function test results are discordant (ie, elevated TSH and elevated free T4 levels or low TSH and low free T4 levels) or difficult to interpret, it would be appropriate to refer the patient to an endocrinologist.

One of the common referrals that we do get from the community is a patient’s thyroid function tests going from hyperthyroid to hypothyroid without a clear explanation or the patient is suboptimally controlled with levothyroxine or methimazole. In those circumstances, it would be worthwhile to send to an endocrinologist try to discern an underlying cause or for optimization of medication.

Dr. Leung and Dr. Tsai had no financial disclosures.
 

A version of this article appeared on Medscape.com.

If you’re like most primary care clinicians, your email inbox is flooded with messages from patients with questions about lab results. A common query: Should I be worried about an abnormal value on a test of thyroid-stimulating hormone (TSH)?

For guidance, this news organization spoke with Angela Leung, MD, associate professor of medicine in the Division of Endocrinology, Diabetes & Metabolism at the UCLA David Geffen School of Medicine and an endocrinologist at UCLA and the VA Greater Los Angeles Healthcare System, and Karen Tsai, MD, assistant clinical professor of endocrinology at City of Hope Comprehensive Cancer Center in Duarte, California. The following interview has been edited for length and clarity.

Question: Why do you usually start by measuring TSH levels?

Dr. Leung: We need to measure the thyroid status in a way that integrates more information about the long-term thyroid status and not small changes in thyroid hormone levels. TSH is made by the pituitary gland in the brain, which integrates information about the signals of high and low levels from each of the different thyroid hormones.

Now we can measure the actual thyroid hormones — primarily we’re talking about T3 and T4 — but if we do that, we are relying on a single snapshot in the bloodstream at that moment. The levels might change throughout the day in response to ongoing metabolism and outside stresses. So we usually start by measuring the TSH level, which is a good representation of the compilation of all those things over the past 30 days or so.

Question: How do you describe a low TSH result to patients?

Dr. Leung: Whenever we encounter a low TSH level, we want to repeat the test because it is a dynamic test, and it can change in response to several factors. If it is indeed low, we’re thinking that perhaps there’s a little bit of extra thyroid hormone in the body. It can be either temporary or more chronic, but that higher amount of thyroid hormone is telling the pituitary gland in the brain to start making less. So TSH levels go low when we need less thyroid hormone.

Question: What are some of the reasons for a low TSH level?

Dr. Leung: One of the most common situations for a temporarily low TSH level I see is what we call nonthyroidal illness, like a common cold or just being under the weather. Other things that can artifactually lower the TSH level could be the use of steroids, such as prednisone for asthma or some sort of a rheumatologic condition. Also, the TSH level could be low if a person has been recently exposed to very high amounts of iodine, such as iodinated contrast needed for a CT scan.

If the TSH level remains persistently low, usually in the presence of high thyroid hormone (T3 and/or T4) levels, the most common reason for hyperthyroidism is Graves disease, in which there are autoantibodies — measurable in the blood — that can stimulate the thyroid gland in the neck to make extra thyroid hormone.

Question: And what does an elevated TSH level mean?

Dr. Leung: Again, we want to confirm that it is elevated. We need at least two tests to confirm a high TSH level. A persistently elevated TSH level is a signal there might be low thyroid hormone levels in the body, which could be transient or more longer lasting.

Question: What are some of the most common causes of an elevated TSH level?

Dr. Leung: If the TSH level is confirmed high and the thyroid hormone levels are low, the most common cause of hypothyroidism here in the United States is Hashimoto thyroiditis.

Globally, iodine deficiency is the most common reason for hypothyroidism and may be a problem in parts of the globe where there are endemically low iodine levels in soil, crops, and the food supply like not having enough iodized salt. The thyroid is reliant on having enough iodine as a micronutrient to make thyroid hormone. If it doesn’t, the thyroid really can’t make thyroid hormone. It’s important to also remember, though, that having too much iodine can result in hypo- or hyperthyroidism.

Dr. Tsai: I take a glance at their medication list. Some of the patients are on methimazole or levothyroxine, and those medications should be adjusted first to normalize the TSH level. Other medications like lithium and amiodarone can also cause elevated TSH levels. We are also seeing a lot of patients on cancer therapies, such as tyrosine kinase inhibitors or immunotherapy, that can cause an elevated TSH level.

Question: If the repeat TSH test shows that TSH levels are still elevated, what comes next in your workup?

Dr. Tsai: If there’s not a real clear-cut diagnosis, I’ll order the thyroid peroxidase antibody and the thyroglobulin antibody, although thyroid peroxidase antibody, which is indicative of autoimmune thyroid disease, alone is usually sufficient to make that diagnosis.

Question: Should clinicians follow thyroid antibodies over time?

Dr. Tsai: I usually don’t repeat the antibody tests. In those circumstances where patients who were diagnosed 50-60 years ago and perhaps it is unknown if they had the thyroid antibodies measured at the time and now they’re saying, “Do I actually have Hashimoto’s?” or “Do I really need to continue this for the rest of my life?” I do repeat antibody tests to help gauge if the patient’s levothyroxine can be stopped.

Question: How important is it to follow T4 or T3 levels?

Dr. Tsai: T4 and T3 levels can help differentiate overt thyroid dysfunction — where T3 and/or T4 levels will be abnormal — from subclinical thyroid dysfunction — where T3 and T4 levels would be normal. In general, although we do not fully appreciate the best metric to monitor hypo- or hyperthyroidism, because some patients with a normal TSH level still may have symptoms of thyroid dysfunction, these peripheral thyroid hormone levels are usually the most helpful at the time of initial diagnosis.

Question: What are your criteria for initiating treatment for hypothyroidism?

Dr. Tsai: If the TSH level > 10 mIU/L, I recommend levothyroxine hormone replacement. A lot of published data support clinical benefit in this group.

There is a gray area in those patients who have a TSH level higher than the upper limit of the reference range but less than 10. If the patient doesn’t have overt hypothyroid symptoms, I discuss the findings with the patient but don’t really feel eager to treat. I recommend checking the levels again in 6 months to see where that TSH goes, and if it worsens or becomes greater than 10 mIU/L, I then recommend levothyroxine hormone replacement.

It is also important to note that a TSH level of 5-7 may be an acceptable range for older patients, and they do not require levothyroxine.

The other category is patients whose TSH level is greater than the upper limit of the normal reference range but less than 10 and with overt hypothyroid symptoms such as fatigue, unintentional weight gain, constipation, or cold intolerance. In these patients, it is worthwhile to try a low dose of levothyroxine (25-50 mcg/d) and repeat TSH and free T4 tests in 6-8 weeks and see if the TSH level normalizes.

Dr. Leung: When you look at subclinical hypothyroidism, the situation of an isolated high TSH level in the setting of normal T4 levels, if the TSH level is mildly elevated in the 5-7 mIU/L range, there’s a 60% chance that it will normalize within 6 months.

Going back to Karen’s point, a lot of people are started and maintained on low doses of thyroid hormone forever and ever. A recent study on levothyroxine use found half of the prescriptions were unnecessary.

Question: In an era where many patients obtain much of their health information from TikTok, what’s your approach with patients with a normal TSH level who feel that they should have more testing or start treatment?

Dr. Tsai: Fatigue is one of the common referrals we get into our endocrinology practice, and everyone is convinced that their thyroid is the culprit. It is important to note, however, that fatigue can be due to different diseases such as anemia, depression, sleep disorders, or a recent viral illness.

TSH tests are readily available and cheap. I don’t mind ordering the lab test again if it helps give the patient some reassurance. I also find that patients are relieved once they hear from their endocrinologist that their thyroid is unlikely to be the cause of their fatigue.

Some other endocrine causes we may consider additionally working up include adrenal insufficiency, vitamin D deficiency, and diabetes. A comprehensive metabolic panel and complete blood count is part of my workup to rule out any gross electrolyte abnormalities or any new diagnosis of anemia, liver disease, or chronic kidney disease.

Question: What are your criteria for recommending that someone see an endocrinologist?

Dr. Tsai: Our primary care colleagues can do a workup and interpretation of thyroid function tests in most cases. In the situations where the thyroid function test results are discordant (ie, elevated TSH and elevated free T4 levels or low TSH and low free T4 levels) or difficult to interpret, it would be appropriate to refer the patient to an endocrinologist.

One of the common referrals that we do get from the community is a patient’s thyroid function tests going from hyperthyroid to hypothyroid without a clear explanation or the patient is suboptimally controlled with levothyroxine or methimazole. In those circumstances, it would be worthwhile to send to an endocrinologist try to discern an underlying cause or for optimization of medication.

Dr. Leung and Dr. Tsai had no financial disclosures.
 

A version of this article appeared on Medscape.com.

If you’re like most primary care clinicians, your email inbox is flooded with messages from patients with questions about lab results. A common query: Should I be worried about an abnormal value on a test of thyroid-stimulating hormone (TSH)?

For guidance, this news organization spoke with Angela Leung, MD, associate professor of medicine in the Division of Endocrinology, Diabetes & Metabolism at the UCLA David Geffen School of Medicine and an endocrinologist at UCLA and the VA Greater Los Angeles Healthcare System, and Karen Tsai, MD, assistant clinical professor of endocrinology at City of Hope Comprehensive Cancer Center in Duarte, California. The following interview has been edited for length and clarity.

Question: Why do you usually start by measuring TSH levels?

Dr. Leung: We need to measure the thyroid status in a way that integrates more information about the long-term thyroid status and not small changes in thyroid hormone levels. TSH is made by the pituitary gland in the brain, which integrates information about the signals of high and low levels from each of the different thyroid hormones.

Now we can measure the actual thyroid hormones — primarily we’re talking about T3 and T4 — but if we do that, we are relying on a single snapshot in the bloodstream at that moment. The levels might change throughout the day in response to ongoing metabolism and outside stresses. So we usually start by measuring the TSH level, which is a good representation of the compilation of all those things over the past 30 days or so.

Question: How do you describe a low TSH result to patients?

Dr. Leung: Whenever we encounter a low TSH level, we want to repeat the test because it is a dynamic test, and it can change in response to several factors. If it is indeed low, we’re thinking that perhaps there’s a little bit of extra thyroid hormone in the body. It can be either temporary or more chronic, but that higher amount of thyroid hormone is telling the pituitary gland in the brain to start making less. So TSH levels go low when we need less thyroid hormone.

Question: What are some of the reasons for a low TSH level?

Dr. Leung: One of the most common situations for a temporarily low TSH level I see is what we call nonthyroidal illness, like a common cold or just being under the weather. Other things that can artifactually lower the TSH level could be the use of steroids, such as prednisone for asthma or some sort of a rheumatologic condition. Also, the TSH level could be low if a person has been recently exposed to very high amounts of iodine, such as iodinated contrast needed for a CT scan.

If the TSH level remains persistently low, usually in the presence of high thyroid hormone (T3 and/or T4) levels, the most common reason for hyperthyroidism is Graves disease, in which there are autoantibodies — measurable in the blood — that can stimulate the thyroid gland in the neck to make extra thyroid hormone.

Question: And what does an elevated TSH level mean?

Dr. Leung: Again, we want to confirm that it is elevated. We need at least two tests to confirm a high TSH level. A persistently elevated TSH level is a signal there might be low thyroid hormone levels in the body, which could be transient or more longer lasting.

Question: What are some of the most common causes of an elevated TSH level?

Dr. Leung: If the TSH level is confirmed high and the thyroid hormone levels are low, the most common cause of hypothyroidism here in the United States is Hashimoto thyroiditis.

Globally, iodine deficiency is the most common reason for hypothyroidism and may be a problem in parts of the globe where there are endemically low iodine levels in soil, crops, and the food supply like not having enough iodized salt. The thyroid is reliant on having enough iodine as a micronutrient to make thyroid hormone. If it doesn’t, the thyroid really can’t make thyroid hormone. It’s important to also remember, though, that having too much iodine can result in hypo- or hyperthyroidism.

Dr. Tsai: I take a glance at their medication list. Some of the patients are on methimazole or levothyroxine, and those medications should be adjusted first to normalize the TSH level. Other medications like lithium and amiodarone can also cause elevated TSH levels. We are also seeing a lot of patients on cancer therapies, such as tyrosine kinase inhibitors or immunotherapy, that can cause an elevated TSH level.

Question: If the repeat TSH test shows that TSH levels are still elevated, what comes next in your workup?

Dr. Tsai: If there’s not a real clear-cut diagnosis, I’ll order the thyroid peroxidase antibody and the thyroglobulin antibody, although thyroid peroxidase antibody, which is indicative of autoimmune thyroid disease, alone is usually sufficient to make that diagnosis.

Question: Should clinicians follow thyroid antibodies over time?

Dr. Tsai: I usually don’t repeat the antibody tests. In those circumstances where patients who were diagnosed 50-60 years ago and perhaps it is unknown if they had the thyroid antibodies measured at the time and now they’re saying, “Do I actually have Hashimoto’s?” or “Do I really need to continue this for the rest of my life?” I do repeat antibody tests to help gauge if the patient’s levothyroxine can be stopped.

Question: How important is it to follow T4 or T3 levels?

