Ted Bosworth

NEW YORK – A questionnaire-based screening tool appears to accelerate the time to diagnosis of axial involvement in patients presenting with psoriasis but no clinical signs of joint pain, according to a study called ATTRACT that was presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

The risk of a delayed diagnosis of an axial component in patients with psoriasis, meaning a delay in the underlying diagnosis of psoriatic arthritis (PsA), is substantial, according to Devis Benfaremo, MD, of the department of clinical and molecular science at Marche Polytechnic University, Ancona, Italy.

Ted Bosworth/MDedge News

There is “no consensus for the best strategy to achieve early detection of joint disease” in patients presenting with psoriasis, but Dr. Benfaremo pointed out that missing axial involvement is a particular problem because it is far more likely than swollen joints to be missed on clinical examination.

While about one in three patients with psoriasis have or will develop psoriatic arthritis, according to the National Psoriasis Foundation, delays in diagnosis are common, according to Dr. Benfaremo. In patients with undiagnosed PsA characterized by axial involvement alone, subtle symptoms can be overlooked or attributed to other causes.

There are several screening questionnaires to detect joint symptoms in patients presenting with psoriasis, such as the five-question Psoriasis Epidemiology Screening Tool, but the questionnaire tested in the ATTRACT trial is focused on detecting axial involvement specifically. It was characterized as the first to do so.

In the ongoing ATTRACT study, 253 patients with psoriasis but no history of PsA or axial disease have been enrolled so far. In the study, patients are screened for PsA based on a patient-completed yes-or-no questionnaire, which takes only a few minutes to complete.

“It is a validated questionnaire for axial [spondyloarthritis], but we have adopted it for detection of psoriasis patients with PsA,” Dr. Benfaremo explained.

The questionnaire for axial spondyloarthritis (axSpA) was initially evaluated and validated by Fabian Proft, MD, head of the clinical trials unit at Charité Hospital, Berlin. In addition to a patient self-completed questionnaire, Dr. Proft and coinvestigators have also created a related questionnaire to be administered by physicians.

In the ATTRACT study, patients completed the questionnaire on an electronic device in the waiting room. Positive answers to specific questions about symptoms, which addressed back pain and joint function as well as joint symptoms, divided patients into three groups:

• Group A patients did not respond positively to any of the symptom questions that would prompt suspicion of axial disease. These represented about one-third of those screened so far.
• Group B patients were those who answered positively to at least two questions that related to a high suspicion of axial involvement. These represented 45% of patients.
• The remaining patients were placed in Group C, a category of intermediate risk based on positive responses to some, but not all, questions relating to axial symptoms.

Those in group B are being referred to rheumatology. Patients in group C are given “conditional” eligibility based on the presence of additional risk factors.
 

AxSpA screening tool ‘makes sense’ for potential use in PsA

The primary outcome of the ATTRACT trial is early identification of axial PsA. Correctly identifying patients with or without peripheral joint involvement is one of several secondary outcomes. The identification of patients who fulfill Assessment Spondyloarthritis International Society (ASAS) criteria for axSpA is another secondary outcome.

Of the 114 patients placed in group B and analyzed so far, 87 have completed an assessment by a rheumatologist with laboratory analyses and imaging, as well as a clinical examination.

Of those 87 assessed by a rheumatologist, 17 did not have either axial or peripheral inflammation. Another 19 were diagnosed with axial disease, including 14 who met ASAS criteria. A total of 10 were classified as having PsA with peripheral inflammation, according to Classification for Psoriatic Arthritis criteria, and 41 are still being considered for a diagnosis of axial or peripheral PsA on the basis of further workup.

“Among the patients with axial PsA, only 10% had elevated C-reactive protein levels,” according to Dr. Benfaremo, echoing previous evidence that inflammatory biomarkers by themselves have limited value for identifying psoriasis patients at high risk of joint involvement.

The findings are preliminary, but Dr. Benfaremo reported that the questionnaire is showing promise for the routine stratification of patients who should be considered for a rheumatology consultation.

If further analyses validate the clinical utility of these stratifications, there is the potential for a substantial acceleration to the diagnosis of PsA.

When contacted to comment about this work, Dr. Proft said that there is an important need for new strategies reduce delay in the diagnosis of PsA among patients presenting with psoriasis. He thinks the screening tool he developed for axSpA “makes sense” as a potential tool in PsA.

“If validated, this could be a very useful for earlier identification of PsA,” Dr. Proft said. He reiterated the importance of focusing on axial involvement.

“Previous screening tools have focused on symptoms of PsA more generally, but inflammation in the peripheral joints is something that you can easily see in most patients,” he said.

In addition to the patient-completed questionnaire and the physician-administered questionnaire, Dr. Proft has also evaluated an online self-referral tool for patients.

“If we can diagnose PsA earlier in the course of disease, we can start treatment earlier, prevent or delay joint damage, and potentially improve outcomes for patients,” Dr. Proft said. He considers this an important direction of research.

Dr. Benfaremo and Dr. Proft reported no potential conflicts of interest.

NEW YORK – A questionnaire-based screening tool appears to accelerate the time to diagnosis of axial involvement in patients presenting with psoriasis but no clinical signs of joint pain, according to a study called ATTRACT that was presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

The risk of a delayed diagnosis of an axial component in patients with psoriasis, meaning a delay in the underlying diagnosis of psoriatic arthritis (PsA), is substantial, according to Devis Benfaremo, MD, of the department of clinical and molecular science at Marche Polytechnic University, Ancona, Italy.

Ted Bosworth/MDedge News

There is “no consensus for the best strategy to achieve early detection of joint disease” in patients presenting with psoriasis, but Dr. Benfaremo pointed out that missing axial involvement is a particular problem because it is far more likely than swollen joints to be missed on clinical examination.

While about one in three patients with psoriasis have or will develop psoriatic arthritis, according to the National Psoriasis Foundation, delays in diagnosis are common, according to Dr. Benfaremo. In patients with undiagnosed PsA characterized by axial involvement alone, subtle symptoms can be overlooked or attributed to other causes.

There are several screening questionnaires to detect joint symptoms in patients presenting with psoriasis, such as the five-question Psoriasis Epidemiology Screening Tool, but the questionnaire tested in the ATTRACT trial is focused on detecting axial involvement specifically. It was characterized as the first to do so.

In the ongoing ATTRACT study, 253 patients with psoriasis but no history of PsA or axial disease have been enrolled so far. In the study, patients are screened for PsA based on a patient-completed yes-or-no questionnaire, which takes only a few minutes to complete.

“It is a validated questionnaire for axial [spondyloarthritis], but we have adopted it for detection of psoriasis patients with PsA,” Dr. Benfaremo explained.

The questionnaire for axial spondyloarthritis (axSpA) was initially evaluated and validated by Fabian Proft, MD, head of the clinical trials unit at Charité Hospital, Berlin. In addition to a patient self-completed questionnaire, Dr. Proft and coinvestigators have also created a related questionnaire to be administered by physicians.

In the ATTRACT study, patients completed the questionnaire on an electronic device in the waiting room. Positive answers to specific questions about symptoms, which addressed back pain and joint function as well as joint symptoms, divided patients into three groups:

• Group A patients did not respond positively to any of the symptom questions that would prompt suspicion of axial disease. These represented about one-third of those screened so far.
• Group B patients were those who answered positively to at least two questions that related to a high suspicion of axial involvement. These represented 45% of patients.
• The remaining patients were placed in Group C, a category of intermediate risk based on positive responses to some, but not all, questions relating to axial symptoms.

Those in group B are being referred to rheumatology. Patients in group C are given “conditional” eligibility based on the presence of additional risk factors.
 

AxSpA screening tool ‘makes sense’ for potential use in PsA

The primary outcome of the ATTRACT trial is early identification of axial PsA. Correctly identifying patients with or without peripheral joint involvement is one of several secondary outcomes. The identification of patients who fulfill Assessment Spondyloarthritis International Society (ASAS) criteria for axSpA is another secondary outcome.

Of the 114 patients placed in group B and analyzed so far, 87 have completed an assessment by a rheumatologist with laboratory analyses and imaging, as well as a clinical examination.

Of those 87 assessed by a rheumatologist, 17 did not have either axial or peripheral inflammation. Another 19 were diagnosed with axial disease, including 14 who met ASAS criteria. A total of 10 were classified as having PsA with peripheral inflammation, according to Classification for Psoriatic Arthritis criteria, and 41 are still being considered for a diagnosis of axial or peripheral PsA on the basis of further workup.

“Among the patients with axial PsA, only 10% had elevated C-reactive protein levels,” according to Dr. Benfaremo, echoing previous evidence that inflammatory biomarkers by themselves have limited value for identifying psoriasis patients at high risk of joint involvement.

The findings are preliminary, but Dr. Benfaremo reported that the questionnaire is showing promise for the routine stratification of patients who should be considered for a rheumatology consultation.

If further analyses validate the clinical utility of these stratifications, there is the potential for a substantial acceleration to the diagnosis of PsA.

When contacted to comment about this work, Dr. Proft said that there is an important need for new strategies reduce delay in the diagnosis of PsA among patients presenting with psoriasis. He thinks the screening tool he developed for axSpA “makes sense” as a potential tool in PsA.

“If validated, this could be a very useful for earlier identification of PsA,” Dr. Proft said. He reiterated the importance of focusing on axial involvement.

“Previous screening tools have focused on symptoms of PsA more generally, but inflammation in the peripheral joints is something that you can easily see in most patients,” he said.

In addition to the patient-completed questionnaire and the physician-administered questionnaire, Dr. Proft has also evaluated an online self-referral tool for patients.

“If we can diagnose PsA earlier in the course of disease, we can start treatment earlier, prevent or delay joint damage, and potentially improve outcomes for patients,” Dr. Proft said. He considers this an important direction of research.

Dr. Benfaremo and Dr. Proft reported no potential conflicts of interest.

NEW YORK – A questionnaire-based screening tool appears to accelerate the time to diagnosis of axial involvement in patients presenting with psoriasis but no clinical signs of joint pain, according to a study called ATTRACT that was presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

The risk of a delayed diagnosis of an axial component in patients with psoriasis, meaning a delay in the underlying diagnosis of psoriatic arthritis (PsA), is substantial, according to Devis Benfaremo, MD, of the department of clinical and molecular science at Marche Polytechnic University, Ancona, Italy.

Ted Bosworth/MDedge News

There is “no consensus for the best strategy to achieve early detection of joint disease” in patients presenting with psoriasis, but Dr. Benfaremo pointed out that missing axial involvement is a particular problem because it is far more likely than swollen joints to be missed on clinical examination.

While about one in three patients with psoriasis have or will develop psoriatic arthritis, according to the National Psoriasis Foundation, delays in diagnosis are common, according to Dr. Benfaremo. In patients with undiagnosed PsA characterized by axial involvement alone, subtle symptoms can be overlooked or attributed to other causes.

There are several screening questionnaires to detect joint symptoms in patients presenting with psoriasis, such as the five-question Psoriasis Epidemiology Screening Tool, but the questionnaire tested in the ATTRACT trial is focused on detecting axial involvement specifically. It was characterized as the first to do so.

In the ongoing ATTRACT study, 253 patients with psoriasis but no history of PsA or axial disease have been enrolled so far. In the study, patients are screened for PsA based on a patient-completed yes-or-no questionnaire, which takes only a few minutes to complete.

“It is a validated questionnaire for axial [spondyloarthritis], but we have adopted it for detection of psoriasis patients with PsA,” Dr. Benfaremo explained.

The questionnaire for axial spondyloarthritis (axSpA) was initially evaluated and validated by Fabian Proft, MD, head of the clinical trials unit at Charité Hospital, Berlin. In addition to a patient self-completed questionnaire, Dr. Proft and coinvestigators have also created a related questionnaire to be administered by physicians.

In the ATTRACT study, patients completed the questionnaire on an electronic device in the waiting room. Positive answers to specific questions about symptoms, which addressed back pain and joint function as well as joint symptoms, divided patients into three groups:

• Group A patients did not respond positively to any of the symptom questions that would prompt suspicion of axial disease. These represented about one-third of those screened so far.
• Group B patients were those who answered positively to at least two questions that related to a high suspicion of axial involvement. These represented 45% of patients.
• The remaining patients were placed in Group C, a category of intermediate risk based on positive responses to some, but not all, questions relating to axial symptoms.

Those in group B are being referred to rheumatology. Patients in group C are given “conditional” eligibility based on the presence of additional risk factors.
 

AxSpA screening tool ‘makes sense’ for potential use in PsA

The primary outcome of the ATTRACT trial is early identification of axial PsA. Correctly identifying patients with or without peripheral joint involvement is one of several secondary outcomes. The identification of patients who fulfill Assessment Spondyloarthritis International Society (ASAS) criteria for axSpA is another secondary outcome.

Of the 114 patients placed in group B and analyzed so far, 87 have completed an assessment by a rheumatologist with laboratory analyses and imaging, as well as a clinical examination.

Of those 87 assessed by a rheumatologist, 17 did not have either axial or peripheral inflammation. Another 19 were diagnosed with axial disease, including 14 who met ASAS criteria. A total of 10 were classified as having PsA with peripheral inflammation, according to Classification for Psoriatic Arthritis criteria, and 41 are still being considered for a diagnosis of axial or peripheral PsA on the basis of further workup.