Dr. Tsai: T4 and T3 levels can help differentiate overt thyroid dysfunction — where T3 and/or T4 levels will be abnormal — from subclinical thyroid dysfunction — where T3 and T4 levels would be normal. In general, although we do not fully appreciate the best metric to monitor hypo- or hyperthyroidism, because some patients with a normal TSH level still may have symptoms of thyroid dysfunction, these peripheral thyroid hormone levels are usually the most helpful at the time of initial diagnosis.

Question: What are your criteria for initiating treatment for hypothyroidism?

Dr. Tsai: If the TSH level > 10 mIU/L, I recommend levothyroxine hormone replacement. A lot of published data support clinical benefit in this group.

There is a gray area in those patients who have a TSH level higher than the upper limit of the reference range but less than 10. If the patient doesn’t have overt hypothyroid symptoms, I discuss the findings with the patient but don’t really feel eager to treat. I recommend checking the levels again in 6 months to see where that TSH goes, and if it worsens or becomes greater than 10 mIU/L, I then recommend levothyroxine hormone replacement.

It is also important to note that a TSH level of 5-7 may be an acceptable range for older patients, and they do not require levothyroxine.

The other category is patients whose TSH level is greater than the upper limit of the normal reference range but less than 10 and with overt hypothyroid symptoms such as fatigue, unintentional weight gain, constipation, or cold intolerance. In these patients, it is worthwhile to try a low dose of levothyroxine (25-50 mcg/d) and repeat TSH and free T4 tests in 6-8 weeks and see if the TSH level normalizes.

Dr. Leung: When you look at subclinical hypothyroidism, the situation of an isolated high TSH level in the setting of normal T4 levels, if the TSH level is mildly elevated in the 5-7 mIU/L range, there’s a 60% chance that it will normalize within 6 months.

Going back to Karen’s point, a lot of people are started and maintained on low doses of thyroid hormone forever and ever. A recent study on levothyroxine use found half of the prescriptions were unnecessary.

Question: In an era where many patients obtain much of their health information from TikTok, what’s your approach with patients with a normal TSH level who feel that they should have more testing or start treatment?

Dr. Tsai: Fatigue is one of the common referrals we get into our endocrinology practice, and everyone is convinced that their thyroid is the culprit. It is important to note, however, that fatigue can be due to different diseases such as anemia, depression, sleep disorders, or a recent viral illness.

TSH tests are readily available and cheap. I don’t mind ordering the lab test again if it helps give the patient some reassurance. I also find that patients are relieved once they hear from their endocrinologist that their thyroid is unlikely to be the cause of their fatigue.

Some other endocrine causes we may consider additionally working up include adrenal insufficiency, vitamin D deficiency, and diabetes. A comprehensive metabolic panel and complete blood count is part of my workup to rule out any gross electrolyte abnormalities or any new diagnosis of anemia, liver disease, or chronic kidney disease.

Question: What are your criteria for recommending that someone see an endocrinologist?

Dr. Tsai: Our primary care colleagues can do a workup and interpretation of thyroid function tests in most cases. In the situations where the thyroid function test results are discordant (ie, elevated TSH and elevated free T4 levels or low TSH and low free T4 levels) or difficult to interpret, it would be appropriate to refer the patient to an endocrinologist.

One of the common referrals that we do get from the community is a patient’s thyroid function tests going from hyperthyroid to hypothyroid without a clear explanation or the patient is suboptimally controlled with levothyroxine or methimazole. In those circumstances, it would be worthwhile to send to an endocrinologist try to discern an underlying cause or for optimization of medication.

Dr. Leung and Dr. Tsai had no financial disclosures.
 

A version of this article appeared on Medscape.com.

The first therapy targeted at modifying a mutant gene associated with amyotrophic lateral sclerosis (ALS), approved in early 2023, has offered reassurance that the biology of ALS, when known, is targetable. Historically, the disease has been considered a clinical diagnosis, but the progress in identifying molecular mechanisms is permitting ALS to be understood as a biological entity and suggests rationally targeted therapies will be the way forward following the inadequacy of nonselective drugs.

Despite a narrow indication, the only therapy targeted at an ALS-associated gene so far, SOD1 ALS, supports the premise that the biology of ALS can be modified, according to Christina N. Fournier, MD, an associate professor in the Department of Neurology, Emory University, Atlanta, Georgia.

About 15% of ALS Has An Identifiable Genetic Cause

A family history of ALS is present in about 10% of cases. A genetic cause can be identified in approximately 15%. Cases without an identifiable genetic etiology are considered sporadic. So far, the only approved therapy that modifies the function of a gene associated with ALS is tofersen (Qalsody, Biogen), an antisense oligonucleotide. Tofersen inhibits RNA transcription of the superoxide dismutase 1 (SOD1) gene to decrease production of the SOD1 protein.

This first gene therapy for ALS is a breakthrough, but it is indicated for only a small proportion of ALS patients. Even though SOD1 gene mutations represent the second most common genetic cause of ALS after the C90rf72 gene, the proportion of patients who are candidates for tofersen is low. Efficacy is expected only in about 1% of those with familial ALS and 1% of those with sporadic ALS, or about 2% of all patients with ALS.

The evidence of benefit from a treatment with a specific target has provided the basis for concluding that “we are onto something,” Dr. Fournier said. An expert in ALS, she sees reason for excitement about the prospects in treatment with the growing focus on the underlying pathways of disease rather than the downstream consequences.

“The hope is that new gene-targeted therapies will be developed in the future to treat the broader ALS population,” said Dr. Fournier, explaining that the move toward rationally targeted treatments, whether related to gene mutations or independent molecular pathways of ALS progression, has created excitement in the field.

Numerous Disease Processes Are Potentially Targetable

As treatments are developed to address nongenetic molecular processes that contribute to the risk or progression of ALS, such as neuroinflammation or abnormal protein misfolding and aggregation, individualized treatment is likely to become key. Just as not all genetic cases share mutations in the same gene, the key molecular drivers of disease are likely to differ between patients. If so, it is hoped that biomarkers reflective of this underlying biology can be identified to appropriately target treatments.

“The excitement behind the newer targets in clinical trials is based on both basic science and early clinical data that support treatment based on specific drivers of disease,” Dr. Fournier said.

In 2023 and just prior to the FDA approval of tofersen, a set of expert consensus guidelines were published calling for genetic testing to be offered to all patients with ALS. These recommendations suggested that SOD1, C9orf72, FUS, and TARDBP should be included routinely into the panel of genes evaluated, calling for additional genes to be added as they emerge as potential therapeutic targets.

Even before these guidelines were released, genetic testing was already being offered at many centers with expertise in ALS. The rationale was to differentiate ALS with a genetic etiology from that with a nongenetic etiology, as well as to counsel family members when genetic risk was identified, but genetic testing has now assumed new urgency. In addition to the potential for offering a specific treatment for SOD1-related ALS, patients with other genetic forms of disease might be candidates for genetically focused clinical trials.

Genetic testing should be performed as soon as a diagnosis of ALS is made, according to Dr. Fournier. Although not all patients have accepted genetic testing, particularly in the past when there was no immediate clinical gain from establishing the presence of a genetic mutation, she said there is no longer any controversy about clinical relevance.
 

Genetic Testing Is Key to Genetic Therapies

“We do not want to miss the opportunity to treat patients when we have the chance,” said Dr. Fournier, referring to both the likely advantage of an early start of the approved gene therapy as well as the opportunity to participate in a clinical trial with other gene therapies in development.

Prior to the approval of tofersen, riluzole and edaravone had been the only disease-modifying agents in widespread use, but these drugs are nonspecific. There are no established biomarkers for establishing which patients are most likely to benefit.

In the case of riluzole, a pivotal trial conducted 30 years ago showed a survival benefit relative to placebo at 12 months (74% vs. 58%; P = 0.014). In a retrospective study published in 2022 that evaluated survival in a database of 4778 ALS patients of whom 3446 received riluzole, early diagnosis of ALS and prompt treatment with riluzole was associated with longer survival than delayed treatment. The benefit of edaravone has been validated with clinical measures, such as the revised Amyotrophic Lateral Sclerosis Functional Scale (ALSFRS-R).

The retrospective study of riluzole provides the basis for predicting better benefits from disease-modifying therapies if started earlier in the course of ALS. The same premise will be explored with newer therapies that target ALS-associated genes.

Early Treatment Presumed More Effective

“We think that earlier treatment in the course of ALS is probably better for gene therapies as well,” Dr. Fournier said. She cautioned that follow-up is not yet long enough to confirm a survival benefit with tofersen, but she said it is reasonable to anticipate better and longer response when neurologic damage is limited. Citing the effect of gene therapy in spinal muscular atrophy (SMA), where progression is halted if gene therapy is initiated early in life, Dr. Fourier suggested that the emphasis on early treatment stems from the low likelihood for treatments to reverse functional impairments.

“It is conceivable that future treatments might be developed to reverse symptoms, but current drug development is largely aimed at slowing progression,” she explained. Under some circumstances, halting progression has the potential to allow some function to be regained, but as the etiologies of ALS and the pathways of progression are better understood, she believes that all targeted therapy will be started as early as possible to prevent rather than treat neurological damage.

Tofersen, the gene therapy for SOD1-ALS, has provided an opportunity to test the idea that it may be possible to prevent ALS. In a phase 3 trial called ATLAS, unaffected carriers of SOD1 variants that are associated with aggressive disease and high or complete penetrance are enrolled for a run-in phase (Part A) during which participants are followed for a rise in neurofilament light chain (NfL) levels. Based on a previous natural history study called the Pre-Symptomatic Familial ALS (Pre-fALS) study, NfL rises in the serum of unaffected SOD1 carriers prior to phenoconversion. A low NfL is an entry criterion for ATLAS.

ATLAS End Point Is Reduction in Phenoconversion to Clinically Manifest ALS

People in whom NfL rises above a predefined threshold during the run-in stage will be eligible for randomization (Part B) to receive either tofersen or placebo. Efficacy will be measured by comparing the rates of phenoconversion to clinically manifest ALS between those who receive placebo and those who receive tofersen.

Two other groups enrolled in ATLAS will be followed on open-label tofersen. One comprises people who phenoconvert during Part B and the other comprises those who develop ALS during the run-in and therefore are not enrolled in Part B. These patients, forming Parts C and D of the study, provide another set of data to evaluate whether earlier rather than later introduction of therapy provides better outcomes.

“There is a lot of interest and optimism about the trial,” said Dr. Fournier, who praised the trial design and thinks the hypothesis being explored “makes sense.”

Michael Benatar, MD, PhD, professor of neurology and public health, University of Miami School of Medicine, Miami, Florida, is the principal investigator of ATLAS and also leads the Pre-Symptomatic Familial ALS study together with a colleague, Joanne Wuu, Associate Director of Research at the University of Miami ALS Center. The hope from these initiatives, according to Dr. Fournier, is that ATLAS will offer broader learnings beyond just the SOD1 population, providing critical information about the optimal timing of treatment initiation.

The benefit from targeting genes considered causative for ALS is not yet a sure thing. A clinical trial targeting C9orf72, for example, failed to support an approvable therapy. There is a trial of a gene therapy for the FUS variant that is ongoing. Yet, the introduction of a gene therapy for SOD1 variant ALS has already established that highly targeted therapies can be effective, an important step forward after so many failed treatment trials with nonspecific drugs.

“We are seeing more and more therapies being developed to address specific ALS biology,” said Dr. Fournier, who predicts a pivot toward conceptualizing ALS as an array of pathologies rather than one disorder driven by a single mechanism. More effort is being directed to recognizing phenotypes as well as genotypes. Hopefully, more biomarkers that distinguish between ALS variants will emerge and help in individualizing treatment.

“We are not there yet, but I think many of us in the field see this as a way forward,” she said.
 

Multidisciplinary Care, Symptomatic Management, and Palliative Care Are Still Essential for ALS

Disease-modifying therapies are the ultimate goal in ALS, but Dr. Fournier said that the other side of the equation is multidisciplinary and palliative care. To the extent that almost all ALS therapies only modify the course of disease modestly, palliative care remains the cornerstone of day-to-day care.

“Multidisciplinary and palliative care are not necessarily novel, but they are still critically important. There are clear data to show that multidisciplinary care improves functional status and quality of life, and that this is meaningful to patients,” Dr. Fournier said.

There have been numerous improvements in the areas of multidisciplinary and palliative care, some of which can be credited to advancing technology. In centers of excellence, the multidisciplinary approach has been focused on helping patients sustain a sense of independence and self-worth.

Now robotics, devices, and software are being increasingly employed to extend patient capabilities even in relatively advanced stages of disease, according to Dr. Fournier. As one example, she cited current work in brain-computer interfaces to record electrical activity in the central nervous system to allow patients to communicate even when speech is impaired.

A focus on patient-centered clinical care is appropriate because it is the best current opportunity to improve the lives of patients with ALS. Clinically, this work is very rewarding, according to Dr. Fournier, who described ALS patients overall as generally ”very invested in advocacy and research initiatives and motivated to help others,” Dr. Fournier said.

“The diagnosis can be tough, but there is satisfaction in helping these patients navigate toward an acceptable and meaningful quality of life. They typically give a lot back,” she added.

Overall, there is a sense of progress in ALS, even though it remains a uniformly fatal disease. Dr. Fournier expressed hope that clinical research is reaching a tipping point and an emphasis on targeted treatments after a long list of failed trials over the past 30 years. However, with only one approved therapy modifying an ALS-associated gene, this approach is still in its early stages.

Dr. Fournier has financial relationships with Amylyx, Biogen, Corcept, Denali, Mitsubishi QurAlis, and Tanabe.
 

Suggested Reading

Benatar M et al. Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study. Neurotherapeutics. 2022 Jul;19(4):1248-1258. doi: 10.1007/s13311-022-01237-4.

Geronimo A et al. Ten Years of Riluzole Use in a Tertiary ALS Clinic. Muscle Nerve. 2022 Jun;65(6):659-666. doi: 10.1002/mus.27541.

Roggenbuck J et al. Evidence-Based Consensus Guidelines for ALS Genetic Testing and Counseling. Ann Clin Transl Neurol. 2023 Nov;10(11):2074-2091. doi: 10.1002/acn3.51895.

The first therapy targeted at modifying a mutant gene associated with amyotrophic lateral sclerosis (ALS), approved in early 2023, has offered reassurance that the biology of ALS, when known, is targetable. Historically, the disease has been considered a clinical diagnosis, but the progress in identifying molecular mechanisms is permitting ALS to be understood as a biological entity and suggests rationally targeted therapies will be the way forward following the inadequacy of nonselective drugs.

Despite a narrow indication, the only therapy targeted at an ALS-associated gene so far, SOD1 ALS, supports the premise that the biology of ALS can be modified, according to Christina N. Fournier, MD, an associate professor in the Department of Neurology, Emory University, Atlanta, Georgia.

About 15% of ALS Has An Identifiable Genetic Cause

A family history of ALS is present in about 10% of cases. A genetic cause can be identified in approximately 15%. Cases without an identifiable genetic etiology are considered sporadic. So far, the only approved therapy that modifies the function of a gene associated with ALS is tofersen (Qalsody, Biogen), an antisense oligonucleotide. Tofersen inhibits RNA transcription of the superoxide dismutase 1 (SOD1) gene to decrease production of the SOD1 protein.

This first gene therapy for ALS is a breakthrough, but it is indicated for only a small proportion of ALS patients. Even though SOD1 gene mutations represent the second most common genetic cause of ALS after the C90rf72 gene, the proportion of patients who are candidates for tofersen is low. Efficacy is expected only in about 1% of those with familial ALS and 1% of those with sporadic ALS, or about 2% of all patients with ALS.

The evidence of benefit from a treatment with a specific target has provided the basis for concluding that “we are onto something,” Dr. Fournier said. An expert in ALS, she sees reason for excitement about the prospects in treatment with the growing focus on the underlying pathways of disease rather than the downstream consequences.

“The hope is that new gene-targeted therapies will be developed in the future to treat the broader ALS population,” said Dr. Fournier, explaining that the move toward rationally targeted treatments, whether related to gene mutations or independent molecular pathways of ALS progression, has created excitement in the field.

Numerous Disease Processes Are Potentially Targetable

As treatments are developed to address nongenetic molecular processes that contribute to the risk or progression of ALS, such as neuroinflammation or abnormal protein misfolding and aggregation, individualized treatment is likely to become key. Just as not all genetic cases share mutations in the same gene, the key molecular drivers of disease are likely to differ between patients. If so, it is hoped that biomarkers reflective of this underlying biology can be identified to appropriately target treatments.

“The excitement behind the newer targets in clinical trials is based on both basic science and early clinical data that support treatment based on specific drivers of disease,” Dr. Fournier said.

In 2023 and just prior to the FDA approval of tofersen, a set of expert consensus guidelines were published calling for genetic testing to be offered to all patients with ALS. These recommendations suggested that SOD1, C9orf72, FUS, and TARDBP should be included routinely into the panel of genes evaluated, calling for additional genes to be added as they emerge as potential therapeutic targets.

Even before these guidelines were released, genetic testing was already being offered at many centers with expertise in ALS. The rationale was to differentiate ALS with a genetic etiology from that with a nongenetic etiology, as well as to counsel family members when genetic risk was identified, but genetic testing has now assumed new urgency. In addition to the potential for offering a specific treatment for SOD1-related ALS, patients with other genetic forms of disease might be candidates for genetically focused clinical trials.

Genetic testing should be performed as soon as a diagnosis of ALS is made, according to Dr. Fournier. Although not all patients have accepted genetic testing, particularly in the past when there was no immediate clinical gain from establishing the presence of a genetic mutation, she said there is no longer any controversy about clinical relevance.
 

Genetic Testing Is Key to Genetic Therapies

“We do not want to miss the opportunity to treat patients when we have the chance,” said Dr. Fournier, referring to both the likely advantage of an early start of the approved gene therapy as well as the opportunity to participate in a clinical trial with other gene therapies in development.

Prior to the approval of tofersen, riluzole and edaravone had been the only disease-modifying agents in widespread use, but these drugs are nonspecific. There are no established biomarkers for establishing which patients are most likely to benefit.

In the case of riluzole, a pivotal trial conducted 30 years ago showed a survival benefit relative to placebo at 12 months (74% vs. 58%; P = 0.014). In a retrospective study published in 2022 that evaluated survival in a database of 4778 ALS patients of whom 3446 received riluzole, early diagnosis of ALS and prompt treatment with riluzole was associated with longer survival than delayed treatment. The benefit of edaravone has been validated with clinical measures, such as the revised Amyotrophic Lateral Sclerosis Functional Scale (ALSFRS-R).

The retrospective study of riluzole provides the basis for predicting better benefits from disease-modifying therapies if started earlier in the course of ALS. The same premise will be explored with newer therapies that target ALS-associated genes.

Early Treatment Presumed More Effective

“We think that earlier treatment in the course of ALS is probably better for gene therapies as well,” Dr. Fournier said. She cautioned that follow-up is not yet long enough to confirm a survival benefit with tofersen, but she said it is reasonable to anticipate better and longer response when neurologic damage is limited. Citing the effect of gene therapy in spinal muscular atrophy (SMA), where progression is halted if gene therapy is initiated early in life, Dr. Fourier suggested that the emphasis on early treatment stems from the low likelihood for treatments to reverse functional impairments.

“It is conceivable that future treatments might be developed to reverse symptoms, but current drug development is largely aimed at slowing progression,” she explained. Under some circumstances, halting progression has the potential to allow some function to be regained, but as the etiologies of ALS and the pathways of progression are better understood, she believes that all targeted therapy will be started as early as possible to prevent rather than treat neurological damage.

Tofersen, the gene therapy for SOD1-ALS, has provided an opportunity to test the idea that it may be possible to prevent ALS. In a phase 3 trial called ATLAS, unaffected carriers of SOD1 variants that are associated with aggressive disease and high or complete penetrance are enrolled for a run-in phase (Part A) during which participants are followed for a rise in neurofilament light chain (NfL) levels. Based on a previous natural history study called the Pre-Symptomatic Familial ALS (Pre-fALS) study, NfL rises in the serum of unaffected SOD1 carriers prior to phenoconversion. A low NfL is an entry criterion for ATLAS.

ATLAS End Point Is Reduction in Phenoconversion to Clinically Manifest ALS

People in whom NfL rises above a predefined threshold during the run-in stage will be eligible for randomization (Part B) to receive either tofersen or placebo. Efficacy will be measured by comparing the rates of phenoconversion to clinically manifest ALS between those who receive placebo and those who receive tofersen.

Two other groups enrolled in ATLAS will be followed on open-label tofersen. One comprises people who phenoconvert during Part B and the other comprises those who develop ALS during the run-in and therefore are not enrolled in Part B. These patients, forming Parts C and D of the study, provide another set of data to evaluate whether earlier rather than later introduction of therapy provides better outcomes.

“There is a lot of interest and optimism about the trial,” said Dr. Fournier, who praised the trial design and thinks the hypothesis being explored “makes sense.”

Michael Benatar, MD, PhD, professor of neurology and public health, University of Miami School of Medicine, Miami, Florida, is the principal investigator of ATLAS and also leads the Pre-Symptomatic Familial ALS study together with a colleague, Joanne Wuu, Associate Director of Research at the University of Miami ALS Center. The hope from these initiatives, according to Dr. Fournier, is that ATLAS will offer broader learnings beyond just the SOD1 population, providing critical information about the optimal timing of treatment initiation.

The benefit from targeting genes considered causative for ALS is not yet a sure thing. A clinical trial targeting C9orf72, for example, failed to support an approvable therapy. There is a trial of a gene therapy for the FUS variant that is ongoing. Yet, the introduction of a gene therapy for SOD1 variant ALS has already established that highly targeted therapies can be effective, an important step forward after so many failed treatment trials with nonspecific drugs.

“We are seeing more and more therapies being developed to address specific ALS biology,” said Dr. Fournier, who predicts a pivot toward conceptualizing ALS as an array of pathologies rather than one disorder driven by a single mechanism. More effort is being directed to recognizing phenotypes as well as genotypes. Hopefully, more biomarkers that distinguish between ALS variants will emerge and help in individualizing treatment.

“We are not there yet, but I think many of us in the field see this as a way forward,” she said.
 

Multidisciplinary Care, Symptomatic Management, and Palliative Care Are Still Essential for ALS

Disease-modifying therapies are the ultimate goal in ALS, but Dr. Fournier said that the other side of the equation is multidisciplinary and palliative care. To the extent that almost all ALS therapies only modify the course of disease modestly, palliative care remains the cornerstone of day-to-day care.

“Multidisciplinary and palliative care are not necessarily novel, but they are still critically important. There are clear data to show that multidisciplinary care improves functional status and quality of life, and that this is meaningful to patients,” Dr. Fournier said.

There have been numerous improvements in the areas of multidisciplinary and palliative care, some of which can be credited to advancing technology. In centers of excellence, the multidisciplinary approach has been focused on helping patients sustain a sense of independence and self-worth.

Now robotics, devices, and software are being increasingly employed to extend patient capabilities even in relatively advanced stages of disease, according to Dr. Fournier. As one example, she cited current work in brain-computer interfaces to record electrical activity in the central nervous system to allow patients to communicate even when speech is impaired.

A focus on patient-centered clinical care is appropriate because it is the best current opportunity to improve the lives of patients with ALS. Clinically, this work is very rewarding, according to Dr. Fournier, who described ALS patients overall as generally ”very invested in advocacy and research initiatives and motivated to help others,” Dr. Fournier said.

“The diagnosis can be tough, but there is satisfaction in helping these patients navigate toward an acceptable and meaningful quality of life. They typically give a lot back,” she added.

Overall, there is a sense of progress in ALS, even though it remains a uniformly fatal disease. Dr. Fournier expressed hope that clinical research is reaching a tipping point and an emphasis on targeted treatments after a long list of failed trials over the past 30 years. However, with only one approved therapy modifying an ALS-associated gene, this approach is still in its early stages.

Dr. Fournier has financial relationships with Amylyx, Biogen, Corcept, Denali, Mitsubishi QurAlis, and Tanabe.
 

Suggested Reading

Benatar M et al. Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study. Neurotherapeutics. 2022 Jul;19(4):1248-1258. doi: 10.1007/s13311-022-01237-4.

Geronimo A et al. Ten Years of Riluzole Use in a Tertiary ALS Clinic. Muscle Nerve. 2022 Jun;65(6):659-666. doi: 10.1002/mus.27541.

Roggenbuck J et al. Evidence-Based Consensus Guidelines for ALS Genetic Testing and Counseling. Ann Clin Transl Neurol. 2023 Nov;10(11):2074-2091. doi: 10.1002/acn3.51895.

The first therapy targeted at modifying a mutant gene associated with amyotrophic lateral sclerosis (ALS), approved in early 2023, has offered reassurance that the biology of ALS, when known, is targetable. Historically, the disease has been considered a clinical diagnosis, but the progress in identifying molecular mechanisms is permitting ALS to be understood as a biological entity and suggests rationally targeted therapies will be the way forward following the inadequacy of nonselective drugs.

Despite a narrow indication, the only therapy targeted at an ALS-associated gene so far, SOD1 ALS, supports the premise that the biology of ALS can be modified, according to Christina N. Fournier, MD, an associate professor in the Department of Neurology, Emory University, Atlanta, Georgia.

About 15% of ALS Has An Identifiable Genetic Cause

A family history of ALS is present in about 10% of cases. A genetic cause can be identified in approximately 15%. Cases without an identifiable genetic etiology are considered sporadic. So far, the only approved therapy that modifies the function of a gene associated with ALS is tofersen (Qalsody, Biogen), an antisense oligonucleotide. Tofersen inhibits RNA transcription of the superoxide dismutase 1 (SOD1) gene to decrease production of the SOD1 protein.

This first gene therapy for ALS is a breakthrough, but it is indicated for only a small proportion of ALS patients. Even though SOD1 gene mutations represent the second most common genetic cause of ALS after the C90rf72 gene, the proportion of patients who are candidates for tofersen is low. Efficacy is expected only in about 1% of those with familial ALS and 1% of those with sporadic ALS, or about 2% of all patients with ALS.

The evidence of benefit from a treatment with a specific target has provided the basis for concluding that “we are onto something,” Dr. Fournier said. An expert in ALS, she sees reason for excitement about the prospects in treatment with the growing focus on the underlying pathways of disease rather than the downstream consequences.

“The hope is that new gene-targeted therapies will be developed in the future to treat the broader ALS population,” said Dr. Fournier, explaining that the move toward rationally targeted treatments, whether related to gene mutations or independent molecular pathways of ALS progression, has created excitement in the field.