“Among the patients with axial PsA, only 10% had elevated C-reactive protein levels,” according to Dr. Benfaremo, echoing previous evidence that inflammatory biomarkers by themselves have limited value for identifying psoriasis patients at high risk of joint involvement.

The findings are preliminary, but Dr. Benfaremo reported that the questionnaire is showing promise for the routine stratification of patients who should be considered for a rheumatology consultation.

If further analyses validate the clinical utility of these stratifications, there is the potential for a substantial acceleration to the diagnosis of PsA.

When contacted to comment about this work, Dr. Proft said that there is an important need for new strategies reduce delay in the diagnosis of PsA among patients presenting with psoriasis. He thinks the screening tool he developed for axSpA “makes sense” as a potential tool in PsA.

“If validated, this could be a very useful for earlier identification of PsA,” Dr. Proft said. He reiterated the importance of focusing on axial involvement.

“Previous screening tools have focused on symptoms of PsA more generally, but inflammation in the peripheral joints is something that you can easily see in most patients,” he said.

In addition to the patient-completed questionnaire and the physician-administered questionnaire, Dr. Proft has also evaluated an online self-referral tool for patients.

“If we can diagnose PsA earlier in the course of disease, we can start treatment earlier, prevent or delay joint damage, and potentially improve outcomes for patients,” Dr. Proft said. He considers this an important direction of research.

Dr. Benfaremo and Dr. Proft reported no potential conflicts of interest.

NEW YORK – Patients with chronic plaque psoriasis face a nearly twofold increased risk of nonalcoholic fatty liver disease (NAFLD), and the risk climbs higher in those with more severe skin involvement – and probably in those with psoriatic arthritis (PsA) as well, according to a systematic review and meta-analysis presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

“Our findings imply that psoriatic patients should be screened with an ultrasonographic exam in cases where there are metabolic features that are associated with NAFLD,” reported Francesco Bellinato, MD, a researcher in the section of dermatology and venereology, University of Verona (Italy).

In the pooled data, the risk of NAFLD among those with psoriasis relative to healthy controls fell just short of a twofold increase (odds ratio, 1.96; 95% CI, 1.70-2.26; P < .001). When stratified by studies that confirmed NAFLD by biopsy relative to ultrasonography, there was no significant heterogeneity.

Eight of the studies included an analysis of relative risk in the context of skin lesion severity defined by Psoriasis Area and Severity Index (PASI) score. Relative to those without NAFLD, psoriatic patients with NAFLD had a significant greater mean PASI score on a pooled weighted mean difference analysis (OR, 3.93; 95% CI, 2.01-5.84; P < .0001).

courtesy Dr. Francesco Belinato

For PsA relative to no PsA in the five studies that compared risk between these two groups, the risk of NAFLD was again nearly twofold higher. This fell short of conventional definition of statistical significance, but it was associated with a strong trend (OR, 1.83; 95% CI, 0.98-3.43; P = .06).

The risk of NAFLD among patients with psoriasis was not found to vary significantly when assessed by univariable meta-regressions across numerous characteristics, such as sex and body mass index.

In one of the largest of the observational studies included in the meta-analysis by Alexis Ogdie, MD, associate professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia, and colleagues, data were analyzed in more than 1.5 million patients, which included 54,251 patients with rheumatoid arthritis. While the hazard ratio of NAFLD was increased for both psoriasis (HR, 2.23) and PsA (HR, 2.11), it was not elevated in those with RA (HR, 0.96).

Risk by severity, possible mechanisms

This study also included an analysis of NAFLD risk according to psoriasis severity. While risk was still significant among those with mild disease (HR, 1.18; 95% CI, 1.07-1.30), it was almost twofold greater in those with moderate to severe psoriasis (HR, 2.23; 95% CI, 1.73-2.87).

Dr. Bellinato conceded that the mechanisms underlying the association between psoriasis and NAFLD are unknown, but he said “metaflammation” is suspected.

“The secretion of proinflammatory, prothrombotic, and oxidative stress mediators in both psoriatic skin and adipose tissue might act systemically and promote insulin resistance and other metabolic derangements that promote the development and progression of NAFLD,” Dr. Bellinato explained.

He thinks that noninvasive screening methods, such as currently used methods to calculate fibrosis score, might be useful for evaluating patients with psoriasis for NAFLD and referring them to a hepatologist when appropriate.

Given the strong association with NAFLD, Dr. Bellinato suggested that “the findings of this meta-analysis pave the way for novel, large, prospective, and histologically based studies.”

Courtesy Dr. Joel M. Gelfand

The association between psoriasis and NAFLD is clinically relevant, agreed Joel M. Gelfand, MD, vice-chair of clinical research and medical director of the clinical studies unit, department of dermatology, University of Pennsylvania, Philadelphia.

“It is not clear if psoriasis causes fatty liver disease or vice versa, but clinicians should be aware of this association,” he said in an interview. Dr. Gelfand was a coauthor of the study by Dr. Ogdie and colleagues and led another more recent population-based study that implicated methotrexate as a factor in psoriasis-related hepatotoxicity.

If NAFLD is identified in a patient with psoriasis, treatments are limited, but Dr. Gelfand suggested that patients should be made aware of the risk. “Clinicians should encourage patients with psoriasis to take measures to protect their liver, such as avoiding drinking alcohol to excess and trying to maintain a healthy body weight,” he said.

Dr. Bellinato reported no conflicts of interest. Dr. Gelfand has financial relationships with more than 10 pharmaceutical companies, including those that make therapies for psoriasis.

NEW YORK – Patients with chronic plaque psoriasis face a nearly twofold increased risk of nonalcoholic fatty liver disease (NAFLD), and the risk climbs higher in those with more severe skin involvement – and probably in those with psoriatic arthritis (PsA) as well, according to a systematic review and meta-analysis presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

“Our findings imply that psoriatic patients should be screened with an ultrasonographic exam in cases where there are metabolic features that are associated with NAFLD,” reported Francesco Bellinato, MD, a researcher in the section of dermatology and venereology, University of Verona (Italy).

In the pooled data, the risk of NAFLD among those with psoriasis relative to healthy controls fell just short of a twofold increase (odds ratio, 1.96; 95% CI, 1.70-2.26; P < .001). When stratified by studies that confirmed NAFLD by biopsy relative to ultrasonography, there was no significant heterogeneity.

Eight of the studies included an analysis of relative risk in the context of skin lesion severity defined by Psoriasis Area and Severity Index (PASI) score. Relative to those without NAFLD, psoriatic patients with NAFLD had a significant greater mean PASI score on a pooled weighted mean difference analysis (OR, 3.93; 95% CI, 2.01-5.84; P < .0001).

courtesy Dr. Francesco Belinato

For PsA relative to no PsA in the five studies that compared risk between these two groups, the risk of NAFLD was again nearly twofold higher. This fell short of conventional definition of statistical significance, but it was associated with a strong trend (OR, 1.83; 95% CI, 0.98-3.43; P = .06).

The risk of NAFLD among patients with psoriasis was not found to vary significantly when assessed by univariable meta-regressions across numerous characteristics, such as sex and body mass index.

In one of the largest of the observational studies included in the meta-analysis by Alexis Ogdie, MD, associate professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia, and colleagues, data were analyzed in more than 1.5 million patients, which included 54,251 patients with rheumatoid arthritis. While the hazard ratio of NAFLD was increased for both psoriasis (HR, 2.23) and PsA (HR, 2.11), it was not elevated in those with RA (HR, 0.96).

Risk by severity, possible mechanisms

This study also included an analysis of NAFLD risk according to psoriasis severity. While risk was still significant among those with mild disease (HR, 1.18; 95% CI, 1.07-1.30), it was almost twofold greater in those with moderate to severe psoriasis (HR, 2.23; 95% CI, 1.73-2.87).

Dr. Bellinato conceded that the mechanisms underlying the association between psoriasis and NAFLD are unknown, but he said “metaflammation” is suspected.

“The secretion of proinflammatory, prothrombotic, and oxidative stress mediators in both psoriatic skin and adipose tissue might act systemically and promote insulin resistance and other metabolic derangements that promote the development and progression of NAFLD,” Dr. Bellinato explained.

He thinks that noninvasive screening methods, such as currently used methods to calculate fibrosis score, might be useful for evaluating patients with psoriasis for NAFLD and referring them to a hepatologist when appropriate.

Given the strong association with NAFLD, Dr. Bellinato suggested that “the findings of this meta-analysis pave the way for novel, large, prospective, and histologically based studies.”

Courtesy Dr. Joel M. Gelfand

The association between psoriasis and NAFLD is clinically relevant, agreed Joel M. Gelfand, MD, vice-chair of clinical research and medical director of the clinical studies unit, department of dermatology, University of Pennsylvania, Philadelphia.

“It is not clear if psoriasis causes fatty liver disease or vice versa, but clinicians should be aware of this association,” he said in an interview. Dr. Gelfand was a coauthor of the study by Dr. Ogdie and colleagues and led another more recent population-based study that implicated methotrexate as a factor in psoriasis-related hepatotoxicity.

If NAFLD is identified in a patient with psoriasis, treatments are limited, but Dr. Gelfand suggested that patients should be made aware of the risk. “Clinicians should encourage patients with psoriasis to take measures to protect their liver, such as avoiding drinking alcohol to excess and trying to maintain a healthy body weight,” he said.

Dr. Bellinato reported no conflicts of interest. Dr. Gelfand has financial relationships with more than 10 pharmaceutical companies, including those that make therapies for psoriasis.

NEW YORK – Patients with chronic plaque psoriasis face a nearly twofold increased risk of nonalcoholic fatty liver disease (NAFLD), and the risk climbs higher in those with more severe skin involvement – and probably in those with psoriatic arthritis (PsA) as well, according to a systematic review and meta-analysis presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

“Our findings imply that psoriatic patients should be screened with an ultrasonographic exam in cases where there are metabolic features that are associated with NAFLD,” reported Francesco Bellinato, MD, a researcher in the section of dermatology and venereology, University of Verona (Italy).

In the pooled data, the risk of NAFLD among those with psoriasis relative to healthy controls fell just short of a twofold increase (odds ratio, 1.96; 95% CI, 1.70-2.26; P < .001). When stratified by studies that confirmed NAFLD by biopsy relative to ultrasonography, there was no significant heterogeneity.

Eight of the studies included an analysis of relative risk in the context of skin lesion severity defined by Psoriasis Area and Severity Index (PASI) score. Relative to those without NAFLD, psoriatic patients with NAFLD had a significant greater mean PASI score on a pooled weighted mean difference analysis (OR, 3.93; 95% CI, 2.01-5.84; P < .0001).

courtesy Dr. Francesco Belinato

For PsA relative to no PsA in the five studies that compared risk between these two groups, the risk of NAFLD was again nearly twofold higher. This fell short of conventional definition of statistical significance, but it was associated with a strong trend (OR, 1.83; 95% CI, 0.98-3.43; P = .06).

The risk of NAFLD among patients with psoriasis was not found to vary significantly when assessed by univariable meta-regressions across numerous characteristics, such as sex and body mass index.

In one of the largest of the observational studies included in the meta-analysis by Alexis Ogdie, MD, associate professor of medicine and epidemiology at the University of Pennsylvania, Philadelphia, and colleagues, data were analyzed in more than 1.5 million patients, which included 54,251 patients with rheumatoid arthritis. While the hazard ratio of NAFLD was increased for both psoriasis (HR, 2.23) and PsA (HR, 2.11), it was not elevated in those with RA (HR, 0.96).

Risk by severity, possible mechanisms

This study also included an analysis of NAFLD risk according to psoriasis severity. While risk was still significant among those with mild disease (HR, 1.18; 95% CI, 1.07-1.30), it was almost twofold greater in those with moderate to severe psoriasis (HR, 2.23; 95% CI, 1.73-2.87).

Dr. Bellinato conceded that the mechanisms underlying the association between psoriasis and NAFLD are unknown, but he said “metaflammation” is suspected.

“The secretion of proinflammatory, prothrombotic, and oxidative stress mediators in both psoriatic skin and adipose tissue might act systemically and promote insulin resistance and other metabolic derangements that promote the development and progression of NAFLD,” Dr. Bellinato explained.

He thinks that noninvasive screening methods, such as currently used methods to calculate fibrosis score, might be useful for evaluating patients with psoriasis for NAFLD and referring them to a hepatologist when appropriate.

Given the strong association with NAFLD, Dr. Bellinato suggested that “the findings of this meta-analysis pave the way for novel, large, prospective, and histologically based studies.”

Courtesy Dr. Joel M. Gelfand

The association between psoriasis and NAFLD is clinically relevant, agreed Joel M. Gelfand, MD, vice-chair of clinical research and medical director of the clinical studies unit, department of dermatology, University of Pennsylvania, Philadelphia.

“It is not clear if psoriasis causes fatty liver disease or vice versa, but clinicians should be aware of this association,” he said in an interview. Dr. Gelfand was a coauthor of the study by Dr. Ogdie and colleagues and led another more recent population-based study that implicated methotrexate as a factor in psoriasis-related hepatotoxicity.

If NAFLD is identified in a patient with psoriasis, treatments are limited, but Dr. Gelfand suggested that patients should be made aware of the risk. “Clinicians should encourage patients with psoriasis to take measures to protect their liver, such as avoiding drinking alcohol to excess and trying to maintain a healthy body weight,” he said.

Dr. Bellinato reported no conflicts of interest. Dr. Gelfand has financial relationships with more than 10 pharmaceutical companies, including those that make therapies for psoriasis.

NEW YORK – On the basis of MRI images of the hand, a neural network has been trained to distinguish seronegative and seropositive rheumatoid arthritis (RA) from psoriatic arthritis (PsA) as well as from each other, according to a study that was presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

In the work so far, the neural network was correct about 70% of the time in the absence of any further clinical analyses, according to David Simon, MD, a rheumatologist in the department of internal medicine at Friedrich-Alexander University, Erlangen, Germany.

Ted Bosworth/MDedge News

Previous to this work, “there has been no study that has exclusively used hand MRI data and deep learning without requiring further expert input for the classification of arthritides,” Dr. Simon said.

In fact, when demographic and clinical data were added, there was no improvement in the performance of patient classification relative to the deep learning classification alone, according to the data presented by Dr. Simon.

The images were evaluated with residual neural networks (ResNet), which represents a sophisticated form of deep learning to facilitate the flow of information across the network layers as they form to improve accuracy in their ability to distinguish one form of disease from the other. The training was performed on images from the T1 coronal, T2 corona1, T1 coronal fat suppressed with contrast, T1 axial fat suppressed with contrast, and T2 fat suppressed axial sequences.

The study included hand MRI scans from 135 patients with seronegative RA, 190 with seropositive RA, 177 with PsA, and 147 with psoriasis. The performance was judged on the basis of area under the receiver operating characteristics curve (AUROC) with and without input of clinical characteristics. Patients who had psoriasis without clinical arthritis were included as a control population.

The AUROC for accuracy was 75% for seropositive RA relative to PsA, 74% for seronegative RA relative to PsA, and 67% for seropositive relative to seronegative RA. Of the patients who had psoriasis without arthritis, 98% were classified as PsA and 2% as RA.

Subsequent to the classification of the patients with psoriasis, 14 of the 147 (9.5%) have developed PsA so far over a relatively short follow-up. All of these were among those identified as PsA by neural network evaluation of the hand MRIs.

This suggests that “a PsA-like pattern may be present early in the course of psoriatic disease,” Dr. Simon said.

In the groups with joint disease, who had mean ages ranging from 56 to 65, the mean disease durations were 2.6 years for those with seropositive RA, 1.3 years for those with seronegative RA, and 0.8 years for those with PsA. The patients with psoriasis were younger (mean age, 40.5 years) but had a longer disease duration (mean 4.2 years).

All of the MRI sequences were relevant for classification, but contrast did not appear to help with accuracy.

“If the images with contrast enhancement were deleted, the loss of performance was only marginal,” Dr. Simon reported.

The accuracy of neural networks increases with data, making it likely that further refinements in methodology will lead to a greater degree of accuracy, according to Dr. Simon. While the methodology is not yet ready for routine use in the clinic, the study demonstrates that neural network analysis of hand MRI to distinguish forms of arthritis “is possible.” Further studies are planned toward the goal of creating a viable clinical tool.

“Of course, if we could create an accurate tool with ultrasound, this would be even more practical,” said Dr. Simon, recognizing the value of an office tool, but he cautioned that this would be far more challenging.

“The precision of MRI is an important factor for effective neural network training,” he said.

Utility: ‘In challenging cases if the accuracy improves’?

A viable method for objectively and rapidly distinguishing inflammatory joint diseases, particularly in patients with an ambiguous clinical presentation, is an unmet need, according to Philip J. Mease, MD, director of rheumatology research at Swedish Medical Center, Seattle.

Although the data presented are promising, Dr. Mease said in an interview that he believes there is a fair amount of work to be done before imaging analysis based on deep learning makes its way into routine clinical care. He is also hoping for methods to distinguish RA from PsA that are easier and less expensive, such as serum biomarkers. However, he agreed that a MRI-based tool could be useful when differentiating disease that is challenging.

“MRI is an expensive way for routine classification of disease, but this approach could be useful in challenging cases if the accuracy improves,” he said.

Meanwhile, other clinical researchers might want to test the principle. “You can try it,” said Dr. Simon, who reported that his team has made the methodology publicly available.

Dr. Simon reported no conflicts of interest. Dr. Mease reported financial relationships with more than 10 pharmaceutical companies, most of which make products used for the treatment of inflammatory joint diseases.

NEW YORK – On the basis of MRI images of the hand, a neural network has been trained to distinguish seronegative and seropositive rheumatoid arthritis (RA) from psoriatic arthritis (PsA) as well as from each other, according to a study that was presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

In the work so far, the neural network was correct about 70% of the time in the absence of any further clinical analyses, according to David Simon, MD, a rheumatologist in the department of internal medicine at Friedrich-Alexander University, Erlangen, Germany.

Ted Bosworth/MDedge News

Previous to this work, “there has been no study that has exclusively used hand MRI data and deep learning without requiring further expert input for the classification of arthritides,” Dr. Simon said.

In fact, when demographic and clinical data were added, there was no improvement in the performance of patient classification relative to the deep learning classification alone, according to the data presented by Dr. Simon.

The images were evaluated with residual neural networks (ResNet), which represents a sophisticated form of deep learning to facilitate the flow of information across the network layers as they form to improve accuracy in their ability to distinguish one form of disease from the other. The training was performed on images from the T1 coronal, T2 corona1, T1 coronal fat suppressed with contrast, T1 axial fat suppressed with contrast, and T2 fat suppressed axial sequences.

The study included hand MRI scans from 135 patients with seronegative RA, 190 with seropositive RA, 177 with PsA, and 147 with psoriasis. The performance was judged on the basis of area under the receiver operating characteristics curve (AUROC) with and without input of clinical characteristics. Patients who had psoriasis without clinical arthritis were included as a control population.

The AUROC for accuracy was 75% for seropositive RA relative to PsA, 74% for seronegative RA relative to PsA, and 67% for seropositive relative to seronegative RA. Of the patients who had psoriasis without arthritis, 98% were classified as PsA and 2% as RA.

Subsequent to the classification of the patients with psoriasis, 14 of the 147 (9.5%) have developed PsA so far over a relatively short follow-up. All of these were among those identified as PsA by neural network evaluation of the hand MRIs.

This suggests that “a PsA-like pattern may be present early in the course of psoriatic disease,” Dr. Simon said.

In the groups with joint disease, who had mean ages ranging from 56 to 65, the mean disease durations were 2.6 years for those with seropositive RA, 1.3 years for those with seronegative RA, and 0.8 years for those with PsA. The patients with psoriasis were younger (mean age, 40.5 years) but had a longer disease duration (mean 4.2 years).

All of the MRI sequences were relevant for classification, but contrast did not appear to help with accuracy.

“If the images with contrast enhancement were deleted, the loss of performance was only marginal,” Dr. Simon reported.

The accuracy of neural networks increases with data, making it likely that further refinements in methodology will lead to a greater degree of accuracy, according to Dr. Simon. While the methodology is not yet ready for routine use in the clinic, the study demonstrates that neural network analysis of hand MRI to distinguish forms of arthritis “is possible.” Further studies are planned toward the goal of creating a viable clinical tool.

“Of course, if we could create an accurate tool with ultrasound, this would be even more practical,” said Dr. Simon, recognizing the value of an office tool, but he cautioned that this would be far more challenging.

“The precision of MRI is an important factor for effective neural network training,” he said.

Utility: ‘In challenging cases if the accuracy improves’?

A viable method for objectively and rapidly distinguishing inflammatory joint diseases, particularly in patients with an ambiguous clinical presentation, is an unmet need, according to Philip J. Mease, MD, director of rheumatology research at Swedish Medical Center, Seattle.

Although the data presented are promising, Dr. Mease said in an interview that he believes there is a fair amount of work to be done before imaging analysis based on deep learning makes its way into routine clinical care. He is also hoping for methods to distinguish RA from PsA that are easier and less expensive, such as serum biomarkers. However, he agreed that a MRI-based tool could be useful when differentiating disease that is challenging.

“MRI is an expensive way for routine classification of disease, but this approach could be useful in challenging cases if the accuracy improves,” he said.

Meanwhile, other clinical researchers might want to test the principle. “You can try it,” said Dr. Simon, who reported that his team has made the methodology publicly available.

Dr. Simon reported no conflicts of interest. Dr. Mease reported financial relationships with more than 10 pharmaceutical companies, most of which make products used for the treatment of inflammatory joint diseases.

NEW YORK – On the basis of MRI images of the hand, a neural network has been trained to distinguish seronegative and seropositive rheumatoid arthritis (RA) from psoriatic arthritis (PsA) as well as from each other, according to a study that was presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

In the work so far, the neural network was correct about 70% of the time in the absence of any further clinical analyses, according to David Simon, MD, a rheumatologist in the department of internal medicine at Friedrich-Alexander University, Erlangen, Germany.

Ted Bosworth/MDedge News

Previous to this work, “there has been no study that has exclusively used hand MRI data and deep learning without requiring further expert input for the classification of arthritides,” Dr. Simon said.

In fact, when demographic and clinical data were added, there was no improvement in the performance of patient classification relative to the deep learning classification alone, according to the data presented by Dr. Simon.

The images were evaluated with residual neural networks (ResNet), which represents a sophisticated form of deep learning to facilitate the flow of information across the network layers as they form to improve accuracy in their ability to distinguish one form of disease from the other. The training was performed on images from the T1 coronal, T2 corona1, T1 coronal fat suppressed with contrast, T1 axial fat suppressed with contrast, and T2 fat suppressed axial sequences.

The study included hand MRI scans from 135 patients with seronegative RA, 190 with seropositive RA, 177 with PsA, and 147 with psoriasis. The performance was judged on the basis of area under the receiver operating characteristics curve (AUROC) with and without input of clinical characteristics. Patients who had psoriasis without clinical arthritis were included as a control population.

The AUROC for accuracy was 75% for seropositive RA relative to PsA, 74% for seronegative RA relative to PsA, and 67% for seropositive relative to seronegative RA. Of the patients who had psoriasis without arthritis, 98% were classified as PsA and 2% as RA.

Subsequent to the classification of the patients with psoriasis, 14 of the 147 (9.5%) have developed PsA so far over a relatively short follow-up. All of these were among those identified as PsA by neural network evaluation of the hand MRIs.

This suggests that “a PsA-like pattern may be present early in the course of psoriatic disease,” Dr. Simon said.

In the groups with joint disease, who had mean ages ranging from 56 to 65, the mean disease durations were 2.6 years for those with seropositive RA, 1.3 years for those with seronegative RA, and 0.8 years for those with PsA. The patients with psoriasis were younger (mean age, 40.5 years) but had a longer disease duration (mean 4.2 years).

All of the MRI sequences were relevant for classification, but contrast did not appear to help with accuracy.

“If the images with contrast enhancement were deleted, the loss of performance was only marginal,” Dr. Simon reported.

The accuracy of neural networks increases with data, making it likely that further refinements in methodology will lead to a greater degree of accuracy, according to Dr. Simon. While the methodology is not yet ready for routine use in the clinic, the study demonstrates that neural network analysis of hand MRI to distinguish forms of arthritis “is possible.” Further studies are planned toward the goal of creating a viable clinical tool.

“Of course, if we could create an accurate tool with ultrasound, this would be even more practical,” said Dr. Simon, recognizing the value of an office tool, but he cautioned that this would be far more challenging.

“The precision of MRI is an important factor for effective neural network training,” he said.

Utility: ‘In challenging cases if the accuracy improves’?

A viable method for objectively and rapidly distinguishing inflammatory joint diseases, particularly in patients with an ambiguous clinical presentation, is an unmet need, according to Philip J. Mease, MD, director of rheumatology research at Swedish Medical Center, Seattle.

Although the data presented are promising, Dr. Mease said in an interview that he believes there is a fair amount of work to be done before imaging analysis based on deep learning makes its way into routine clinical care. He is also hoping for methods to distinguish RA from PsA that are easier and less expensive, such as serum biomarkers. However, he agreed that a MRI-based tool could be useful when differentiating disease that is challenging.

“MRI is an expensive way for routine classification of disease, but this approach could be useful in challenging cases if the accuracy improves,” he said.

Meanwhile, other clinical researchers might want to test the principle. “You can try it,” said Dr. Simon, who reported that his team has made the methodology publicly available.

Dr. Simon reported no conflicts of interest. Dr. Mease reported financial relationships with more than 10 pharmaceutical companies, most of which make products used for the treatment of inflammatory joint diseases.

NEW YORK – An algorithm in development for psoriatic arthritis (PsA) is showing promise for directing patients to the biologic with the greatest likelihood of producing disease control, according to a proof-of-concept study presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

“Our technique involves a more precise functional assay showing exact T-cell behavior, compared to the previous assessments that only analyzed cellular phenotypes,” reported Gizem Ayan, MD, a fellow in rheumatology at Hacettepe University Faculty of Medicine, Ankara, Turkey.

Ted Bosworth/MDedge News

The concept of precision medicine in PsA as well as other autoimmune diseases is not new. Phenotypes and biomarkers have already shown potential for guiding treatment, according to Dr. Ayan, but she said none are yet guideline recommended or proven to improve patient outcomes.

The principle of the new algorithm that she and her coinvestigators are pursing is based on immunophenotype analysis conducted with a flow-cytometric cytokine secretion assay (FCCSA). In the protocol, monocytes obtained from peripheral blood undergo activation before an FCCSA to distinguish patients by their T-cell behavior.