Numerous Disease Processes Are Potentially Targetable

As treatments are developed to address nongenetic molecular processes that contribute to the risk or progression of ALS, such as neuroinflammation or abnormal protein misfolding and aggregation, individualized treatment is likely to become key. Just as not all genetic cases share mutations in the same gene, the key molecular drivers of disease are likely to differ between patients. If so, it is hoped that biomarkers reflective of this underlying biology can be identified to appropriately target treatments.

“The excitement behind the newer targets in clinical trials is based on both basic science and early clinical data that support treatment based on specific drivers of disease,” Dr. Fournier said.

In 2023 and just prior to the FDA approval of tofersen, a set of expert consensus guidelines were published calling for genetic testing to be offered to all patients with ALS. These recommendations suggested that SOD1, C9orf72, FUS, and TARDBP should be included routinely into the panel of genes evaluated, calling for additional genes to be added as they emerge as potential therapeutic targets.

Even before these guidelines were released, genetic testing was already being offered at many centers with expertise in ALS. The rationale was to differentiate ALS with a genetic etiology from that with a nongenetic etiology, as well as to counsel family members when genetic risk was identified, but genetic testing has now assumed new urgency. In addition to the potential for offering a specific treatment for SOD1-related ALS, patients with other genetic forms of disease might be candidates for genetically focused clinical trials.

Genetic testing should be performed as soon as a diagnosis of ALS is made, according to Dr. Fournier. Although not all patients have accepted genetic testing, particularly in the past when there was no immediate clinical gain from establishing the presence of a genetic mutation, she said there is no longer any controversy about clinical relevance.
 

Genetic Testing Is Key to Genetic Therapies

“We do not want to miss the opportunity to treat patients when we have the chance,” said Dr. Fournier, referring to both the likely advantage of an early start of the approved gene therapy as well as the opportunity to participate in a clinical trial with other gene therapies in development.

Prior to the approval of tofersen, riluzole and edaravone had been the only disease-modifying agents in widespread use, but these drugs are nonspecific. There are no established biomarkers for establishing which patients are most likely to benefit.

In the case of riluzole, a pivotal trial conducted 30 years ago showed a survival benefit relative to placebo at 12 months (74% vs. 58%; P = 0.014). In a retrospective study published in 2022 that evaluated survival in a database of 4778 ALS patients of whom 3446 received riluzole, early diagnosis of ALS and prompt treatment with riluzole was associated with longer survival than delayed treatment. The benefit of edaravone has been validated with clinical measures, such as the revised Amyotrophic Lateral Sclerosis Functional Scale (ALSFRS-R).

The retrospective study of riluzole provides the basis for predicting better benefits from disease-modifying therapies if started earlier in the course of ALS. The same premise will be explored with newer therapies that target ALS-associated genes.

Early Treatment Presumed More Effective

“We think that earlier treatment in the course of ALS is probably better for gene therapies as well,” Dr. Fournier said. She cautioned that follow-up is not yet long enough to confirm a survival benefit with tofersen, but she said it is reasonable to anticipate better and longer response when neurologic damage is limited. Citing the effect of gene therapy in spinal muscular atrophy (SMA), where progression is halted if gene therapy is initiated early in life, Dr. Fourier suggested that the emphasis on early treatment stems from the low likelihood for treatments to reverse functional impairments.

“It is conceivable that future treatments might be developed to reverse symptoms, but current drug development is largely aimed at slowing progression,” she explained. Under some circumstances, halting progression has the potential to allow some function to be regained, but as the etiologies of ALS and the pathways of progression are better understood, she believes that all targeted therapy will be started as early as possible to prevent rather than treat neurological damage.

Tofersen, the gene therapy for SOD1-ALS, has provided an opportunity to test the idea that it may be possible to prevent ALS. In a phase 3 trial called ATLAS, unaffected carriers of SOD1 variants that are associated with aggressive disease and high or complete penetrance are enrolled for a run-in phase (Part A) during which participants are followed for a rise in neurofilament light chain (NfL) levels. Based on a previous natural history study called the Pre-Symptomatic Familial ALS (Pre-fALS) study, NfL rises in the serum of unaffected SOD1 carriers prior to phenoconversion. A low NfL is an entry criterion for ATLAS.

ATLAS End Point Is Reduction in Phenoconversion to Clinically Manifest ALS

People in whom NfL rises above a predefined threshold during the run-in stage will be eligible for randomization (Part B) to receive either tofersen or placebo. Efficacy will be measured by comparing the rates of phenoconversion to clinically manifest ALS between those who receive placebo and those who receive tofersen.

Two other groups enrolled in ATLAS will be followed on open-label tofersen. One comprises people who phenoconvert during Part B and the other comprises those who develop ALS during the run-in and therefore are not enrolled in Part B. These patients, forming Parts C and D of the study, provide another set of data to evaluate whether earlier rather than later introduction of therapy provides better outcomes.

“There is a lot of interest and optimism about the trial,” said Dr. Fournier, who praised the trial design and thinks the hypothesis being explored “makes sense.”

Michael Benatar, MD, PhD, professor of neurology and public health, University of Miami School of Medicine, Miami, Florida, is the principal investigator of ATLAS and also leads the Pre-Symptomatic Familial ALS study together with a colleague, Joanne Wuu, Associate Director of Research at the University of Miami ALS Center. The hope from these initiatives, according to Dr. Fournier, is that ATLAS will offer broader learnings beyond just the SOD1 population, providing critical information about the optimal timing of treatment initiation.

The benefit from targeting genes considered causative for ALS is not yet a sure thing. A clinical trial targeting C9orf72, for example, failed to support an approvable therapy. There is a trial of a gene therapy for the FUS variant that is ongoing. Yet, the introduction of a gene therapy for SOD1 variant ALS has already established that highly targeted therapies can be effective, an important step forward after so many failed treatment trials with nonspecific drugs.

“We are seeing more and more therapies being developed to address specific ALS biology,” said Dr. Fournier, who predicts a pivot toward conceptualizing ALS as an array of pathologies rather than one disorder driven by a single mechanism. More effort is being directed to recognizing phenotypes as well as genotypes. Hopefully, more biomarkers that distinguish between ALS variants will emerge and help in individualizing treatment.

“We are not there yet, but I think many of us in the field see this as a way forward,” she said.
 

Multidisciplinary Care, Symptomatic Management, and Palliative Care Are Still Essential for ALS

Disease-modifying therapies are the ultimate goal in ALS, but Dr. Fournier said that the other side of the equation is multidisciplinary and palliative care. To the extent that almost all ALS therapies only modify the course of disease modestly, palliative care remains the cornerstone of day-to-day care.

“Multidisciplinary and palliative care are not necessarily novel, but they are still critically important. There are clear data to show that multidisciplinary care improves functional status and quality of life, and that this is meaningful to patients,” Dr. Fournier said.

There have been numerous improvements in the areas of multidisciplinary and palliative care, some of which can be credited to advancing technology. In centers of excellence, the multidisciplinary approach has been focused on helping patients sustain a sense of independence and self-worth.

Now robotics, devices, and software are being increasingly employed to extend patient capabilities even in relatively advanced stages of disease, according to Dr. Fournier. As one example, she cited current work in brain-computer interfaces to record electrical activity in the central nervous system to allow patients to communicate even when speech is impaired.

A focus on patient-centered clinical care is appropriate because it is the best current opportunity to improve the lives of patients with ALS. Clinically, this work is very rewarding, according to Dr. Fournier, who described ALS patients overall as generally ”very invested in advocacy and research initiatives and motivated to help others,” Dr. Fournier said.

“The diagnosis can be tough, but there is satisfaction in helping these patients navigate toward an acceptable and meaningful quality of life. They typically give a lot back,” she added.

Overall, there is a sense of progress in ALS, even though it remains a uniformly fatal disease. Dr. Fournier expressed hope that clinical research is reaching a tipping point and an emphasis on targeted treatments after a long list of failed trials over the past 30 years. However, with only one approved therapy modifying an ALS-associated gene, this approach is still in its early stages.

Dr. Fournier has financial relationships with Amylyx, Biogen, Corcept, Denali, Mitsubishi QurAlis, and Tanabe.
 

Suggested Reading

Benatar M et al. Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study. Neurotherapeutics. 2022 Jul;19(4):1248-1258. doi: 10.1007/s13311-022-01237-4.

Geronimo A et al. Ten Years of Riluzole Use in a Tertiary ALS Clinic. Muscle Nerve. 2022 Jun;65(6):659-666. doi: 10.1002/mus.27541.

Roggenbuck J et al. Evidence-Based Consensus Guidelines for ALS Genetic Testing and Counseling. Ann Clin Transl Neurol. 2023 Nov;10(11):2074-2091. doi: 10.1002/acn3.51895.

COPENHAGEN — Multiple Sclerosis (MS) experts are recommending updates to the 2017 McDonald diagnostic criteria in order to make diagnosis easier, faster, and more accurate.

Among its recommendations, the expert panel advises incorporating optic nerve imaging for diagnosis and applying stricter criteria for older patients. In addition, it proposes that radiologically isolated syndrome (RIS) may be diagnosed as MS in certain cases and that disease dissemination in time (DIT) should no longer be required. 

The proposed criteria changes were presented at the 2024 ECTRIMS annual meeting.

Committee member Xavier Montalban, MD, PhD, from the Department of Neurology and the MS Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, Spain, told conference attendees that MS is a diagnosis of exclusion.

Brain and spinal cord MRI remains the most useful paraclinical test to diagnose the disease, he said, and an abnormal MRI showing typical lesions is required.

Dr. Montalban noted that optic neuritis is the first manifestation of MS in 25%-35% of cases with clinically isolated syndrome (CIS) — one of the four MS disease courses.

Therefore, he said, the panel is recommending that the optic nerve serve as the “fifth topography” or a fifth anatomical location to demonstrate dissemination in space (DIS) if there’s no better explanation for optic nerve pathology, he said. 

Considerable evidence supports the minimal threshold of at least one lesion in at least two of the five topographies after including the optic nerve, he added.
 

DIS Alone Sufficient?

The panel also concluded that demonstrating DIS alone, without the need for DIT or positive cerebrospinal fluid (CSF), may be sufficient for an MS diagnosis. Currently, both DIS and DIT are required.

The committee broached the topic of RIS, which is identified by the incidental discovery of central nervous system (CNS) white matter T2-weighted hyperintense foci on MRI. These hyperintense foci demonstrate morphological and spatial characteristics highly typical of MS but without clinical symptomatology related to inflammatory demyelination.

Dr. Montalban noted that most patients with RIS will develop MS within 10 years. For these individuals, the panel concluded that the following criteria are sufficient for an MS diagnosis: fulfilling both DIS and DIT; fulfilling DIS and the presence of oligoclonal bands (OCBs) in the cerebrospinal fluid; or fulfilling DIS along with six or more central vein signs (CVS).

The panel proposes the addition of CVS and paramagnetic rim lesions, which are MRI markers of chronic active lesions, as optional tools for MS diagnosis in certain situations. Demonstration of CVS by MRI can increase specificity, said Dr. Montalban.

Evidence also suggests that kappa free light chains (KFLCs) could serve as a valid, simpler, and rater-independent alternative to detecting OCBs, he added. Because KFLCs are interchangeable with OCBs, they can be used in place of OCBs for diagnosing MS through CSF analysis.
 

Stricter Criteria

The panel is also calling for stricter criteria for confirming an MS diagnosis in those over age 50 or individuals with headache or vascular disorders. In such patients, they strongly recommend additional features such as a spinal cord lesion, positive CSF, and CVS select 6 (six positive lesions).

The panel is also recommending laboratory tests (MOG-IgG Ab) to confirm a diagnosis in children and adolescents. Dr. Montalban noted the presence of CVS in about 50% of T2 lesions strongly suggests MS in this population.

Primary progressive MS (PPMS) requires evidence of clinical progression over at least 12 months. The committee determined that the same criteria for relapsing-remitting MS could be used for PPMS. 

Having a single, unified framework of diagnostic criteria will be “very useful,” said Dr. Montalban.

During the same meeting session, Marcello Moccia, MD, PhD, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, London, England, presented examples of patients for whom the revised criteria could be beneficial. 

These examples help illustrate how using the new criteria, for example optic nerve imaging, could lead to earlier diagnoses, and, in some cases, easier diagnoses, possibly with less CSF, he said. It could also lead to fewer misdiagnoses, he added, thanks to high-specificity tools.

Implementing the new criteria could offer greater flexibility and reduce complexity, Dr. Moccia concluded, adding that not every patient with suspected MS requires exhaustive testing.

The committee’s next steps will include consulting with the wider MS community and preparing the information for publication, said Dr. Montalban.

Commenting on the proposals, Bruce Bebo, executive vice president of research, National MS Society, agreed the proposed changes to the McDonald Criteria will make diagnosing MS “faster and easier.”

“Importantly, we are providing guidance that is inclusive — how to confirm diagnoses in children, or in people over the age of 50,” said Dr. Bebo. “We’re bringing the latest research and imaging technology to the forefront, to help people with MS get treatment faster, so they can live their best lives.”