The treatment decision tree is based on median ratios of tumor necrosis factor (TNF)-alpha, interleukin (IL)–22, IL-17, and interferon-gamma expression among CD4+ and CD8+ cells. Based on a yes-or-no response to specific immune patterns, the patient is funneled to a biologic that inhibits a dominant cytokine.

The proof-of-concept study, which enrolled 8 patients with PsA who were naive to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and 11 patients with PsA who were naive to biologic DMARDs (bDMARDs), was designed to demonstrate feasibility. It did not test clinical benefit, but it did show that immunophenotyping with this methodology can be performed efficiently.

“From the time a blood sample is obtained, the method provided results within 24 hours,” according to Dr. Ayan, who is now planning a randomized trial to test the ability of the algorithm to improve clinical outcomes.

In the decision tree, there are five yes-no pathways to a treatment choice. The first step of the algorithm is to test the ratio of TNF-alpha to interferon-gamma CD4+ T cells. A “yes’ response is produced if the ratio is greater than or equal to 2. These patients are then evaluated for the ratio of TNF-alpha to interferon-gamma CD8+ T cells. A yes response is produced if the ratio is greater than or equal to 0.5. If yes, they are candidates for a TNF-alpha inhibitor. If no, they are directed to an IL-12/23 inhibitor.

If the answer at the first decision point in the algorithm is a “no,” meaning they do not have a TNF-alpha to interferon-gamma CD4+ ratio of 2 or higher, they are evaluated for percentage of CD4+ T cells expressing IL-22 or IL-17. Is it greater than or equal to 2%? If the answer is “no,” they are candidates for an IL-12/23 inhibitor.

If “yes,” they are evaluated for percentage of IL-22 to IL-17 CD4+. If the IL-22 CD4+ percentage is lower than the IL-17 CD4+ percentage, meaning a “yes” to this decision point, they are directed to an IL-17 inhibitor. If the answer at this decision point is “no,” they are directed to an IL-12/23 inhibitor.

Prior to enrollment in this proof-of-concept study, 10 of the bDMARD patients were scheduled to receive an anti-TNF drug and 1 was scheduled to receive an IL-12/23 inhibitor. On the basis of this algorithm, only 5 patients were directed to an anti-TNF drug. Of the remaining, 5 were directed to an IL-17 inhibitor, and 1 was directed to an IL-12/23 inhibitor.

All 19 participants in the proof-of-concept study had peripheral arthritis; their median age was 45 years. Approximately 90% had skin lesions. Axial involvement was present in only one patient. Based on these and other characteristics and the median ratios of the cytokines measured, Dr. Ayan called this a representative population.

Based on the feasibility of this method for subtyping patients by T-cell behavior to guide drug selection, Dr. Ayan anticipates pursuing the additional steps that would show the algorithm makes a difference to patient care, including such adjunctive benefits as more cost-effective treatment selection.

“We aim to develop a treatment decision algorithm that can be implemented in daily practice,” Dr. Ayan said.

Is peripheral blood sampling adequate?

In addition to saying that the algorithm will need to prove that it alters outcomes, Samuel Tzen-yue Hwang, MD, PhD, professor and chair of the department of dermatology at the University of California, Davis, Sacramento, pointed out some potential practical issues.

“Flow cytometry is not typically available as a rapid throughput, and the cost is high,” he said. Moreover, he remains skeptical about performing this algorithm on the basis of peripheral blood samples.

“It is debatable that looking at peripheral cells would provide adequate information about what is taking place at sites of inflammation,” he said. Although it would “be fantastic” to develop an algorithm that required only a peripheral blood sample, he pointed out that “only a fraction of these cells is relevant” to disease activity.

Aspirating fluid from an involved joint “might be more useful,” but it is more work, he added. Yet, Dr. Hwang acknowledged that this approach is intriguing. He agreed that there is considerable heterogeneity among patients with PsA in their response to specific biologics, and a method to better direct patients to the treatment most likely to elicit a response is needed.

Dr. Ayan and Dr. Hwang reported no potential conflicts of interest.

NEW YORK – An algorithm in development for psoriatic arthritis (PsA) is showing promise for directing patients to the biologic with the greatest likelihood of producing disease control, according to a proof-of-concept study presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

“Our technique involves a more precise functional assay showing exact T-cell behavior, compared to the previous assessments that only analyzed cellular phenotypes,” reported Gizem Ayan, MD, a fellow in rheumatology at Hacettepe University Faculty of Medicine, Ankara, Turkey.

Ted Bosworth/MDedge News

The concept of precision medicine in PsA as well as other autoimmune diseases is not new. Phenotypes and biomarkers have already shown potential for guiding treatment, according to Dr. Ayan, but she said none are yet guideline recommended or proven to improve patient outcomes.

The principle of the new algorithm that she and her coinvestigators are pursing is based on immunophenotype analysis conducted with a flow-cytometric cytokine secretion assay (FCCSA). In the protocol, monocytes obtained from peripheral blood undergo activation before an FCCSA to distinguish patients by their T-cell behavior.

The treatment decision tree is based on median ratios of tumor necrosis factor (TNF)-alpha, interleukin (IL)–22, IL-17, and interferon-gamma expression among CD4+ and CD8+ cells. Based on a yes-or-no response to specific immune patterns, the patient is funneled to a biologic that inhibits a dominant cytokine.

The proof-of-concept study, which enrolled 8 patients with PsA who were naive to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and 11 patients with PsA who were naive to biologic DMARDs (bDMARDs), was designed to demonstrate feasibility. It did not test clinical benefit, but it did show that immunophenotyping with this methodology can be performed efficiently.

“From the time a blood sample is obtained, the method provided results within 24 hours,” according to Dr. Ayan, who is now planning a randomized trial to test the ability of the algorithm to improve clinical outcomes.

In the decision tree, there are five yes-no pathways to a treatment choice. The first step of the algorithm is to test the ratio of TNF-alpha to interferon-gamma CD4+ T cells. A “yes’ response is produced if the ratio is greater than or equal to 2. These patients are then evaluated for the ratio of TNF-alpha to interferon-gamma CD8+ T cells. A yes response is produced if the ratio is greater than or equal to 0.5. If yes, they are candidates for a TNF-alpha inhibitor. If no, they are directed to an IL-12/23 inhibitor.

If the answer at the first decision point in the algorithm is a “no,” meaning they do not have a TNF-alpha to interferon-gamma CD4+ ratio of 2 or higher, they are evaluated for percentage of CD4+ T cells expressing IL-22 or IL-17. Is it greater than or equal to 2%? If the answer is “no,” they are candidates for an IL-12/23 inhibitor.

If “yes,” they are evaluated for percentage of IL-22 to IL-17 CD4+. If the IL-22 CD4+ percentage is lower than the IL-17 CD4+ percentage, meaning a “yes” to this decision point, they are directed to an IL-17 inhibitor. If the answer at this decision point is “no,” they are directed to an IL-12/23 inhibitor.

Prior to enrollment in this proof-of-concept study, 10 of the bDMARD patients were scheduled to receive an anti-TNF drug and 1 was scheduled to receive an IL-12/23 inhibitor. On the basis of this algorithm, only 5 patients were directed to an anti-TNF drug. Of the remaining, 5 were directed to an IL-17 inhibitor, and 1 was directed to an IL-12/23 inhibitor.

All 19 participants in the proof-of-concept study had peripheral arthritis; their median age was 45 years. Approximately 90% had skin lesions. Axial involvement was present in only one patient. Based on these and other characteristics and the median ratios of the cytokines measured, Dr. Ayan called this a representative population.

Based on the feasibility of this method for subtyping patients by T-cell behavior to guide drug selection, Dr. Ayan anticipates pursuing the additional steps that would show the algorithm makes a difference to patient care, including such adjunctive benefits as more cost-effective treatment selection.

“We aim to develop a treatment decision algorithm that can be implemented in daily practice,” Dr. Ayan said.

Is peripheral blood sampling adequate?

In addition to saying that the algorithm will need to prove that it alters outcomes, Samuel Tzen-yue Hwang, MD, PhD, professor and chair of the department of dermatology at the University of California, Davis, Sacramento, pointed out some potential practical issues.

“Flow cytometry is not typically available as a rapid throughput, and the cost is high,” he said. Moreover, he remains skeptical about performing this algorithm on the basis of peripheral blood samples.

“It is debatable that looking at peripheral cells would provide adequate information about what is taking place at sites of inflammation,” he said. Although it would “be fantastic” to develop an algorithm that required only a peripheral blood sample, he pointed out that “only a fraction of these cells is relevant” to disease activity.

Aspirating fluid from an involved joint “might be more useful,” but it is more work, he added. Yet, Dr. Hwang acknowledged that this approach is intriguing. He agreed that there is considerable heterogeneity among patients with PsA in their response to specific biologics, and a method to better direct patients to the treatment most likely to elicit a response is needed.

Dr. Ayan and Dr. Hwang reported no potential conflicts of interest.

NEW YORK – An algorithm in development for psoriatic arthritis (PsA) is showing promise for directing patients to the biologic with the greatest likelihood of producing disease control, according to a proof-of-concept study presented at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

“Our technique involves a more precise functional assay showing exact T-cell behavior, compared to the previous assessments that only analyzed cellular phenotypes,” reported Gizem Ayan, MD, a fellow in rheumatology at Hacettepe University Faculty of Medicine, Ankara, Turkey.

Ted Bosworth/MDedge News

The concept of precision medicine in PsA as well as other autoimmune diseases is not new. Phenotypes and biomarkers have already shown potential for guiding treatment, according to Dr. Ayan, but she said none are yet guideline recommended or proven to improve patient outcomes.

The principle of the new algorithm that she and her coinvestigators are pursing is based on immunophenotype analysis conducted with a flow-cytometric cytokine secretion assay (FCCSA). In the protocol, monocytes obtained from peripheral blood undergo activation before an FCCSA to distinguish patients by their T-cell behavior.

The treatment decision tree is based on median ratios of tumor necrosis factor (TNF)-alpha, interleukin (IL)–22, IL-17, and interferon-gamma expression among CD4+ and CD8+ cells. Based on a yes-or-no response to specific immune patterns, the patient is funneled to a biologic that inhibits a dominant cytokine.

The proof-of-concept study, which enrolled 8 patients with PsA who were naive to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and 11 patients with PsA who were naive to biologic DMARDs (bDMARDs), was designed to demonstrate feasibility. It did not test clinical benefit, but it did show that immunophenotyping with this methodology can be performed efficiently.

“From the time a blood sample is obtained, the method provided results within 24 hours,” according to Dr. Ayan, who is now planning a randomized trial to test the ability of the algorithm to improve clinical outcomes.

In the decision tree, there are five yes-no pathways to a treatment choice. The first step of the algorithm is to test the ratio of TNF-alpha to interferon-gamma CD4+ T cells. A “yes’ response is produced if the ratio is greater than or equal to 2. These patients are then evaluated for the ratio of TNF-alpha to interferon-gamma CD8+ T cells. A yes response is produced if the ratio is greater than or equal to 0.5. If yes, they are candidates for a TNF-alpha inhibitor. If no, they are directed to an IL-12/23 inhibitor.

If the answer at the first decision point in the algorithm is a “no,” meaning they do not have a TNF-alpha to interferon-gamma CD4+ ratio of 2 or higher, they are evaluated for percentage of CD4+ T cells expressing IL-22 or IL-17. Is it greater than or equal to 2%? If the answer is “no,” they are candidates for an IL-12/23 inhibitor.

If “yes,” they are evaluated for percentage of IL-22 to IL-17 CD4+. If the IL-22 CD4+ percentage is lower than the IL-17 CD4+ percentage, meaning a “yes” to this decision point, they are directed to an IL-17 inhibitor. If the answer at this decision point is “no,” they are directed to an IL-12/23 inhibitor.

Prior to enrollment in this proof-of-concept study, 10 of the bDMARD patients were scheduled to receive an anti-TNF drug and 1 was scheduled to receive an IL-12/23 inhibitor. On the basis of this algorithm, only 5 patients were directed to an anti-TNF drug. Of the remaining, 5 were directed to an IL-17 inhibitor, and 1 was directed to an IL-12/23 inhibitor.

All 19 participants in the proof-of-concept study had peripheral arthritis; their median age was 45 years. Approximately 90% had skin lesions. Axial involvement was present in only one patient. Based on these and other characteristics and the median ratios of the cytokines measured, Dr. Ayan called this a representative population.

Based on the feasibility of this method for subtyping patients by T-cell behavior to guide drug selection, Dr. Ayan anticipates pursuing the additional steps that would show the algorithm makes a difference to patient care, including such adjunctive benefits as more cost-effective treatment selection.

“We aim to develop a treatment decision algorithm that can be implemented in daily practice,” Dr. Ayan said.

Is peripheral blood sampling adequate?

In addition to saying that the algorithm will need to prove that it alters outcomes, Samuel Tzen-yue Hwang, MD, PhD, professor and chair of the department of dermatology at the University of California, Davis, Sacramento, pointed out some potential practical issues.

“Flow cytometry is not typically available as a rapid throughput, and the cost is high,” he said. Moreover, he remains skeptical about performing this algorithm on the basis of peripheral blood samples.