Dr. Montalban’s institution has received compensation for lecture honoraria and travel expenses, participation in scientific meetings, clinical trial steering committee membership, or clinical advisory board participation in recent years from AbbVie, Actelion, Alexion, Bial PD, Biogen, Bristol Myers Squibb/Celgene, EMD Serona, Genzyme, Hoffmann-La Roche, Immunic Therapeutics, Janssen Pharmaceuticals, MedDay, Merck, Mylan, Nervgen, Neuraxpharm, Novartis, PeerVoice, Samsung-Biosys Sandoz Sanofi-Genzyme, Teva Pharmaceuticals, TG Therapeutics, EXCEMED, ECTRIMS, MSIF, and NMSS or any of their affiliates. Dr. Moccia reports receiving a salary from University of Naples, Policlinico University Hospital (Naples) and Neurology (US); research grants from MUR PNRR Extended Partnership, ECTRIMS-MAGNIMS, UK MS Society, and Merck; honoraria from AbbVie, Biogen, BMS Celgene, Ipsen, Jansen, Merck, Novartis, Roche, and Sanofi-Genzyme. 

A version of this article appeared on Medscape.com.

COPENHAGEN — Multiple Sclerosis (MS) experts are recommending updates to the 2017 McDonald diagnostic criteria in order to make diagnosis easier, faster, and more accurate.

Among its recommendations, the expert panel advises incorporating optic nerve imaging for diagnosis and applying stricter criteria for older patients. In addition, it proposes that radiologically isolated syndrome (RIS) may be diagnosed as MS in certain cases and that disease dissemination in time (DIT) should no longer be required. 

The proposed criteria changes were presented at the 2024 ECTRIMS annual meeting.

Committee member Xavier Montalban, MD, PhD, from the Department of Neurology and the MS Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, Spain, told conference attendees that MS is a diagnosis of exclusion.

Brain and spinal cord MRI remains the most useful paraclinical test to diagnose the disease, he said, and an abnormal MRI showing typical lesions is required.

Dr. Montalban noted that optic neuritis is the first manifestation of MS in 25%-35% of cases with clinically isolated syndrome (CIS) — one of the four MS disease courses.

Therefore, he said, the panel is recommending that the optic nerve serve as the “fifth topography” or a fifth anatomical location to demonstrate dissemination in space (DIS) if there’s no better explanation for optic nerve pathology, he said. 

Considerable evidence supports the minimal threshold of at least one lesion in at least two of the five topographies after including the optic nerve, he added.
 

DIS Alone Sufficient?

The panel also concluded that demonstrating DIS alone, without the need for DIT or positive cerebrospinal fluid (CSF), may be sufficient for an MS diagnosis. Currently, both DIS and DIT are required.

The committee broached the topic of RIS, which is identified by the incidental discovery of central nervous system (CNS) white matter T2-weighted hyperintense foci on MRI. These hyperintense foci demonstrate morphological and spatial characteristics highly typical of MS but without clinical symptomatology related to inflammatory demyelination.

Dr. Montalban noted that most patients with RIS will develop MS within 10 years. For these individuals, the panel concluded that the following criteria are sufficient for an MS diagnosis: fulfilling both DIS and DIT; fulfilling DIS and the presence of oligoclonal bands (OCBs) in the cerebrospinal fluid; or fulfilling DIS along with six or more central vein signs (CVS).

The panel proposes the addition of CVS and paramagnetic rim lesions, which are MRI markers of chronic active lesions, as optional tools for MS diagnosis in certain situations. Demonstration of CVS by MRI can increase specificity, said Dr. Montalban.

Evidence also suggests that kappa free light chains (KFLCs) could serve as a valid, simpler, and rater-independent alternative to detecting OCBs, he added. Because KFLCs are interchangeable with OCBs, they can be used in place of OCBs for diagnosing MS through CSF analysis.
 

Stricter Criteria

The panel is also calling for stricter criteria for confirming an MS diagnosis in those over age 50 or individuals with headache or vascular disorders. In such patients, they strongly recommend additional features such as a spinal cord lesion, positive CSF, and CVS select 6 (six positive lesions).

The panel is also recommending laboratory tests (MOG-IgG Ab) to confirm a diagnosis in children and adolescents. Dr. Montalban noted the presence of CVS in about 50% of T2 lesions strongly suggests MS in this population.

Primary progressive MS (PPMS) requires evidence of clinical progression over at least 12 months. The committee determined that the same criteria for relapsing-remitting MS could be used for PPMS. 

Having a single, unified framework of diagnostic criteria will be “very useful,” said Dr. Montalban.

During the same meeting session, Marcello Moccia, MD, PhD, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, London, England, presented examples of patients for whom the revised criteria could be beneficial. 

These examples help illustrate how using the new criteria, for example optic nerve imaging, could lead to earlier diagnoses, and, in some cases, easier diagnoses, possibly with less CSF, he said. It could also lead to fewer misdiagnoses, he added, thanks to high-specificity tools.

Implementing the new criteria could offer greater flexibility and reduce complexity, Dr. Moccia concluded, adding that not every patient with suspected MS requires exhaustive testing.

The committee’s next steps will include consulting with the wider MS community and preparing the information for publication, said Dr. Montalban.

Commenting on the proposals, Bruce Bebo, executive vice president of research, National MS Society, agreed the proposed changes to the McDonald Criteria will make diagnosing MS “faster and easier.”

“Importantly, we are providing guidance that is inclusive — how to confirm diagnoses in children, or in people over the age of 50,” said Dr. Bebo. “We’re bringing the latest research and imaging technology to the forefront, to help people with MS get treatment faster, so they can live their best lives.”

Dr. Montalban’s institution has received compensation for lecture honoraria and travel expenses, participation in scientific meetings, clinical trial steering committee membership, or clinical advisory board participation in recent years from AbbVie, Actelion, Alexion, Bial PD, Biogen, Bristol Myers Squibb/Celgene, EMD Serona, Genzyme, Hoffmann-La Roche, Immunic Therapeutics, Janssen Pharmaceuticals, MedDay, Merck, Mylan, Nervgen, Neuraxpharm, Novartis, PeerVoice, Samsung-Biosys Sandoz Sanofi-Genzyme, Teva Pharmaceuticals, TG Therapeutics, EXCEMED, ECTRIMS, MSIF, and NMSS or any of their affiliates. Dr. Moccia reports receiving a salary from University of Naples, Policlinico University Hospital (Naples) and Neurology (US); research grants from MUR PNRR Extended Partnership, ECTRIMS-MAGNIMS, UK MS Society, and Merck; honoraria from AbbVie, Biogen, BMS Celgene, Ipsen, Jansen, Merck, Novartis, Roche, and Sanofi-Genzyme. 

A version of this article appeared on Medscape.com.

COPENHAGEN — Multiple Sclerosis (MS) experts are recommending updates to the 2017 McDonald diagnostic criteria in order to make diagnosis easier, faster, and more accurate.

Among its recommendations, the expert panel advises incorporating optic nerve imaging for diagnosis and applying stricter criteria for older patients. In addition, it proposes that radiologically isolated syndrome (RIS) may be diagnosed as MS in certain cases and that disease dissemination in time (DIT) should no longer be required. 

The proposed criteria changes were presented at the 2024 ECTRIMS annual meeting.

Committee member Xavier Montalban, MD, PhD, from the Department of Neurology and the MS Centre of Catalonia at Vall d’Hebron University Hospital in Barcelona, Spain, told conference attendees that MS is a diagnosis of exclusion.

Brain and spinal cord MRI remains the most useful paraclinical test to diagnose the disease, he said, and an abnormal MRI showing typical lesions is required.

Dr. Montalban noted that optic neuritis is the first manifestation of MS in 25%-35% of cases with clinically isolated syndrome (CIS) — one of the four MS disease courses.

Therefore, he said, the panel is recommending that the optic nerve serve as the “fifth topography” or a fifth anatomical location to demonstrate dissemination in space (DIS) if there’s no better explanation for optic nerve pathology, he said. 

Considerable evidence supports the minimal threshold of at least one lesion in at least two of the five topographies after including the optic nerve, he added.
 

DIS Alone Sufficient?

The panel also concluded that demonstrating DIS alone, without the need for DIT or positive cerebrospinal fluid (CSF), may be sufficient for an MS diagnosis. Currently, both DIS and DIT are required.

The committee broached the topic of RIS, which is identified by the incidental discovery of central nervous system (CNS) white matter T2-weighted hyperintense foci on MRI. These hyperintense foci demonstrate morphological and spatial characteristics highly typical of MS but without clinical symptomatology related to inflammatory demyelination.

Dr. Montalban noted that most patients with RIS will develop MS within 10 years. For these individuals, the panel concluded that the following criteria are sufficient for an MS diagnosis: fulfilling both DIS and DIT; fulfilling DIS and the presence of oligoclonal bands (OCBs) in the cerebrospinal fluid; or fulfilling DIS along with six or more central vein signs (CVS).

The panel proposes the addition of CVS and paramagnetic rim lesions, which are MRI markers of chronic active lesions, as optional tools for MS diagnosis in certain situations. Demonstration of CVS by MRI can increase specificity, said Dr. Montalban.

Evidence also suggests that kappa free light chains (KFLCs) could serve as a valid, simpler, and rater-independent alternative to detecting OCBs, he added. Because KFLCs are interchangeable with OCBs, they can be used in place of OCBs for diagnosing MS through CSF analysis.
 

Stricter Criteria

The panel is also calling for stricter criteria for confirming an MS diagnosis in those over age 50 or individuals with headache or vascular disorders. In such patients, they strongly recommend additional features such as a spinal cord lesion, positive CSF, and CVS select 6 (six positive lesions).

The panel is also recommending laboratory tests (MOG-IgG Ab) to confirm a diagnosis in children and adolescents. Dr. Montalban noted the presence of CVS in about 50% of T2 lesions strongly suggests MS in this population.

Primary progressive MS (PPMS) requires evidence of clinical progression over at least 12 months. The committee determined that the same criteria for relapsing-remitting MS could be used for PPMS. 

Having a single, unified framework of diagnostic criteria will be “very useful,” said Dr. Montalban.

During the same meeting session, Marcello Moccia, MD, PhD, University College London (UCL) Queen Square Institute of Neurology, Faculty of Brain Sciences, London, England, presented examples of patients for whom the revised criteria could be beneficial. 

These examples help illustrate how using the new criteria, for example optic nerve imaging, could lead to earlier diagnoses, and, in some cases, easier diagnoses, possibly with less CSF, he said. It could also lead to fewer misdiagnoses, he added, thanks to high-specificity tools.

Implementing the new criteria could offer greater flexibility and reduce complexity, Dr. Moccia concluded, adding that not every patient with suspected MS requires exhaustive testing.

The committee’s next steps will include consulting with the wider MS community and preparing the information for publication, said Dr. Montalban.

Commenting on the proposals, Bruce Bebo, executive vice president of research, National MS Society, agreed the proposed changes to the McDonald Criteria will make diagnosing MS “faster and easier.”

“Importantly, we are providing guidance that is inclusive — how to confirm diagnoses in children, or in people over the age of 50,” said Dr. Bebo. “We’re bringing the latest research and imaging technology to the forefront, to help people with MS get treatment faster, so they can live their best lives.”

Dr. Montalban’s institution has received compensation for lecture honoraria and travel expenses, participation in scientific meetings, clinical trial steering committee membership, or clinical advisory board participation in recent years from AbbVie, Actelion, Alexion, Bial PD, Biogen, Bristol Myers Squibb/Celgene, EMD Serona, Genzyme, Hoffmann-La Roche, Immunic Therapeutics, Janssen Pharmaceuticals, MedDay, Merck, Mylan, Nervgen, Neuraxpharm, Novartis, PeerVoice, Samsung-Biosys Sandoz Sanofi-Genzyme, Teva Pharmaceuticals, TG Therapeutics, EXCEMED, ECTRIMS, MSIF, and NMSS or any of their affiliates. Dr. Moccia reports receiving a salary from University of Naples, Policlinico University Hospital (Naples) and Neurology (US); research grants from MUR PNRR Extended Partnership, ECTRIMS-MAGNIMS, UK MS Society, and Merck; honoraria from AbbVie, Biogen, BMS Celgene, Ipsen, Jansen, Merck, Novartis, Roche, and Sanofi-Genzyme. 

A version of this article appeared on Medscape.com.

COPENHAGEN — A higher cumulative genetic burden for depression is associated with an increased risk for relapse and worsening disability in people with multiple sclerosis (MS), early results of a new study showed.

Unlike the previous research, the current analysis used polygenic risk scores for depression, which summarize the estimated effect of genetic variants to determine the potential association with MS disease activity, so results are less likely to be explained by reverse causality.

This study increases awareness of the link between depression and MS, said study investigator Kaarina Kowalec, PhD, assistant professor, College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. “We’re starting to understand how depression affects relapses and disability progression in MS,” she said.

The findings were presented at the 2024 ECTRIMS annual meeting.
 

Common Comorbidity

Depression is a common comorbidity in patients with MS and is associated with increased relapse and disability progression. Depression risk is partly polygenic in nature, involving numerous common genetic variants, said Dr. Kowalec.

The case-control study included 3420 relapsing-onset MS cases of European ancestry from four existing cohorts in three countries.

The Canadian cohort included those enrolled in a prospective longitudinal study of psychiatric comorbidity in chronic immune-mediated inflammatory disease (IMID), including MS; the Swedish cohort was an MS registry (SSReg) that encompasses 64 MS clinics (the cohort was split into two groups); and the US cohort was enrolled in a clinical trial of combined therapy with interferon and glatiramer acetate (CombiRx) in patients with MS.

The median follow-up in these cohorts ranged from 3 to 5 years.

Not surprisingly, most participants were women (from 71% in one of the Swedish cohorts to 83% in the Canadian cohort), and the age at MS onset ranged from 29 years in the Canadian cohort to 35 years in one of the Swedish cohorts.

The median baseline Expanded Disability Status Scale (EDSS) score was higher in the Canadian cohort (3.5) than in the Swedish (1.5) and US (2.0) cohorts, “reflective of the Canadian cohort being slightly more progressed,” said Dr. Kowalec.
 

Inherited Variants

To measure depression heritability, researchers generated a polygenic risk score in whole-genome imputed genotypes. The score reflects the number of inherited common genetic variants, weighted by effect sizes.

Researchers investigated the association between depression polygenic risk scores (top 20% vs. bottom 80%) with annualized relapse rate and worsening disability in MS measured by the rate of change in EDSS score. In the US cohort, they also explored the association between depression polygenic risk scores and time to relapse and confirmed EDSS worsening.

Covariates included use of disease-modifying therapy, age, sex, and the first five genetic ancestry principal components. The latter was done to capture residual stratification by genetic ancestry, although Dr. Kowalec stressed analyses were done only in those of European ancestry.

Investigators found a higher depression polygenic risk score was associated with relapse risk (incident rate ratio, 1.23; 95% CI, 1.01-1.49).

“Essentially, for every one standard deviation increase in the depression polygenic score, we found a significant increased hazard of 23% for experiencing a relapse over the follow-up period,” said Dr. Kowalec, who is also affiliated with the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

She noted the Canadian cohort did not have many relapses, while the US and Swedish cohorts “had an increased rate.”

Other analyses examined the risk of having a relapse or worsening disability. Every one SD increase in the depression polygenic risk score was significantly associated with a 2.2 greater risk of experiencing relapse (hazard ratio [HR], 2.20; 95% CI, 1.35-3.60) and a 51% increased risk for confirmed EDSS progression (HR, 1.51; 95% CI, 1.03-2.22).
 

‘An Ideal Marker’

Use of polygenetic risk scores reduces the possibility of reverse causation, noted Dr. Kowalec. “These markers are fixed at birth and don’t change over your lifespan, so they’re really an ideal marker.”

The results suggest polygenetic risk scores represent a potential biomarker for risk stratification in people with MS, said Dr. Kowalec. Although depression polygenic risk scores are not currently available in clinical practice, “I would hope this would change in the next 3-4 years,” she said.

Asked by a delegate if confounding by a third variable is possible, Dr. Kowalec said because genetic markers don’t change over time, there is a hint that the direction is causal and that depression is driving the outcome. However, she added, further confirmation is needed.

Dr. Kowalec noted that there were no data on antidepressant use but noted that about half of the Canadian and US cohorts — and likely the same number in the Swedish cohorts — self-reported depression.

A limitation of the study was that it included only participants of European ancestry.
 

Clinical Implications Unclear

Commenting on the research, Lauren Gluck, MD, program director, Montefiore Multiple Sclerosis Center, Bronx, New York, described the study as “fascinating” but noted that it’s unclear how to use this new information in clinical practice.

“Clinicians frequently ask people with MS about mood symptoms and offer interventions like antidepressants and referrals to therapists. However, genetic testing is not routine, so we don’t yet know who to target based on these data.”

Preexisting depression or more severe depression could be viewed as a “red flag” for risk for more disease activity in the future, she said.

“This could encourage clinicians to use more highly effective therapy in these patients, similar to our strategies for people with MS with frequent attacks and more disease burden on MRIs.”

The study received support from the Consortium of Multiple Sclerosis Centers and the Congressionally Directed Medical Research Programs, Department of Defense.

Dr. Kowalec reported no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

COPENHAGEN — A higher cumulative genetic burden for depression is associated with an increased risk for relapse and worsening disability in people with multiple sclerosis (MS), early results of a new study showed.

Unlike the previous research, the current analysis used polygenic risk scores for depression, which summarize the estimated effect of genetic variants to determine the potential association with MS disease activity, so results are less likely to be explained by reverse causality.

This study increases awareness of the link between depression and MS, said study investigator Kaarina Kowalec, PhD, assistant professor, College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. “We’re starting to understand how depression affects relapses and disability progression in MS,” she said.

The findings were presented at the 2024 ECTRIMS annual meeting.
 

Common Comorbidity

Depression is a common comorbidity in patients with MS and is associated with increased relapse and disability progression. Depression risk is partly polygenic in nature, involving numerous common genetic variants, said Dr. Kowalec.

The case-control study included 3420 relapsing-onset MS cases of European ancestry from four existing cohorts in three countries.

The Canadian cohort included those enrolled in a prospective longitudinal study of psychiatric comorbidity in chronic immune-mediated inflammatory disease (IMID), including MS; the Swedish cohort was an MS registry (SSReg) that encompasses 64 MS clinics (the cohort was split into two groups); and the US cohort was enrolled in a clinical trial of combined therapy with interferon and glatiramer acetate (CombiRx) in patients with MS.

The median follow-up in these cohorts ranged from 3 to 5 years.

Not surprisingly, most participants were women (from 71% in one of the Swedish cohorts to 83% in the Canadian cohort), and the age at MS onset ranged from 29 years in the Canadian cohort to 35 years in one of the Swedish cohorts.

The median baseline Expanded Disability Status Scale (EDSS) score was higher in the Canadian cohort (3.5) than in the Swedish (1.5) and US (2.0) cohorts, “reflective of the Canadian cohort being slightly more progressed,” said Dr. Kowalec.
 

Inherited Variants

To measure depression heritability, researchers generated a polygenic risk score in whole-genome imputed genotypes. The score reflects the number of inherited common genetic variants, weighted by effect sizes.

Researchers investigated the association between depression polygenic risk scores (top 20% vs. bottom 80%) with annualized relapse rate and worsening disability in MS measured by the rate of change in EDSS score. In the US cohort, they also explored the association between depression polygenic risk scores and time to relapse and confirmed EDSS worsening.

Covariates included use of disease-modifying therapy, age, sex, and the first five genetic ancestry principal components. The latter was done to capture residual stratification by genetic ancestry, although Dr. Kowalec stressed analyses were done only in those of European ancestry.

Investigators found a higher depression polygenic risk score was associated with relapse risk (incident rate ratio, 1.23; 95% CI, 1.01-1.49).

“Essentially, for every one standard deviation increase in the depression polygenic score, we found a significant increased hazard of 23% for experiencing a relapse over the follow-up period,” said Dr. Kowalec, who is also affiliated with the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

She noted the Canadian cohort did not have many relapses, while the US and Swedish cohorts “had an increased rate.”

Other analyses examined the risk of having a relapse or worsening disability. Every one SD increase in the depression polygenic risk score was significantly associated with a 2.2 greater risk of experiencing relapse (hazard ratio [HR], 2.20; 95% CI, 1.35-3.60) and a 51% increased risk for confirmed EDSS progression (HR, 1.51; 95% CI, 1.03-2.22).
 

‘An Ideal Marker’

Use of polygenetic risk scores reduces the possibility of reverse causation, noted Dr. Kowalec. “These markers are fixed at birth and don’t change over your lifespan, so they’re really an ideal marker.”

The results suggest polygenetic risk scores represent a potential biomarker for risk stratification in people with MS, said Dr. Kowalec. Although depression polygenic risk scores are not currently available in clinical practice, “I would hope this would change in the next 3-4 years,” she said.

Asked by a delegate if confounding by a third variable is possible, Dr. Kowalec said because genetic markers don’t change over time, there is a hint that the direction is causal and that depression is driving the outcome. However, she added, further confirmation is needed.

Dr. Kowalec noted that there were no data on antidepressant use but noted that about half of the Canadian and US cohorts — and likely the same number in the Swedish cohorts — self-reported depression.

A limitation of the study was that it included only participants of European ancestry.
 

Clinical Implications Unclear

Commenting on the research, Lauren Gluck, MD, program director, Montefiore Multiple Sclerosis Center, Bronx, New York, described the study as “fascinating” but noted that it’s unclear how to use this new information in clinical practice.

“Clinicians frequently ask people with MS about mood symptoms and offer interventions like antidepressants and referrals to therapists. However, genetic testing is not routine, so we don’t yet know who to target based on these data.”

Preexisting depression or more severe depression could be viewed as a “red flag” for risk for more disease activity in the future, she said.

“This could encourage clinicians to use more highly effective therapy in these patients, similar to our strategies for people with MS with frequent attacks and more disease burden on MRIs.”

The study received support from the Consortium of Multiple Sclerosis Centers and the Congressionally Directed Medical Research Programs, Department of Defense.

Dr. Kowalec reported no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

COPENHAGEN — A higher cumulative genetic burden for depression is associated with an increased risk for relapse and worsening disability in people with multiple sclerosis (MS), early results of a new study showed.

Unlike the previous research, the current analysis used polygenic risk scores for depression, which summarize the estimated effect of genetic variants to determine the potential association with MS disease activity, so results are less likely to be explained by reverse causality.

This study increases awareness of the link between depression and MS, said study investigator Kaarina Kowalec, PhD, assistant professor, College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. “We’re starting to understand how depression affects relapses and disability progression in MS,” she said.

The findings were presented at the 2024 ECTRIMS annual meeting.
 

Common Comorbidity

Depression is a common comorbidity in patients with MS and is associated with increased relapse and disability progression. Depression risk is partly polygenic in nature, involving numerous common genetic variants, said Dr. Kowalec.

The case-control study included 3420 relapsing-onset MS cases of European ancestry from four existing cohorts in three countries.

The Canadian cohort included those enrolled in a prospective longitudinal study of psychiatric comorbidity in chronic immune-mediated inflammatory disease (IMID), including MS; the Swedish cohort was an MS registry (SSReg) that encompasses 64 MS clinics (the cohort was split into two groups); and the US cohort was enrolled in a clinical trial of combined therapy with interferon and glatiramer acetate (CombiRx) in patients with MS.

The median follow-up in these cohorts ranged from 3 to 5 years.

Not surprisingly, most participants were women (from 71% in one of the Swedish cohorts to 83% in the Canadian cohort), and the age at MS onset ranged from 29 years in the Canadian cohort to 35 years in one of the Swedish cohorts.

The median baseline Expanded Disability Status Scale (EDSS) score was higher in the Canadian cohort (3.5) than in the Swedish (1.5) and US (2.0) cohorts, “reflective of the Canadian cohort being slightly more progressed,” said Dr. Kowalec.
 

Inherited Variants

To measure depression heritability, researchers generated a polygenic risk score in whole-genome imputed genotypes. The score reflects the number of inherited common genetic variants, weighted by effect sizes.

Researchers investigated the association between depression polygenic risk scores (top 20% vs. bottom 80%) with annualized relapse rate and worsening disability in MS measured by the rate of change in EDSS score. In the US cohort, they also explored the association between depression polygenic risk scores and time to relapse and confirmed EDSS worsening.

Covariates included use of disease-modifying therapy, age, sex, and the first five genetic ancestry principal components. The latter was done to capture residual stratification by genetic ancestry, although Dr. Kowalec stressed analyses were done only in those of European ancestry.

Investigators found a higher depression polygenic risk score was associated with relapse risk (incident rate ratio, 1.23; 95% CI, 1.01-1.49).

“Essentially, for every one standard deviation increase in the depression polygenic score, we found a significant increased hazard of 23% for experiencing a relapse over the follow-up period,” said Dr. Kowalec, who is also affiliated with the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

She noted the Canadian cohort did not have many relapses, while the US and Swedish cohorts “had an increased rate.”

Other analyses examined the risk of having a relapse or worsening disability. Every one SD increase in the depression polygenic risk score was significantly associated with a 2.2 greater risk of experiencing relapse (hazard ratio [HR], 2.20; 95% CI, 1.35-3.60) and a 51% increased risk for confirmed EDSS progression (HR, 1.51; 95% CI, 1.03-2.22).
 

‘An Ideal Marker’

Use of polygenetic risk scores reduces the possibility of reverse causation, noted Dr. Kowalec. “These markers are fixed at birth and don’t change over your lifespan, so they’re really an ideal marker.”

The results suggest polygenetic risk scores represent a potential biomarker for risk stratification in people with MS, said Dr. Kowalec. Although depression polygenic risk scores are not currently available in clinical practice, “I would hope this would change in the next 3-4 years,” she said.

Asked by a delegate if confounding by a third variable is possible, Dr. Kowalec said because genetic markers don’t change over time, there is a hint that the direction is causal and that depression is driving the outcome. However, she added, further confirmation is needed.

Dr. Kowalec noted that there were no data on antidepressant use but noted that about half of the Canadian and US cohorts — and likely the same number in the Swedish cohorts — self-reported depression.

A limitation of the study was that it included only participants of European ancestry.
 

Clinical Implications Unclear

Commenting on the research, Lauren Gluck, MD, program director, Montefiore Multiple Sclerosis Center, Bronx, New York, described the study as “fascinating” but noted that it’s unclear how to use this new information in clinical practice.

“Clinicians frequently ask people with MS about mood symptoms and offer interventions like antidepressants and referrals to therapists. However, genetic testing is not routine, so we don’t yet know who to target based on these data.”