“It is debatable that looking at peripheral cells would provide adequate information about what is taking place at sites of inflammation,” he said. Although it would “be fantastic” to develop an algorithm that required only a peripheral blood sample, he pointed out that “only a fraction of these cells is relevant” to disease activity.

Aspirating fluid from an involved joint “might be more useful,” but it is more work, he added. Yet, Dr. Hwang acknowledged that this approach is intriguing. He agreed that there is considerable heterogeneity among patients with PsA in their response to specific biologics, and a method to better direct patients to the treatment most likely to elicit a response is needed.

Dr. Ayan and Dr. Hwang reported no potential conflicts of interest.

Among transgender youth who receive puberty-delaying or gender-affirming hormone therapy, bone mineral density (BMD) is lower relative to age-based norms, and this is true regardless of gender assignment at birth.

The problem worsens as the time during which these patients receive sex steroid hormones increases. So far, the “bone mineral density effects of these therapies are understudied,” warned Natalie Nokoff, MD, who presented a cross-sectional study at the annual meeting of the Endocrine Society.

The study of bone density is part of a larger body of research being conducted by Dr. Nokoff and her co-investigators on the long-term health effects of gender-affirming therapy in children and adolescents. In one of several recent studies, transgender youths taking gonadotropin-releasing hormone (GnRH) agonists, which effectively block puberty, were shown to be at greater risk of adverse changes in body composition and markers of cardiometabolic health than youths who were not taking them.

“We need more information on the optimal length of treatment with puberty-delaying medications before either discontinuation or introduction of gender-affirming hormones,” said Dr. Nokoff, an assistant professor of pediatrics and endocrinology at the University of Colorado School of Medicine, Aurora.

In this study, 56 transgender youth underwent total body dual-energy x-ray absorptiometry (DEXA). The patients ranged in age from 10 years to almost 20 years. Just over half (53%) were assigned female sex at birth.

The mean Z scores, signifying deviation from age-matched norms, were lower regardless of current use or past use of GnRH agonists in both transgender males or transgender females, relative to age-matched norms.

Asked to comment, Michele A. O’Connell, MBBCh, department of endocrinology and diabetes, Royal Children’s Hospital, Victoria, Australia, said the risk of bone loss is real.

“Monitoring of bone health is recommended for all transgender-diverse adolescents treated with gonadotropin-releasing hormone agonists,” said Dr. O’Connell. He referred to multiple guidelines, including those issued by the World Professional Association of Transgender Health in 2012 and those from the Endocrine Society that were issued in 2017.
 

Inverse correlation between duration of GnRH agonist therapy and Z scores

In Dr. Nokoff’s study, for transgender males, the BMD Z score was reduced 0.2 relative to male norms and by 0.4 relative to female norms. For transgender females, the scores were reduced by 0.4 relative to male norms and by 0.2 relative to female norms.

Among transgender males who were taking testosterone and who had previously been exposed to GnRH agonists, the Z score was significantly lower than those taking testosterone alone (P = .004). There were no differences in Z score for transgender females taking estradiol alone relative to estradiol with current or past use of GnRH agonists.

There was a significant inverse correlation for duration of GnRH agonist therapy and Z scores for transgender females relative to male norms (P = .005) or female norms (P = .029). However, Z scores were unrelated to length of time receiving testosterone or estradiol therapy or to sex steroid concentrations.

The number of children and adolescents taking puberty-delaying or gender-affirming therapies is increasing. Although reliable data are limited, the exploration of gender identify appears to have become more common with the growing social acceptance of gender dysphoria. That term refers to a sense of unease among individuals who feel that their biological sex does not match their gender identity, according to Dr. Nokoff.

“It is now estimated that 2% of youths identify as transgender,” she said.

Findings from studies investigating the relationship between gender-affirming therapy and bone loss among adults have not been consistent. In a single-center study that followed 543 transgender men and 711 transgender women who had undergone DEXA scanning at baseline prior to starting hormone therapy, there did not appear to be any substantial negative effects on lumbar bone density over time (J Bone Min Res. 2018 Dec;34:447-54).

For adolescents, there is growing evidence of the risk of bone loss in relation to gender-affirming therapy, but there is limited agreement on clinical risks and how they can be avoided. Relevant variables include genetics and diet, as well as the types, doses, and length of time receiving gender-affirming therapy.
 

Monitor bone in transgender youth; Use vitamin D and weight-bearing exercise

Dr. O’Connell is the first author of a recent summary of the pharmacologic management of trans and gender-diverse adolescents. That summary covered multiple topics in addition to risk of bone loss, including the impact on growth, cognition, and mental health (J Clin Endocrinol Metab. 2022 Jan;107:241-257).

Overall, she believes that bone health should be monitored for children receiving puberty-delaying or gender-affirming therapies but agrees with Dr. Nokoff that the clinical impact remains poorly defined.

“Long-term follow-up studies will be required to assess the impact, if any, on functional outcomes such as fracture risk,” she reported. Still, she encouraged use of standard ways of improving bone health, including adequate vitamin D intake and weight-bearing exercise.

Dr. Nokoff and Dr. O’Connell have disclosed no relevant financial relationships.

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

Among transgender youth who receive puberty-delaying or gender-affirming hormone therapy, bone mineral density (BMD) is lower relative to age-based norms, and this is true regardless of gender assignment at birth.

The problem worsens as the time during which these patients receive sex steroid hormones increases. So far, the “bone mineral density effects of these therapies are understudied,” warned Natalie Nokoff, MD, who presented a cross-sectional study at the annual meeting of the Endocrine Society.

The study of bone density is part of a larger body of research being conducted by Dr. Nokoff and her co-investigators on the long-term health effects of gender-affirming therapy in children and adolescents. In one of several recent studies, transgender youths taking gonadotropin-releasing hormone (GnRH) agonists, which effectively block puberty, were shown to be at greater risk of adverse changes in body composition and markers of cardiometabolic health than youths who were not taking them.

“We need more information on the optimal length of treatment with puberty-delaying medications before either discontinuation or introduction of gender-affirming hormones,” said Dr. Nokoff, an assistant professor of pediatrics and endocrinology at the University of Colorado School of Medicine, Aurora.

In this study, 56 transgender youth underwent total body dual-energy x-ray absorptiometry (DEXA). The patients ranged in age from 10 years to almost 20 years. Just over half (53%) were assigned female sex at birth.

The mean Z scores, signifying deviation from age-matched norms, were lower regardless of current use or past use of GnRH agonists in both transgender males or transgender females, relative to age-matched norms.

Asked to comment, Michele A. O’Connell, MBBCh, department of endocrinology and diabetes, Royal Children’s Hospital, Victoria, Australia, said the risk of bone loss is real.

“Monitoring of bone health is recommended for all transgender-diverse adolescents treated with gonadotropin-releasing hormone agonists,” said Dr. O’Connell. He referred to multiple guidelines, including those issued by the World Professional Association of Transgender Health in 2012 and those from the Endocrine Society that were issued in 2017.
 

Inverse correlation between duration of GnRH agonist therapy and Z scores

In Dr. Nokoff’s study, for transgender males, the BMD Z score was reduced 0.2 relative to male norms and by 0.4 relative to female norms. For transgender females, the scores were reduced by 0.4 relative to male norms and by 0.2 relative to female norms.

Among transgender males who were taking testosterone and who had previously been exposed to GnRH agonists, the Z score was significantly lower than those taking testosterone alone (P = .004). There were no differences in Z score for transgender females taking estradiol alone relative to estradiol with current or past use of GnRH agonists.

There was a significant inverse correlation for duration of GnRH agonist therapy and Z scores for transgender females relative to male norms (P = .005) or female norms (P = .029). However, Z scores were unrelated to length of time receiving testosterone or estradiol therapy or to sex steroid concentrations.

The number of children and adolescents taking puberty-delaying or gender-affirming therapies is increasing. Although reliable data are limited, the exploration of gender identify appears to have become more common with the growing social acceptance of gender dysphoria. That term refers to a sense of unease among individuals who feel that their biological sex does not match their gender identity, according to Dr. Nokoff.

“It is now estimated that 2% of youths identify as transgender,” she said.

Findings from studies investigating the relationship between gender-affirming therapy and bone loss among adults have not been consistent. In a single-center study that followed 543 transgender men and 711 transgender women who had undergone DEXA scanning at baseline prior to starting hormone therapy, there did not appear to be any substantial negative effects on lumbar bone density over time (J Bone Min Res. 2018 Dec;34:447-54).

For adolescents, there is growing evidence of the risk of bone loss in relation to gender-affirming therapy, but there is limited agreement on clinical risks and how they can be avoided. Relevant variables include genetics and diet, as well as the types, doses, and length of time receiving gender-affirming therapy.
 

Monitor bone in transgender youth; Use vitamin D and weight-bearing exercise

Dr. O’Connell is the first author of a recent summary of the pharmacologic management of trans and gender-diverse adolescents. That summary covered multiple topics in addition to risk of bone loss, including the impact on growth, cognition, and mental health (J Clin Endocrinol Metab. 2022 Jan;107:241-257).

Overall, she believes that bone health should be monitored for children receiving puberty-delaying or gender-affirming therapies but agrees with Dr. Nokoff that the clinical impact remains poorly defined.

“Long-term follow-up studies will be required to assess the impact, if any, on functional outcomes such as fracture risk,” she reported. Still, she encouraged use of standard ways of improving bone health, including adequate vitamin D intake and weight-bearing exercise.

Dr. Nokoff and Dr. O’Connell have disclosed no relevant financial relationships.

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

Among transgender youth who receive puberty-delaying or gender-affirming hormone therapy, bone mineral density (BMD) is lower relative to age-based norms, and this is true regardless of gender assignment at birth.

The problem worsens as the time during which these patients receive sex steroid hormones increases. So far, the “bone mineral density effects of these therapies are understudied,” warned Natalie Nokoff, MD, who presented a cross-sectional study at the annual meeting of the Endocrine Society.

The study of bone density is part of a larger body of research being conducted by Dr. Nokoff and her co-investigators on the long-term health effects of gender-affirming therapy in children and adolescents. In one of several recent studies, transgender youths taking gonadotropin-releasing hormone (GnRH) agonists, which effectively block puberty, were shown to be at greater risk of adverse changes in body composition and markers of cardiometabolic health than youths who were not taking them.

“We need more information on the optimal length of treatment with puberty-delaying medications before either discontinuation or introduction of gender-affirming hormones,” said Dr. Nokoff, an assistant professor of pediatrics and endocrinology at the University of Colorado School of Medicine, Aurora.

In this study, 56 transgender youth underwent total body dual-energy x-ray absorptiometry (DEXA). The patients ranged in age from 10 years to almost 20 years. Just over half (53%) were assigned female sex at birth.

The mean Z scores, signifying deviation from age-matched norms, were lower regardless of current use or past use of GnRH agonists in both transgender males or transgender females, relative to age-matched norms.

Asked to comment, Michele A. O’Connell, MBBCh, department of endocrinology and diabetes, Royal Children’s Hospital, Victoria, Australia, said the risk of bone loss is real.

“Monitoring of bone health is recommended for all transgender-diverse adolescents treated with gonadotropin-releasing hormone agonists,” said Dr. O’Connell. He referred to multiple guidelines, including those issued by the World Professional Association of Transgender Health in 2012 and those from the Endocrine Society that were issued in 2017.
 

Inverse correlation between duration of GnRH agonist therapy and Z scores

In Dr. Nokoff’s study, for transgender males, the BMD Z score was reduced 0.2 relative to male norms and by 0.4 relative to female norms. For transgender females, the scores were reduced by 0.4 relative to male norms and by 0.2 relative to female norms.

Among transgender males who were taking testosterone and who had previously been exposed to GnRH agonists, the Z score was significantly lower than those taking testosterone alone (P = .004). There were no differences in Z score for transgender females taking estradiol alone relative to estradiol with current or past use of GnRH agonists.

There was a significant inverse correlation for duration of GnRH agonist therapy and Z scores for transgender females relative to male norms (P = .005) or female norms (P = .029). However, Z scores were unrelated to length of time receiving testosterone or estradiol therapy or to sex steroid concentrations.

The number of children and adolescents taking puberty-delaying or gender-affirming therapies is increasing. Although reliable data are limited, the exploration of gender identify appears to have become more common with the growing social acceptance of gender dysphoria. That term refers to a sense of unease among individuals who feel that their biological sex does not match their gender identity, according to Dr. Nokoff.

“It is now estimated that 2% of youths identify as transgender,” she said.

Findings from studies investigating the relationship between gender-affirming therapy and bone loss among adults have not been consistent. In a single-center study that followed 543 transgender men and 711 transgender women who had undergone DEXA scanning at baseline prior to starting hormone therapy, there did not appear to be any substantial negative effects on lumbar bone density over time (J Bone Min Res. 2018 Dec;34:447-54).

For adolescents, there is growing evidence of the risk of bone loss in relation to gender-affirming therapy, but there is limited agreement on clinical risks and how they can be avoided. Relevant variables include genetics and diet, as well as the types, doses, and length of time receiving gender-affirming therapy.
 

Monitor bone in transgender youth; Use vitamin D and weight-bearing exercise

Dr. O’Connell is the first author of a recent summary of the pharmacologic management of trans and gender-diverse adolescents. That summary covered multiple topics in addition to risk of bone loss, including the impact on growth, cognition, and mental health (J Clin Endocrinol Metab. 2022 Jan;107:241-257).