Preexisting depression or more severe depression could be viewed as a “red flag” for risk for more disease activity in the future, she said.

“This could encourage clinicians to use more highly effective therapy in these patients, similar to our strategies for people with MS with frequent attacks and more disease burden on MRIs.”

The study received support from the Consortium of Multiple Sclerosis Centers and the Congressionally Directed Medical Research Programs, Department of Defense.

Dr. Kowalec reported no relevant conflicts of interest.
 

A version of this article appeared on Medscape.com.

As a psychiatrist specializing in eating disorders, Kim Dennis, MD, has seen firsthand the complex relationship between obesity treatment and mental health in adolescents.

Now, with the rising popularity of medications like Ozempic for weight loss, she fears she will care for more teens with eating disorders who are seeking glucagon-like peptide 1 (GLP-1) agonists or who have developed a disorder while taking them.

“We haven’t seen patients yet, but I’m sure they are on their way,” said Dr. Dennis, a clinical assistant professor in the Department of Psychiatry at the University of Illinois College of Medicine in Chicago. She is also the cofounder and chief medical officer of SunCloud Health, an outpatient eating disorder treatment center in Illinois.

Dr. Dennis’ concerns reflect a growing unease among eating disorder specialists as obesity medications gain traction for adolescent use. A recent study published in JAMA Pediatrics showed nearly 80% of teens in treatment for obesity reported symptoms of disordered eating at the outset of an intervention. These included signs of binge eating and loss of control.

The randomized clinical trial, conducted from 2018 to 2023, examined 141 adolescents with obesity undergoing interventions like low-energy diets or intermittent energy restriction. Almost half scored as having risk for an undiagnosed eating disorder, as defined by the Eating Disorder Examination Questionnaire (EDE-Q).

At the end of the intervention, many teens continued to have symptoms of disordered eating, while a smaller group was newly scored as having a risk for an eating disorder.
 

Weight Loss and Eating Disorders: A Balancing Act

The findings illuminate a significant challenge for pediatricians and primary care clinicians: Balancing effective weight management with the risk of exacerbating or triggering eating disorders, said Hiba Jebeile, PhD, a research dietitian at The Children’s Hospital at Westmead in Australia, and the study’s lead author. Adding weight loss medication on top of the equation can further complicate care.

“It is helpful for obesity and eating disorder services to work together, with clear referral pathways, to manage these adolescents,” Dr. Jebeile said.

The US Food and Drug Administration approved semaglutide for weight loss in adolescents aged 12-17 years in December 2020. One study found that the number of adolescents prescribed GLP-1 receptor agonists (GLP-1 RAs) for type 2 diabetes and weight management rose from 8722 to 60,567 between 2020 and 2023 — a nearly sevenfold increase.

“The number of adolescents taking these medications is going up because they work,” said Suzanne Cuda, MD, medical director of Alamo City Healthy Kids and Families, a medical weight management clinic in San Antonio. The medications have been shown to treat type 2 diabetes, lower blood pressure, and reduce the risk for cardiovascular diseases.

“The younger you are, the better the outcome,” Dr. Cuda said.

How GLP-1 agonists may affect adolescents in the long run is not yet clear. Existing studies on GLP-1 medications in patients with eating disorders have shown mixed results. Some studies indicate that the drugs decrease binge episodes for those with binge eating disorder or bulimia nervosa. However, these studies had small sample sizes and measured only short-term effects, leaving long-term outcomes and risks unknown.

Traditional treatments for eating disorders emphasize regular eating patterns, body acceptance, addressing weight stigma, and improving attunement to hunger and fullness cues — approaches that may conflict with the effects of GLP-1 agonists. These drugs suppress appetite, alter metabolic signals, and may unintentionally reinforce weight loss as a primary goal, creating a potential disconnect between the aims of recovery from eating disorders and the biologic effects of the medication, experts said.

Dr. Cuda said she has cared for adolescents with diagnosed eating disorders in her practice who are seeking GLP-1 agonists. She said she first works with patients to treat the underlying disorder before prescribing medication.

“One of the concerns is the extreme reductions in calories that could be induced by GLP-1 RA in children and adolescents,” she said. Unlike adults, adolescents use caloric energy not just for physical activity but also for growing and developing, she said.

“They can’t catch up on that growth and development,” she added.
 

Advice for Screening and Monitoring

The National Eating Disorders Association raised concerns about the potential misuse of these medications and their potential to exacerbate eating disorder behaviors in people who are already at a higher risk of developing one of the conditions, including those with existing mental health disorders, stress, who have already dieted, and who have experienced weight-centric bullying.

Clinicians should be on the lookout for patients seeking GLP-1s who present with symptoms of an eating disorder that may be less apparent, such as picky eating, insomnia or difficulty sleeping, or, for girls, irregular menstrual periods, Dr. Dennis said. These patients may be more likely to go undiagnosed or misdiagnosed. Research also suggests that people of color are less likely to be diagnosed or receive specialty care for eating disorders.

Discussions between patients and clinicians about obesity treatment prior to prescribing provide a crucial opportunity to screen and monitor for disordered eating, which Dr. Dennis said does not universally occur currently.

Dr. Dennis recommended initial assessments using validated screening tools like the EDE-Q and the Center for Epidemiologic Studies Depression Scale Revised, 10-Item Version.

Ongoing monitoring throughout treatment is essential, with initial monthly check-ins that include dietary counseling to detect subtle changes in eating behaviors or attitudes toward food and body image, Dr. Cuda said.

The Obesity Medicine Association (OMA) has stressed the importance of a collaborative approach involving connections with mental health professionals specializing in eating disorders and dietitians.

“If you have a chance to send them to an obesity medicine specialist, you should do that,” said Dr. Cuda, who coauthored the OMA statement. “It’s impractical to expect a primary care physician to do everything: Screen for dietary disorders, do a full dietary counseling, follow up on their activity.”

For patients showing signs of disordered eating, clinicians should avoid recommending restrictive dietary approaches, like cutting out food groups such as carbohydrates or a restricted calorie goal. Instead, they can suggest focusing on healthier lifestyle habits and referring to a psychotherapist, the experts said. Clinicians also should be prepared to adjust or pause GLP-1 agonists if disordered eating disorder symptoms worsen.

“I think a weight-agnostic approach where the focus of care is not weight loss but increase in health protective behaviors and nutritional intake is safest for all kids, especially those with eating disorders or eating disorder risk factors,” Dr. Dennis said.

Various authors of the eating disorder study reported receiving grants, advisory board fees, and speaker fees from entities including the National Health and Medical Research Council of Australia, Eli Lilly, Novo Nordisk, Nu-Mega Ingredients, and the National Institutes of Health, among others.
 

A version of this article appeared on Medscape.com.

As a psychiatrist specializing in eating disorders, Kim Dennis, MD, has seen firsthand the complex relationship between obesity treatment and mental health in adolescents.

Now, with the rising popularity of medications like Ozempic for weight loss, she fears she will care for more teens with eating disorders who are seeking glucagon-like peptide 1 (GLP-1) agonists or who have developed a disorder while taking them.

“We haven’t seen patients yet, but I’m sure they are on their way,” said Dr. Dennis, a clinical assistant professor in the Department of Psychiatry at the University of Illinois College of Medicine in Chicago. She is also the cofounder and chief medical officer of SunCloud Health, an outpatient eating disorder treatment center in Illinois.

Dr. Dennis’ concerns reflect a growing unease among eating disorder specialists as obesity medications gain traction for adolescent use. A recent study published in JAMA Pediatrics showed nearly 80% of teens in treatment for obesity reported symptoms of disordered eating at the outset of an intervention. These included signs of binge eating and loss of control.

The randomized clinical trial, conducted from 2018 to 2023, examined 141 adolescents with obesity undergoing interventions like low-energy diets or intermittent energy restriction. Almost half scored as having risk for an undiagnosed eating disorder, as defined by the Eating Disorder Examination Questionnaire (EDE-Q).

At the end of the intervention, many teens continued to have symptoms of disordered eating, while a smaller group was newly scored as having a risk for an eating disorder.
 

Weight Loss and Eating Disorders: A Balancing Act

The findings illuminate a significant challenge for pediatricians and primary care clinicians: Balancing effective weight management with the risk of exacerbating or triggering eating disorders, said Hiba Jebeile, PhD, a research dietitian at The Children’s Hospital at Westmead in Australia, and the study’s lead author. Adding weight loss medication on top of the equation can further complicate care.

“It is helpful for obesity and eating disorder services to work together, with clear referral pathways, to manage these adolescents,” Dr. Jebeile said.

The US Food and Drug Administration approved semaglutide for weight loss in adolescents aged 12-17 years in December 2020. One study found that the number of adolescents prescribed GLP-1 receptor agonists (GLP-1 RAs) for type 2 diabetes and weight management rose from 8722 to 60,567 between 2020 and 2023 — a nearly sevenfold increase.

“The number of adolescents taking these medications is going up because they work,” said Suzanne Cuda, MD, medical director of Alamo City Healthy Kids and Families, a medical weight management clinic in San Antonio. The medications have been shown to treat type 2 diabetes, lower blood pressure, and reduce the risk for cardiovascular diseases.

“The younger you are, the better the outcome,” Dr. Cuda said.

How GLP-1 agonists may affect adolescents in the long run is not yet clear. Existing studies on GLP-1 medications in patients with eating disorders have shown mixed results. Some studies indicate that the drugs decrease binge episodes for those with binge eating disorder or bulimia nervosa. However, these studies had small sample sizes and measured only short-term effects, leaving long-term outcomes and risks unknown.

Traditional treatments for eating disorders emphasize regular eating patterns, body acceptance, addressing weight stigma, and improving attunement to hunger and fullness cues — approaches that may conflict with the effects of GLP-1 agonists. These drugs suppress appetite, alter metabolic signals, and may unintentionally reinforce weight loss as a primary goal, creating a potential disconnect between the aims of recovery from eating disorders and the biologic effects of the medication, experts said.

Dr. Cuda said she has cared for adolescents with diagnosed eating disorders in her practice who are seeking GLP-1 agonists. She said she first works with patients to treat the underlying disorder before prescribing medication.

“One of the concerns is the extreme reductions in calories that could be induced by GLP-1 RA in children and adolescents,” she said. Unlike adults, adolescents use caloric energy not just for physical activity but also for growing and developing, she said.

“They can’t catch up on that growth and development,” she added.
 

Advice for Screening and Monitoring

The National Eating Disorders Association raised concerns about the potential misuse of these medications and their potential to exacerbate eating disorder behaviors in people who are already at a higher risk of developing one of the conditions, including those with existing mental health disorders, stress, who have already dieted, and who have experienced weight-centric bullying.

Clinicians should be on the lookout for patients seeking GLP-1s who present with symptoms of an eating disorder that may be less apparent, such as picky eating, insomnia or difficulty sleeping, or, for girls, irregular menstrual periods, Dr. Dennis said. These patients may be more likely to go undiagnosed or misdiagnosed. Research also suggests that people of color are less likely to be diagnosed or receive specialty care for eating disorders.

Discussions between patients and clinicians about obesity treatment prior to prescribing provide a crucial opportunity to screen and monitor for disordered eating, which Dr. Dennis said does not universally occur currently.

Dr. Dennis recommended initial assessments using validated screening tools like the EDE-Q and the Center for Epidemiologic Studies Depression Scale Revised, 10-Item Version.

Ongoing monitoring throughout treatment is essential, with initial monthly check-ins that include dietary counseling to detect subtle changes in eating behaviors or attitudes toward food and body image, Dr. Cuda said.

The Obesity Medicine Association (OMA) has stressed the importance of a collaborative approach involving connections with mental health professionals specializing in eating disorders and dietitians.

“If you have a chance to send them to an obesity medicine specialist, you should do that,” said Dr. Cuda, who coauthored the OMA statement. “It’s impractical to expect a primary care physician to do everything: Screen for dietary disorders, do a full dietary counseling, follow up on their activity.”

For patients showing signs of disordered eating, clinicians should avoid recommending restrictive dietary approaches, like cutting out food groups such as carbohydrates or a restricted calorie goal. Instead, they can suggest focusing on healthier lifestyle habits and referring to a psychotherapist, the experts said. Clinicians also should be prepared to adjust or pause GLP-1 agonists if disordered eating disorder symptoms worsen.

“I think a weight-agnostic approach where the focus of care is not weight loss but increase in health protective behaviors and nutritional intake is safest for all kids, especially those with eating disorders or eating disorder risk factors,” Dr. Dennis said.

Various authors of the eating disorder study reported receiving grants, advisory board fees, and speaker fees from entities including the National Health and Medical Research Council of Australia, Eli Lilly, Novo Nordisk, Nu-Mega Ingredients, and the National Institutes of Health, among others.
 

A version of this article appeared on Medscape.com.

As a psychiatrist specializing in eating disorders, Kim Dennis, MD, has seen firsthand the complex relationship between obesity treatment and mental health in adolescents.

Now, with the rising popularity of medications like Ozempic for weight loss, she fears she will care for more teens with eating disorders who are seeking glucagon-like peptide 1 (GLP-1) agonists or who have developed a disorder while taking them.

“We haven’t seen patients yet, but I’m sure they are on their way,” said Dr. Dennis, a clinical assistant professor in the Department of Psychiatry at the University of Illinois College of Medicine in Chicago. She is also the cofounder and chief medical officer of SunCloud Health, an outpatient eating disorder treatment center in Illinois.

Dr. Dennis’ concerns reflect a growing unease among eating disorder specialists as obesity medications gain traction for adolescent use. A recent study published in JAMA Pediatrics showed nearly 80% of teens in treatment for obesity reported symptoms of disordered eating at the outset of an intervention. These included signs of binge eating and loss of control.

The randomized clinical trial, conducted from 2018 to 2023, examined 141 adolescents with obesity undergoing interventions like low-energy diets or intermittent energy restriction. Almost half scored as having risk for an undiagnosed eating disorder, as defined by the Eating Disorder Examination Questionnaire (EDE-Q).

At the end of the intervention, many teens continued to have symptoms of disordered eating, while a smaller group was newly scored as having a risk for an eating disorder.
 

Weight Loss and Eating Disorders: A Balancing Act

The findings illuminate a significant challenge for pediatricians and primary care clinicians: Balancing effective weight management with the risk of exacerbating or triggering eating disorders, said Hiba Jebeile, PhD, a research dietitian at The Children’s Hospital at Westmead in Australia, and the study’s lead author. Adding weight loss medication on top of the equation can further complicate care.

“It is helpful for obesity and eating disorder services to work together, with clear referral pathways, to manage these adolescents,” Dr. Jebeile said.

The US Food and Drug Administration approved semaglutide for weight loss in adolescents aged 12-17 years in December 2020. One study found that the number of adolescents prescribed GLP-1 receptor agonists (GLP-1 RAs) for type 2 diabetes and weight management rose from 8722 to 60,567 between 2020 and 2023 — a nearly sevenfold increase.

“The number of adolescents taking these medications is going up because they work,” said Suzanne Cuda, MD, medical director of Alamo City Healthy Kids and Families, a medical weight management clinic in San Antonio. The medications have been shown to treat type 2 diabetes, lower blood pressure, and reduce the risk for cardiovascular diseases.

“The younger you are, the better the outcome,” Dr. Cuda said.

How GLP-1 agonists may affect adolescents in the long run is not yet clear. Existing studies on GLP-1 medications in patients with eating disorders have shown mixed results. Some studies indicate that the drugs decrease binge episodes for those with binge eating disorder or bulimia nervosa. However, these studies had small sample sizes and measured only short-term effects, leaving long-term outcomes and risks unknown.

Traditional treatments for eating disorders emphasize regular eating patterns, body acceptance, addressing weight stigma, and improving attunement to hunger and fullness cues — approaches that may conflict with the effects of GLP-1 agonists. These drugs suppress appetite, alter metabolic signals, and may unintentionally reinforce weight loss as a primary goal, creating a potential disconnect between the aims of recovery from eating disorders and the biologic effects of the medication, experts said.

Dr. Cuda said she has cared for adolescents with diagnosed eating disorders in her practice who are seeking GLP-1 agonists. She said she first works with patients to treat the underlying disorder before prescribing medication.

“One of the concerns is the extreme reductions in calories that could be induced by GLP-1 RA in children and adolescents,” she said. Unlike adults, adolescents use caloric energy not just for physical activity but also for growing and developing, she said.

“They can’t catch up on that growth and development,” she added.
 

Advice for Screening and Monitoring

The National Eating Disorders Association raised concerns about the potential misuse of these medications and their potential to exacerbate eating disorder behaviors in people who are already at a higher risk of developing one of the conditions, including those with existing mental health disorders, stress, who have already dieted, and who have experienced weight-centric bullying.

Clinicians should be on the lookout for patients seeking GLP-1s who present with symptoms of an eating disorder that may be less apparent, such as picky eating, insomnia or difficulty sleeping, or, for girls, irregular menstrual periods, Dr. Dennis said. These patients may be more likely to go undiagnosed or misdiagnosed. Research also suggests that people of color are less likely to be diagnosed or receive specialty care for eating disorders.

Discussions between patients and clinicians about obesity treatment prior to prescribing provide a crucial opportunity to screen and monitor for disordered eating, which Dr. Dennis said does not universally occur currently.

Dr. Dennis recommended initial assessments using validated screening tools like the EDE-Q and the Center for Epidemiologic Studies Depression Scale Revised, 10-Item Version.

Ongoing monitoring throughout treatment is essential, with initial monthly check-ins that include dietary counseling to detect subtle changes in eating behaviors or attitudes toward food and body image, Dr. Cuda said.

The Obesity Medicine Association (OMA) has stressed the importance of a collaborative approach involving connections with mental health professionals specializing in eating disorders and dietitians.

“If you have a chance to send them to an obesity medicine specialist, you should do that,” said Dr. Cuda, who coauthored the OMA statement. “It’s impractical to expect a primary care physician to do everything: Screen for dietary disorders, do a full dietary counseling, follow up on their activity.”

For patients showing signs of disordered eating, clinicians should avoid recommending restrictive dietary approaches, like cutting out food groups such as carbohydrates or a restricted calorie goal. Instead, they can suggest focusing on healthier lifestyle habits and referring to a psychotherapist, the experts said. Clinicians also should be prepared to adjust or pause GLP-1 agonists if disordered eating disorder symptoms worsen.

“I think a weight-agnostic approach where the focus of care is not weight loss but increase in health protective behaviors and nutritional intake is safest for all kids, especially those with eating disorders or eating disorder risk factors,” Dr. Dennis said.

Various authors of the eating disorder study reported receiving grants, advisory board fees, and speaker fees from entities including the National Health and Medical Research Council of Australia, Eli Lilly, Novo Nordisk, Nu-Mega Ingredients, and the National Institutes of Health, among others.
 

A version of this article appeared on Medscape.com.

In a review of 32 mixed-type human studies, multinational researchers found a growing association between various classes of environmental pollutants and the risk for inflammatory bowel disease (IBD).

The culprit environmental substances include heavy and transition metals, air pollutants, pesticides, and industrial contaminants. The latter encompass synthetic chemicals such as perfluoroalkyls and polyfluoroalkyls (PFAs), which are present in many common household products.

In contrast, zinc exposure may have a protective, anti-inflammatory effect, according to a research group led by Maria Manuela Estevinho, MD, of the Department of Gastroenterology of the Unidade Local de Saúde Gaia e Espinho in Vila Nova de Gaia, Portugal.

Published in Gut , the review also found limited data suggesting adverse IBD outcomes such as hospitalizations are more prevalent with increased exposure to air contaminants in particular.

“These data carry relevance toward counseling patients and family members,” coauthor Manasi Agrawal, MD, assistant professor of medicine at the Icahn School of Medicine, Mount Sinai, and a gastroenterologist at Mount Sinai Hospital in New York City, said in an interview. “At the individual level, we can try to decrease our exposure to chemicals; for example, to minimize use of pesticides and products containing in our homes. However, at the broader community level, health policy changes are needed to help with mitigation strategies and curb production.”

Icahn School of Medicine at Mount Sinai

• Heavy and transition metals such as copper, lead, and cadmium were associated with gut dysbiosis, overgrowth of undesirable species of microorganisms, and loss of tight junction proteins leading to leaky gut. In all studies, individuals with IBD showed higher concentrations of such metals than healthy control individuals. While the specific profile of heavy metals varied across studies, lead, copper, and iron, were linked to IBD risk in more than one study.
• The particulate matter present in air pollution — including agricultural and wood dust as well as volcanic ash and hydrocarbon dioxin — was linked to dysbiosis and tight junction protein loss. Air pollution has also been linked to increased incidence of irritable bowel syndrome.
• Industrial and organic pollutants such as perfluoroalkyl and polyfluoroalkyl compounds, triclocarban, and polychlorinated biphenyls were also associated with gut permeability and/or reduced microbial diversity.
• Pesticides such as PFAs, organochloride and organophosphate compounds, and pyrethroids were associated with loss of tight junction proteins.
• Zinc was linked to an increase in tight junction proteins.

Commenting on the review but not involved in it, Ashwin N. Ananthakrishnan, MBBS, MD, MPH, AGAF, director of the Crohn’s and Colitis Center at Massachusetts General Hospital, and associate professor at Harvard Medical School in Boston, called it a very important study that expands our understanding of the role of environment in IBD.

A version of this article appeared on Medscape.com.

In a review of 32 mixed-type human studies, multinational researchers found a growing association between various classes of environmental pollutants and the risk for inflammatory bowel disease (IBD).

The culprit environmental substances include heavy and transition metals, air pollutants, pesticides, and industrial contaminants. The latter encompass synthetic chemicals such as perfluoroalkyls and polyfluoroalkyls (PFAs), which are present in many common household products.

In contrast, zinc exposure may have a protective, anti-inflammatory effect, according to a research group led by Maria Manuela Estevinho, MD, of the Department of Gastroenterology of the Unidade Local de Saúde Gaia e Espinho in Vila Nova de Gaia, Portugal.

Published in Gut , the review also found limited data suggesting adverse IBD outcomes such as hospitalizations are more prevalent with increased exposure to air contaminants in particular.

“These data carry relevance toward counseling patients and family members,” coauthor Manasi Agrawal, MD, assistant professor of medicine at the Icahn School of Medicine, Mount Sinai, and a gastroenterologist at Mount Sinai Hospital in New York City, said in an interview. “At the individual level, we can try to decrease our exposure to chemicals; for example, to minimize use of pesticides and products containing in our homes. However, at the broader community level, health policy changes are needed to help with mitigation strategies and curb production.”

Icahn School of Medicine at Mount Sinai

• Heavy and transition metals such as copper, lead, and cadmium were associated with gut dysbiosis, overgrowth of undesirable species of microorganisms, and loss of tight junction proteins leading to leaky gut. In all studies, individuals with IBD showed higher concentrations of such metals than healthy control individuals. While the specific profile of heavy metals varied across studies, lead, copper, and iron, were linked to IBD risk in more than one study.
• The particulate matter present in air pollution — including agricultural and wood dust as well as volcanic ash and hydrocarbon dioxin — was linked to dysbiosis and tight junction protein loss. Air pollution has also been linked to increased incidence of irritable bowel syndrome.
• Industrial and organic pollutants such as perfluoroalkyl and polyfluoroalkyl compounds, triclocarban, and polychlorinated biphenyls were also associated with gut permeability and/or reduced microbial diversity.
• Pesticides such as PFAs, organochloride and organophosphate compounds, and pyrethroids were associated with loss of tight junction proteins.
• Zinc was linked to an increase in tight junction proteins.

Commenting on the review but not involved in it, Ashwin N. Ananthakrishnan, MBBS, MD, MPH, AGAF, director of the Crohn’s and Colitis Center at Massachusetts General Hospital, and associate professor at Harvard Medical School in Boston, called it a very important study that expands our understanding of the role of environment in IBD.

A version of this article appeared on Medscape.com.

In a review of 32 mixed-type human studies, multinational researchers found a growing association between various classes of environmental pollutants and the risk for inflammatory bowel disease (IBD).

The culprit environmental substances include heavy and transition metals, air pollutants, pesticides, and industrial contaminants. The latter encompass synthetic chemicals such as perfluoroalkyls and polyfluoroalkyls (PFAs), which are present in many common household products.

In contrast, zinc exposure may have a protective, anti-inflammatory effect, according to a research group led by Maria Manuela Estevinho, MD, of the Department of Gastroenterology of the Unidade Local de Saúde Gaia e Espinho in Vila Nova de Gaia, Portugal.

Published in Gut , the review also found limited data suggesting adverse IBD outcomes such as hospitalizations are more prevalent with increased exposure to air contaminants in particular.

“These data carry relevance toward counseling patients and family members,” coauthor Manasi Agrawal, MD, assistant professor of medicine at the Icahn School of Medicine, Mount Sinai, and a gastroenterologist at Mount Sinai Hospital in New York City, said in an interview. “At the individual level, we can try to decrease our exposure to chemicals; for example, to minimize use of pesticides and products containing in our homes. However, at the broader community level, health policy changes are needed to help with mitigation strategies and curb production.”

Icahn School of Medicine at Mount Sinai

• Heavy and transition metals such as copper, lead, and cadmium were associated with gut dysbiosis, overgrowth of undesirable species of microorganisms, and loss of tight junction proteins leading to leaky gut. In all studies, individuals with IBD showed higher concentrations of such metals than healthy control individuals. While the specific profile of heavy metals varied across studies, lead, copper, and iron, were linked to IBD risk in more than one study.
• The particulate matter present in air pollution — including agricultural and wood dust as well as volcanic ash and hydrocarbon dioxin — was linked to dysbiosis and tight junction protein loss. Air pollution has also been linked to increased incidence of irritable bowel syndrome.
• Industrial and organic pollutants such as perfluoroalkyl and polyfluoroalkyl compounds, triclocarban, and polychlorinated biphenyls were also associated with gut permeability and/or reduced microbial diversity.
• Pesticides such as PFAs, organochloride and organophosphate compounds, and pyrethroids were associated with loss of tight junction proteins.
• Zinc was linked to an increase in tight junction proteins.

Commenting on the review but not involved in it, Ashwin N. Ananthakrishnan, MBBS, MD, MPH, AGAF, director of the Crohn’s and Colitis Center at Massachusetts General Hospital, and associate professor at Harvard Medical School in Boston, called it a very important study that expands our understanding of the role of environment in IBD.

A version of this article appeared on Medscape.com.