Overall, she believes that bone health should be monitored for children receiving puberty-delaying or gender-affirming therapies but agrees with Dr. Nokoff that the clinical impact remains poorly defined.

“Long-term follow-up studies will be required to assess the impact, if any, on functional outcomes such as fracture risk,” she reported. Still, she encouraged use of standard ways of improving bone health, including adequate vitamin D intake and weight-bearing exercise.

Dr. Nokoff and Dr. O’Connell have disclosed no relevant financial relationships.

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

Wireless devices, like smart phones and tablets, appear to induce compulsive or even addictive use in many individuals, leading to adverse health consequences that are likely to be curtailed only through often difficult behavior modification, according to a pediatric endocrinologist’s take on the problem.

While the summary was based in part on the analysis of 234 published papers drawn from the medical literature, the lead author, Nidhi Gupta, MD, said the data reinforce her own clinical experience.

Lisa Nainggolin/MDedge News

“As a pediatric endocrinologist, the trend in smartphone-associated health disorders, such as obesity, sleep, and behavior issues, worries me,” Dr. Gupta, director of KAP Pediatric Endocrinology, Nashville, Tenn., said at the annual meeting of the Endocrine Society.

Based on her search of the medical literature, the available data raise concern. In one study she cited, for example, each hour per day of screen time was found to translate into a body mass index increase of 0.5 to 0.7 kg/m² (P < .001).

With this type of progressive rise in BMI comes prediabetes, dyslipidemia, and other metabolic disorders associated with major health risks, including cardiovascular disease. And there are others. Dr. Gupta cited data suggesting screen time before bed disturbs sleep, which has its own set of health risks.

“When I say health, it includes physical health, mental health, and emotional health,” said Dr. Gupta.

In the U.S. and other countries with a growing obesity epidemic, lack of physical activity and unhealthy eating are widely considered the major culprits. Excessive screen time contributes to both.

“When we are engaged with our devices, we are often snacking subconsciously and not very mindful that we are making unhealthy choices,” Dr. Gupta said.

The problem is that there is a vicious circle. Compulsive use of devices follows the same loop as other types of addictive behaviors, according to Dr. Gupta. She traced overuse of wireless devices to the dopaminergic system, which is a powerful neuroendocrine-mediated process of craving, response, and reward.

Like fat, sugar, and salt, which provoke a neuroendocrine reward signal, the chimes and buzzes of a cell phone provide their own cues for reward in the form of a dopamine surge. As a result, these become the “triggers of an irresistible and irrational urge to check our device that makes the dopamine go high in our brain,” Dr. Gupta explained.

Although the vicious cycle can be thwarted by turning off the device, Dr. Gupta characterized this as “impractical” when smartphones are so vital to daily communication. Rather, Dr. Gupta advocated a program of moderation, reserving the phone for useful tasks without succumbing to the siren song of apps that waste time.

The most conspicuous culprit is social media, which Dr. Gupta considers to be among the most Pavlovian triggers of cell phone addiction. However, she acknowledged that participation in social media has its justifications.

“I, myself, use social media for my own branding and marketing,” Dr. Gupta said.

The problem that users have is distinguishing between screen time that does and does not have value, according to Dr. Gupta. She indicated that many of those overusing their smart devices are being driven by the dopaminergic reward system, which is generally divorced from the real goals of life, such as personal satisfaction and activity that is rewarding monetarily or in other ways.

“I am not asking for these devices to be thrown out the window. I am advocating for moderation, balance, and real-life engagement,” Dr. Gupta said at the meeting, held in Atlanta and virtually.

She outlined a long list of practical suggestions, including turning off the alarms, chimes, and messages that engage the user into the vicious dopaminergic-reward system loop. She suggested mindfulness so that the user can distinguish between valuable device use and activity that is simply procrastination.

“The devices are designed to be addictive. They are designed to manipulate our brain,” she said. “Eliminate the reward. Let’s try to make our devices boring, unappealing, or enticing so that they only work as tools.”

The medical literature is filled with data that support the potential harms of excessive screen use, leading many others to make some of the same points. In 2017, Thomas N. Robinson, MD, professor of child health at Stanford (Calif.) University, reviewed data showing an association between screen media exposure and obesity in children and adolescents.

“This is an area crying out for more research,” Dr. Robinson said in an interview. The problem of screen time, sedentary behavior, and weight gain has been an issue since the television was invented, which was the point he made in his 2017 paper, but he agreed that the problem is only getting worse.

“Digital technology has become ubiquitous, touching nearly every aspect of people’s lives,” he said. Yet, as evidence grows that overuse of this technology can be harmful, it is creating a problem without a clear solution.

“There are few data about the efficacy of specific strategies to reduce harmful impacts of digital screen use,” he said.

While some of the solutions that Dr. Gupta described make sense, they are more easily described than executed. The dopaminergic reward system is strong and largely experienced subconsciously. Recruiting patients to recognize that dopaminergic rewards are not rewards in any true sense is already a challenge. Enlisting patients to take the difficult steps to avoid the behavioral cues might be even more difficult.

Dr. Gupta and Dr. Robinson report no potential conflicts of interest.

Wireless devices, like smart phones and tablets, appear to induce compulsive or even addictive use in many individuals, leading to adverse health consequences that are likely to be curtailed only through often difficult behavior modification, according to a pediatric endocrinologist’s take on the problem.

While the summary was based in part on the analysis of 234 published papers drawn from the medical literature, the lead author, Nidhi Gupta, MD, said the data reinforce her own clinical experience.

Lisa Nainggolin/MDedge News

“As a pediatric endocrinologist, the trend in smartphone-associated health disorders, such as obesity, sleep, and behavior issues, worries me,” Dr. Gupta, director of KAP Pediatric Endocrinology, Nashville, Tenn., said at the annual meeting of the Endocrine Society.

Based on her search of the medical literature, the available data raise concern. In one study she cited, for example, each hour per day of screen time was found to translate into a body mass index increase of 0.5 to 0.7 kg/m² (P < .001).

With this type of progressive rise in BMI comes prediabetes, dyslipidemia, and other metabolic disorders associated with major health risks, including cardiovascular disease. And there are others. Dr. Gupta cited data suggesting screen time before bed disturbs sleep, which has its own set of health risks.

“When I say health, it includes physical health, mental health, and emotional health,” said Dr. Gupta.

In the U.S. and other countries with a growing obesity epidemic, lack of physical activity and unhealthy eating are widely considered the major culprits. Excessive screen time contributes to both.

“When we are engaged with our devices, we are often snacking subconsciously and not very mindful that we are making unhealthy choices,” Dr. Gupta said.

The problem is that there is a vicious circle. Compulsive use of devices follows the same loop as other types of addictive behaviors, according to Dr. Gupta. She traced overuse of wireless devices to the dopaminergic system, which is a powerful neuroendocrine-mediated process of craving, response, and reward.

Like fat, sugar, and salt, which provoke a neuroendocrine reward signal, the chimes and buzzes of a cell phone provide their own cues for reward in the form of a dopamine surge. As a result, these become the “triggers of an irresistible and irrational urge to check our device that makes the dopamine go high in our brain,” Dr. Gupta explained.

Although the vicious cycle can be thwarted by turning off the device, Dr. Gupta characterized this as “impractical” when smartphones are so vital to daily communication. Rather, Dr. Gupta advocated a program of moderation, reserving the phone for useful tasks without succumbing to the siren song of apps that waste time.

The most conspicuous culprit is social media, which Dr. Gupta considers to be among the most Pavlovian triggers of cell phone addiction. However, she acknowledged that participation in social media has its justifications.

“I, myself, use social media for my own branding and marketing,” Dr. Gupta said.

The problem that users have is distinguishing between screen time that does and does not have value, according to Dr. Gupta. She indicated that many of those overusing their smart devices are being driven by the dopaminergic reward system, which is generally divorced from the real goals of life, such as personal satisfaction and activity that is rewarding monetarily or in other ways.

“I am not asking for these devices to be thrown out the window. I am advocating for moderation, balance, and real-life engagement,” Dr. Gupta said at the meeting, held in Atlanta and virtually.

She outlined a long list of practical suggestions, including turning off the alarms, chimes, and messages that engage the user into the vicious dopaminergic-reward system loop. She suggested mindfulness so that the user can distinguish between valuable device use and activity that is simply procrastination.

“The devices are designed to be addictive. They are designed to manipulate our brain,” she said. “Eliminate the reward. Let’s try to make our devices boring, unappealing, or enticing so that they only work as tools.”

The medical literature is filled with data that support the potential harms of excessive screen use, leading many others to make some of the same points. In 2017, Thomas N. Robinson, MD, professor of child health at Stanford (Calif.) University, reviewed data showing an association between screen media exposure and obesity in children and adolescents.

“This is an area crying out for more research,” Dr. Robinson said in an interview. The problem of screen time, sedentary behavior, and weight gain has been an issue since the television was invented, which was the point he made in his 2017 paper, but he agreed that the problem is only getting worse.

“Digital technology has become ubiquitous, touching nearly every aspect of people’s lives,” he said. Yet, as evidence grows that overuse of this technology can be harmful, it is creating a problem without a clear solution.

“There are few data about the efficacy of specific strategies to reduce harmful impacts of digital screen use,” he said.

While some of the solutions that Dr. Gupta described make sense, they are more easily described than executed. The dopaminergic reward system is strong and largely experienced subconsciously. Recruiting patients to recognize that dopaminergic rewards are not rewards in any true sense is already a challenge. Enlisting patients to take the difficult steps to avoid the behavioral cues might be even more difficult.

Dr. Gupta and Dr. Robinson report no potential conflicts of interest.

Wireless devices, like smart phones and tablets, appear to induce compulsive or even addictive use in many individuals, leading to adverse health consequences that are likely to be curtailed only through often difficult behavior modification, according to a pediatric endocrinologist’s take on the problem.

While the summary was based in part on the analysis of 234 published papers drawn from the medical literature, the lead author, Nidhi Gupta, MD, said the data reinforce her own clinical experience.

Lisa Nainggolin/MDedge News

“As a pediatric endocrinologist, the trend in smartphone-associated health disorders, such as obesity, sleep, and behavior issues, worries me,” Dr. Gupta, director of KAP Pediatric Endocrinology, Nashville, Tenn., said at the annual meeting of the Endocrine Society.

Based on her search of the medical literature, the available data raise concern. In one study she cited, for example, each hour per day of screen time was found to translate into a body mass index increase of 0.5 to 0.7 kg/m² (P < .001).

With this type of progressive rise in BMI comes prediabetes, dyslipidemia, and other metabolic disorders associated with major health risks, including cardiovascular disease. And there are others. Dr. Gupta cited data suggesting screen time before bed disturbs sleep, which has its own set of health risks.

“When I say health, it includes physical health, mental health, and emotional health,” said Dr. Gupta.

In the U.S. and other countries with a growing obesity epidemic, lack of physical activity and unhealthy eating are widely considered the major culprits. Excessive screen time contributes to both.

“When we are engaged with our devices, we are often snacking subconsciously and not very mindful that we are making unhealthy choices,” Dr. Gupta said.

The problem is that there is a vicious circle. Compulsive use of devices follows the same loop as other types of addictive behaviors, according to Dr. Gupta. She traced overuse of wireless devices to the dopaminergic system, which is a powerful neuroendocrine-mediated process of craving, response, and reward.

Like fat, sugar, and salt, which provoke a neuroendocrine reward signal, the chimes and buzzes of a cell phone provide their own cues for reward in the form of a dopamine surge. As a result, these become the “triggers of an irresistible and irrational urge to check our device that makes the dopamine go high in our brain,” Dr. Gupta explained.

Although the vicious cycle can be thwarted by turning off the device, Dr. Gupta characterized this as “impractical” when smartphones are so vital to daily communication. Rather, Dr. Gupta advocated a program of moderation, reserving the phone for useful tasks without succumbing to the siren song of apps that waste time.

The most conspicuous culprit is social media, which Dr. Gupta considers to be among the most Pavlovian triggers of cell phone addiction. However, she acknowledged that participation in social media has its justifications.

“I, myself, use social media for my own branding and marketing,” Dr. Gupta said.

The problem that users have is distinguishing between screen time that does and does not have value, according to Dr. Gupta. She indicated that many of those overusing their smart devices are being driven by the dopaminergic reward system, which is generally divorced from the real goals of life, such as personal satisfaction and activity that is rewarding monetarily or in other ways.

“I am not asking for these devices to be thrown out the window. I am advocating for moderation, balance, and real-life engagement,” Dr. Gupta said at the meeting, held in Atlanta and virtually.

She outlined a long list of practical suggestions, including turning off the alarms, chimes, and messages that engage the user into the vicious dopaminergic-reward system loop. She suggested mindfulness so that the user can distinguish between valuable device use and activity that is simply procrastination.

“The devices are designed to be addictive. They are designed to manipulate our brain,” she said. “Eliminate the reward. Let’s try to make our devices boring, unappealing, or enticing so that they only work as tools.”

The medical literature is filled with data that support the potential harms of excessive screen use, leading many others to make some of the same points. In 2017, Thomas N. Robinson, MD, professor of child health at Stanford (Calif.) University, reviewed data showing an association between screen media exposure and obesity in children and adolescents.

“This is an area crying out for more research,” Dr. Robinson said in an interview. The problem of screen time, sedentary behavior, and weight gain has been an issue since the television was invented, which was the point he made in his 2017 paper, but he agreed that the problem is only getting worse.

“Digital technology has become ubiquitous, touching nearly every aspect of people’s lives,” he said. Yet, as evidence grows that overuse of this technology can be harmful, it is creating a problem without a clear solution.

“There are few data about the efficacy of specific strategies to reduce harmful impacts of digital screen use,” he said.

While some of the solutions that Dr. Gupta described make sense, they are more easily described than executed. The dopaminergic reward system is strong and largely experienced subconsciously. Recruiting patients to recognize that dopaminergic rewards are not rewards in any true sense is already a challenge. Enlisting patients to take the difficult steps to avoid the behavioral cues might be even more difficult.

Dr. Gupta and Dr. Robinson report no potential conflicts of interest.

Similar to a phenomenon already well documented in women, inadequate nutrition appears to be linked to hormonal abnormalities and potentially preventable tibial cortical bone density loss in athletic men, according to results of a small, prospective study.

Based on these findings, “we suspect that a subset of male runners might not be fueling their bodies with enough nutrition and calories for their physical activity,” reported Melanie S. Haines, MD, at the annual meeting of the Endocrine Society.

This is not the first study to suggest male athletes are at risk of a condition equivalent to what has been commonly referred to as the female athlete triad, but it enlarges the objective data that the phenomenon is real, and it makes insufficient availability of energy the likely cause.

In women, the triad is described as a lack of adequate stored energy, irregular menses, and bone density loss. In men, menstrual cycles are not relevant, of course, but this study like others suggests a link between the failure to maintain adequate stores of energy, disturbances in hormone function, and decreased bone density in both men and women, Dr. Haines explained.
 

RED-S vs. male or female athlete triad

“There is now a move away from the term female athlete triad or male athlete triad,” Dr. Haines reported. Rather the factors of failing to maintain adequate energy for metabolic demands, hormonal disturbances, and bone density loss appear to be relevant to both sexes, according to Dr. Haines, an endocrinologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston. She said several groups, including the International Olympic Committee (IOC), have transitioned to the term RED-S to apply to both sexes.

“RED-S is an acronym for relative energy deficiency in sport, and it appears to be gaining traction,” Dr. Haines said in an interview.

According to her study and others, excessive lean body mass from failure to supply sufficient energy for physiological needs “negatively affects hormones and bone,” Dr. Haines explained. In men and women, endocrine disturbances are triggered when insufficient calories lead to inadequate macro- and micronutrients.

In this study, 31 men aged 16-30 years were evaluated. Fifteen were in the athlete group, defined by running at least 30 miles per week for at least the previous 6 months. There were 16 control subjects; all exercised less than 2 hours per week and did not participate in team sports, but they were not permitted in the study if their body mass index exceeded 27.5 kg/m².
 

Athletes vs. otherwise healthy controls

Conditions that affect bone health were exclusion criteria in both groups, and neither group was permitted to take medications affecting bone health other than dietary calcium or vitamin D supplements for 2 months prior to the study.

Tibial cortical porosity was significantly greater – signaling deterioration in microarchitecture – in athletes, compared with control subjects (P = .003), according to quantitative computed tomography measurements. There was also significantly lower tibial cortical bone mineral density (P = .008) among athletes relative to controls.

Conversely, tibial trabecular measures of bone density and architecture were better among athletes than controls, but this was expected and did not contradict the hypothesis of the study.

“Trabecular bone refers to the inner part of the bone, which increases with weight-bearing exercise, but cortical bone is the outer shell, and the source of stress fractures,” Dr. Haines explained.

The median age of both the athletes and the controls was 24 years. Baseline measurements were similar. Body mass index, fat mass, estradiol, and leptin were all numerically lower in the athletes than controls, but none were significant, although there was a trend for the difference in leptin (P = .085).
 

Hormones correlated with tibial failure load

When these characteristics were evaluated in the context of mean tibial failure load, a metric related to strength, there was a strongly significant positive association with lean body mass (R = 0.85; P < 0.001) and estradiol level (R = 0.66; P = .007). The relationship with leptin also reached significance (R = 0.59; P = .046).

Unexpectedly, there was no relationship between testosterone and tibial failure load. The reason is unclear, but Dr. Haines’s interpretation is that the relationship between specific hormonal disturbances and bone density loss “might not be as simple” as once hypothesized.

The next step is a longitudinal evaluation of the same group of athletes to follow changes in the relationship between these variables over time, according to Dr. Haines.

Eventually, with evidence that there is a causal relationship between nutrition, hormonal changes, and bone loss, the research in this area will focus on better detection of risk and prophylactic strategies.

“Intervention trials to show that we can prevent stress factors will be difficult to perform,” Dr. Haines acknowledged, but she said that preventing adverse changes in bone at relatively young ages could have implications for long-term bone health, including protection from osteoporosis later in life.

The research presented by Dr. Haines is consistent with an area of research that is several decades old, at least in females, according to Siobhan M. Statuta, MD, a sports medicine primary care specialist at the University of Virginia, Charlottesville. The evidence that the same phenomenon occurs in men is more recent, but she said that it is now well accepted the there is a parallel hormonal issue in men and women.

“It is not a question of not eating enough. Often, athletes continue to consume the same diet, but their activity increases,” Dr. Statuta explained. “The problem is that they are not supplying enough of the calories they need to sustain the energy they are expending. You might say they are not fueling their engines appropriately.”

In 2014, the International Olympic Committee published a consensus statement on RED-S. They described this as a condition in which a state of energy deficiency leads to numerous complications in athletes, not just osteoporosis. Rather, a host of physiological systems, ranging from gastrointestinal complaints to cardiovascular events, were described.
 

RED-S addresses health beyond bones

“The RED-S theory is better described as a spoke-and-wheel concept rather than a triad. While inadequate energy availability is important to both, RED-S places this at the center of the wheel with spokes leading to all the possible complications rather than as a first event in a limited triad,” Dr. Statuta said in an interview.

However, she noted that the term RED-S is not yet appropriate to replace that of the male and female athlete triad.

“More research is required to hash out the relationship of a body in a state of energy deficiency and how it affects the entire body, which is the principle of RED-S,” Dr. Statuta said. “There likely are scientific effects, and we are currently investigating these relationships more.”

“These are really quite similar entities but have different foci,” she added. Based on data collected over several decades, “the triad narrows in on two body systems affected by low energy – the reproductive system and bones. RED-S incorporates these same systems yet adds on many more organ systems.

The original group of researchers have remained loyal to the concept of the triad that involves inadequate availability of energy followed by hormonal irregularities and osteoporosis. This group, the Female and Male Athlete Triad Coalition, has issued publications on this topic several times. Consensus statements were updated last year.

“The premise is that the triad leading to bone loss is shared by both men and women, even if the clinical manifestations differ,” said Dr. Statuta. The most notable difference is that men do not experience menstrual irregularities, but Dr. Statuta suggested that the clinical consequences are not necessarily any less.

“Males do not have menstrual cycles as an outward marker of an endocrine disturbance, so it is harder to recognize clinically, but I think there is agreement that not having enough energy available is the trigger of endocrine changes and then bone loss is relevant to both sexes,” she said. She said this is supported by a growing body of evidence, including the data presented by Dr. Haines at the Endocrine Society meeting.

Dr. Haines and Dr. Statuta report no potential conflicts of interest.

Similar to a phenomenon already well documented in women, inadequate nutrition appears to be linked to hormonal abnormalities and potentially preventable tibial cortical bone density loss in athletic men, according to results of a small, prospective study.

Based on these findings, “we suspect that a subset of male runners might not be fueling their bodies with enough nutrition and calories for their physical activity,” reported Melanie S. Haines, MD, at the annual meeting of the Endocrine Society.

This is not the first study to suggest male athletes are at risk of a condition equivalent to what has been commonly referred to as the female athlete triad, but it enlarges the objective data that the phenomenon is real, and it makes insufficient availability of energy the likely cause.

In women, the triad is described as a lack of adequate stored energy, irregular menses, and bone density loss. In men, menstrual cycles are not relevant, of course, but this study like others suggests a link between the failure to maintain adequate stores of energy, disturbances in hormone function, and decreased bone density in both men and women, Dr. Haines explained.
 

RED-S vs. male or female athlete triad

“There is now a move away from the term female athlete triad or male athlete triad,” Dr. Haines reported. Rather the factors of failing to maintain adequate energy for metabolic demands, hormonal disturbances, and bone density loss appear to be relevant to both sexes, according to Dr. Haines, an endocrinologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston. She said several groups, including the International Olympic Committee (IOC), have transitioned to the term RED-S to apply to both sexes.

“RED-S is an acronym for relative energy deficiency in sport, and it appears to be gaining traction,” Dr. Haines said in an interview.

According to her study and others, excessive lean body mass from failure to supply sufficient energy for physiological needs “negatively affects hormones and bone,” Dr. Haines explained. In men and women, endocrine disturbances are triggered when insufficient calories lead to inadequate macro- and micronutrients.

In this study, 31 men aged 16-30 years were evaluated. Fifteen were in the athlete group, defined by running at least 30 miles per week for at least the previous 6 months. There were 16 control subjects; all exercised less than 2 hours per week and did not participate in team sports, but they were not permitted in the study if their body mass index exceeded 27.5 kg/m².
 

Athletes vs. otherwise healthy controls

Conditions that affect bone health were exclusion criteria in both groups, and neither group was permitted to take medications affecting bone health other than dietary calcium or vitamin D supplements for 2 months prior to the study.

Tibial cortical porosity was significantly greater – signaling deterioration in microarchitecture – in athletes, compared with control subjects (P = .003), according to quantitative computed tomography measurements. There was also significantly lower tibial cortical bone mineral density (P = .008) among athletes relative to controls.

Conversely, tibial trabecular measures of bone density and architecture were better among athletes than controls, but this was expected and did not contradict the hypothesis of the study.

“Trabecular bone refers to the inner part of the bone, which increases with weight-bearing exercise, but cortical bone is the outer shell, and the source of stress fractures,” Dr. Haines explained.

The median age of both the athletes and the controls was 24 years. Baseline measurements were similar. Body mass index, fat mass, estradiol, and leptin were all numerically lower in the athletes than controls, but none were significant, although there was a trend for the difference in leptin (P = .085).
 

Hormones correlated with tibial failure load

When these characteristics were evaluated in the context of mean tibial failure load, a metric related to strength, there was a strongly significant positive association with lean body mass (R = 0.85; P < 0.001) and estradiol level (R = 0.66; P = .007). The relationship with leptin also reached significance (R = 0.59; P = .046).

Unexpectedly, there was no relationship between testosterone and tibial failure load. The reason is unclear, but Dr. Haines’s interpretation is that the relationship between specific hormonal disturbances and bone density loss “might not be as simple” as once hypothesized.

The next step is a longitudinal evaluation of the same group of athletes to follow changes in the relationship between these variables over time, according to Dr. Haines.

Eventually, with evidence that there is a causal relationship between nutrition, hormonal changes, and bone loss, the research in this area will focus on better detection of risk and prophylactic strategies.

“Intervention trials to show that we can prevent stress factors will be difficult to perform,” Dr. Haines acknowledged, but she said that preventing adverse changes in bone at relatively young ages could have implications for long-term bone health, including protection from osteoporosis later in life.

The research presented by Dr. Haines is consistent with an area of research that is several decades old, at least in females, according to Siobhan M. Statuta, MD, a sports medicine primary care specialist at the University of Virginia, Charlottesville. The evidence that the same phenomenon occurs in men is more recent, but she said that it is now well accepted the there is a parallel hormonal issue in men and women.

“It is not a question of not eating enough. Often, athletes continue to consume the same diet, but their activity increases,” Dr. Statuta explained. “The problem is that they are not supplying enough of the calories they need to sustain the energy they are expending. You might say they are not fueling their engines appropriately.”

In 2014, the International Olympic Committee published a consensus statement on RED-S. They described this as a condition in which a state of energy deficiency leads to numerous complications in athletes, not just osteoporosis. Rather, a host of physiological systems, ranging from gastrointestinal complaints to cardiovascular events, were described.
 

RED-S addresses health beyond bones

“The RED-S theory is better described as a spoke-and-wheel concept rather than a triad. While inadequate energy availability is important to both, RED-S places this at the center of the wheel with spokes leading to all the possible complications rather than as a first event in a limited triad,” Dr. Statuta said in an interview.

However, she noted that the term RED-S is not yet appropriate to replace that of the male and female athlete triad.

“More research is required to hash out the relationship of a body in a state of energy deficiency and how it affects the entire body, which is the principle of RED-S,” Dr. Statuta said. “There likely are scientific effects, and we are currently investigating these relationships more.”

“These are really quite similar entities but have different foci,” she added. Based on data collected over several decades, “the triad narrows in on two body systems affected by low energy – the reproductive system and bones. RED-S incorporates these same systems yet adds on many more organ systems.

The original group of researchers have remained loyal to the concept of the triad that involves inadequate availability of energy followed by hormonal irregularities and osteoporosis. This group, the Female and Male Athlete Triad Coalition, has issued publications on this topic several times. Consensus statements were updated last year.

“The premise is that the triad leading to bone loss is shared by both men and women, even if the clinical manifestations differ,” said Dr. Statuta. The most notable difference is that men do not experience menstrual irregularities, but Dr. Statuta suggested that the clinical consequences are not necessarily any less.

“Males do not have menstrual cycles as an outward marker of an endocrine disturbance, so it is harder to recognize clinically, but I think there is agreement that not having enough energy available is the trigger of endocrine changes and then bone loss is relevant to both sexes,” she said. She said this is supported by a growing body of evidence, including the data presented by Dr. Haines at the Endocrine Society meeting.

Dr. Haines and Dr. Statuta report no potential conflicts of interest.

Similar to a phenomenon already well documented in women, inadequate nutrition appears to be linked to hormonal abnormalities and potentially preventable tibial cortical bone density loss in athletic men, according to results of a small, prospective study.

Based on these findings, “we suspect that a subset of male runners might not be fueling their bodies with enough nutrition and calories for their physical activity,” reported Melanie S. Haines, MD, at the annual meeting of the Endocrine Society.

This is not the first study to suggest male athletes are at risk of a condition equivalent to what has been commonly referred to as the female athlete triad, but it enlarges the objective data that the phenomenon is real, and it makes insufficient availability of energy the likely cause.

In women, the triad is described as a lack of adequate stored energy, irregular menses, and bone density loss. In men, menstrual cycles are not relevant, of course, but this study like others suggests a link between the failure to maintain adequate stores of energy, disturbances in hormone function, and decreased bone density in both men and women, Dr. Haines explained.
 

RED-S vs. male or female athlete triad

“There is now a move away from the term female athlete triad or male athlete triad,” Dr. Haines reported. Rather the factors of failing to maintain adequate energy for metabolic demands, hormonal disturbances, and bone density loss appear to be relevant to both sexes, according to Dr. Haines, an endocrinologist at Massachusetts General Hospital and assistant professor of medicine at Harvard Medical School, both in Boston. She said several groups, including the International Olympic Committee (IOC), have transitioned to the term RED-S to apply to both sexes.

“RED-S is an acronym for relative energy deficiency in sport, and it appears to be gaining traction,” Dr. Haines said in an interview.

According to her study and others, excessive lean body mass from failure to supply sufficient energy for physiological needs “negatively affects hormones and bone,” Dr. Haines explained. In men and women, endocrine disturbances are triggered when insufficient calories lead to inadequate macro- and micronutrients.

In this study, 31 men aged 16-30 years were evaluated. Fifteen were in the athlete group, defined by running at least 30 miles per week for at least the previous 6 months. There were 16 control subjects; all exercised less than 2 hours per week and did not participate in team sports, but they were not permitted in the study if their body mass index exceeded 27.5 kg/m².
 

Athletes vs. otherwise healthy controls

Conditions that affect bone health were exclusion criteria in both groups, and neither group was permitted to take medications affecting bone health other than dietary calcium or vitamin D supplements for 2 months prior to the study.

Tibial cortical porosity was significantly greater – signaling deterioration in microarchitecture – in athletes, compared with control subjects (P = .003), according to quantitative computed tomography measurements. There was also significantly lower tibial cortical bone mineral density (P = .008) among athletes relative to controls.

Conversely, tibial trabecular measures of bone density and architecture were better among athletes than controls, but this was expected and did not contradict the hypothesis of the study.

“Trabecular bone refers to the inner part of the bone, which increases with weight-bearing exercise, but cortical bone is the outer shell, and the source of stress fractures,” Dr. Haines explained.

The median age of both the athletes and the controls was 24 years. Baseline measurements were similar. Body mass index, fat mass, estradiol, and leptin were all numerically lower in the athletes than controls, but none were significant, although there was a trend for the difference in leptin (P = .085).
 

Hormones correlated with tibial failure load

When these characteristics were evaluated in the context of mean tibial failure load, a metric related to strength, there was a strongly significant positive association with lean body mass (R = 0.85; P < 0.001) and estradiol level (R = 0.66; P = .007). The relationship with leptin also reached significance (R = 0.59; P = .046).

Unexpectedly, there was no relationship between testosterone and tibial failure load. The reason is unclear, but Dr. Haines’s interpretation is that the relationship between specific hormonal disturbances and bone density loss “might not be as simple” as once hypothesized.

The next step is a longitudinal evaluation of the same group of athletes to follow changes in the relationship between these variables over time, according to Dr. Haines.

Eventually, with evidence that there is a causal relationship between nutrition, hormonal changes, and bone loss, the research in this area will focus on better detection of risk and prophylactic strategies.

“Intervention trials to show that we can prevent stress factors will be difficult to perform,” Dr. Haines acknowledged, but she said that preventing adverse changes in bone at relatively young ages could have implications for long-term bone health, including protection from osteoporosis later in life.

The research presented by Dr. Haines is consistent with an area of research that is several decades old, at least in females, according to Siobhan M. Statuta, MD, a sports medicine primary care specialist at the University of Virginia, Charlottesville. The evidence that the same phenomenon occurs in men is more recent, but she said that it is now well accepted the there is a parallel hormonal issue in men and women.

“It is not a question of not eating enough. Often, athletes continue to consume the same diet, but their activity increases,” Dr. Statuta explained. “The problem is that they are not supplying enough of the calories they need to sustain the energy they are expending. You might say they are not fueling their engines appropriately.”

In 2014, the International Olympic Committee published a consensus statement on RED-S. They described this as a condition in which a state of energy deficiency leads to numerous complications in athletes, not just osteoporosis. Rather, a host of physiological systems, ranging from gastrointestinal complaints to cardiovascular events, were described.
 

RED-S addresses health beyond bones

“The RED-S theory is better described as a spoke-and-wheel concept rather than a triad. While inadequate energy availability is important to both, RED-S places this at the center of the wheel with spokes leading to all the possible complications rather than as a first event in a limited triad,” Dr. Statuta said in an interview.

However, she noted that the term RED-S is not yet appropriate to replace that of the male and female athlete triad.

“More research is required to hash out the relationship of a body in a state of energy deficiency and how it affects the entire body, which is the principle of RED-S,” Dr. Statuta said. “There likely are scientific effects, and we are currently investigating these relationships more.”

“These are really quite similar entities but have different foci,” she added. Based on data collected over several decades, “the triad narrows in on two body systems affected by low energy – the reproductive system and bones. RED-S incorporates these same systems yet adds on many more organ systems.

The original group of researchers have remained loyal to the concept of the triad that involves inadequate availability of energy followed by hormonal irregularities and osteoporosis. This group, the Female and Male Athlete Triad Coalition, has issued publications on this topic several times. Consensus statements were updated last year.

“The premise is that the triad leading to bone loss is shared by both men and women, even if the clinical manifestations differ,” said Dr. Statuta. The most notable difference is that men do not experience menstrual irregularities, but Dr. Statuta suggested that the clinical consequences are not necessarily any less.

“Males do not have menstrual cycles as an outward marker of an endocrine disturbance, so it is harder to recognize clinically, but I think there is agreement that not having enough energy available is the trigger of endocrine changes and then bone loss is relevant to both sexes,” she said. She said this is supported by a growing body of evidence, including the data presented by Dr. Haines at the Endocrine Society meeting.

Dr. Haines and Dr. Statuta report no potential conflicts of interest.

A phase 3 trial has associated the neurokinin-3 (NK3)–receptor inhibitor fezolinetant, an oral therapy taken once daily, with substantial control over the symptoms of menopause, according to results of the randomized SKYLIGHT 2 trial.

The nonhormonal therapy has the potential to address an important unmet need, Genevieve Neal-Perry, MD, PhD, said at the annual meeting of the Endocrine Society.

The health risks of hormone therapy (HT) have “caused quite a few women to consider whether hormone replacement is right for them, and, in addition, there are other individuals who have hormone-responsive cancers or other disorders that might prohibit them [from using HT],” Dr. Neal-Perry said.

The NK3 receptor stimulates the thermoregulatory center in the hypothalamus. By blocking the NK3 receptor, vasodilation and other downstream effects are inhibited, explained Dr. Neal-Perry. She credited relatively recent advances in understanding the mechanisms of menopausal symptoms for identifying this and other potentially targetable mediators.

SKYLIGHT 2 trial: Two phases

In the double-blind multinational phase 3 SKYLIGHT 2 trial, 484 otherwise healthy symptomatic menopausal women were randomized to 30 mg of fezolinetant, 45 mg of fezolinetant, or placebo. The 120 participating centers were in North American and Europe.

In the first phase, safety and efficacy were evaluated over 12 weeks. In a second extension phase, placebo patients were rerandomized to one of the fezolinetant study doses. Those on active therapy remained in their assigned groups. All patients were then followed for an additional 40 weeks.

The coprimary endpoints were frequency and severity of moderate to severe vasomotor symptoms as reported by patients using an electronic diary. There were several secondary endpoints, including patient-reported outcomes regarding sleep quality.

As expected from other controlled trials, placebo patients achieved about a 40% reduction in moderate to severe vasomotor symptom frequency over the first 12 weeks. Relative to placebo, symptom frequency declined more quickly and steeply on fezolinetant. By week 12, both achieved reductions of about 60%. Statistical P values for the differences in the three arms were not provided, but Dr. Neal-Perry reported they were significant.

Vasomotor severity, like frequency, is reduced

The change in vasomotor severity, which subjects in the trial rated as better or worse, was also significant. The differences in the severity curves were less, but they separated in favor of the two active treatment arms by about 2 weeks, and the curves continued to show an advantage for fezolinetant over both the first 12 weeks and then the remaining 40 weeks.

Overall, the decline in vasomotor symptom frequency remained on a persistent downward slope on both doses of fezolinetant for the full 52 weeks of the study, so that the reduction at 52 weeks was on the order of 25% greater than that seen at 12 weeks.

At 52 weeks, “you can see that individuals on placebo who were crossed over to an active treatment had a significant reduction in their hot flashes and look very much like those who were randomized to fezolinetant at the beginning of the study,” said Dr. Neal-Perry, who is chair of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.

Other outcomes also favored fezolinetant over placebo. For example, a reduction in sleep disturbance observed at 12 weeks was sustained over the full 52 weeks of the study. The reduction in sleep symptoms appeared to be slightly greater on the higher dose, but the benefit at 52 weeks among patients after the crossover was similar on either active arm.

No serious side effects identified

There were no serious drug-related treatment-emergent adverse events in any treatment group. One patient in the placebo arm (< 1%), two patients in the 30-mg fezolinetant arm (1.2%), and five patients in the 45-mg arm (3%) discontinued therapy for an adverse event considered to be treatment related.

“The most common side effect associated with fezolinetant was headache. There were no other side effects that led patients to pull out of the study,” Dr. Neal-Perry reported at the meeting, which was held in Atlanta and virtually.

According to Dr. Neal-Perry the vasomotor symptoms relative to menopause, which occur in almost all women, are moderate to severe in an estimated 35%-45%. Some groups, such as those with an elevated body mass index and African Americans, appear to be at even greater risk. Study enrollment was specifically designed to include these high-risk groups, but the subgroup efficacy data have not yet been analyzed.

Other drugs with a similar mechanism of action have not been brought forward because of concern about elevated liver enzymes, but Dr. Neal-Perry said that this does not appear to be an issue for fezolinetant, which was designed with greater specificity for the NK3 target than previous treatments.

If fezolinetant is approved, Dr. Neal-Perry expects this agent to fulfill an important unmet need because of the limitations of other nonhormonal solutions for control of menopause symptoms.

HT alternatives limited

For control of many menopause symptoms, particularly hot flashes, hormone therapy (HT) is the most efficacious, but Richard J. Santen, MD, emeritus professor and an endocrinologist at the University of Virginia, Charlottesville, agreed there is a need for alternatives.

In addition to those who have contraindications for HT, Dr. Santen said in an interview that this option is not acceptable to others “for a variety of reasons.” The problem is that the alternatives are limited.

“The SSRI agents and gabapentin are alternative nonhormonal agents, but they have side effects and are not as effective,” he said. Hot flashes “can be a major disruptor of quality of life,” so he is intrigued with the positive results achieved with fezolinetant.

“A new drug such as reported at the Endocrine Society meeting would be an important new addition to the armamentarium,” he said.

Dr. Neal-Perry reports no conflicts of interest.

A phase 3 trial has associated the neurokinin-3 (NK3)–receptor inhibitor fezolinetant, an oral therapy taken once daily, with substantial control over the symptoms of menopause, according to results of the randomized SKYLIGHT 2 trial.

The nonhormonal therapy has the potential to address an important unmet need, Genevieve Neal-Perry, MD, PhD, said at the annual meeting of the Endocrine Society.

The health risks of hormone therapy (HT) have “caused quite a few women to consider whether hormone replacement is right for them, and, in addition, there are other individuals who have hormone-responsive cancers or other disorders that might prohibit them [from using HT],” Dr. Neal-Perry said.

The NK3 receptor stimulates the thermoregulatory center in the hypothalamus. By blocking the NK3 receptor, vasodilation and other downstream effects are inhibited, explained Dr. Neal-Perry. She credited relatively recent advances in understanding the mechanisms of menopausal symptoms for identifying this and other potentially targetable mediators.

SKYLIGHT 2 trial: Two phases

In the double-blind multinational phase 3 SKYLIGHT 2 trial, 484 otherwise healthy symptomatic menopausal women were randomized to 30 mg of fezolinetant, 45 mg of fezolinetant, or placebo. The 120 participating centers were in North American and Europe.

In the first phase, safety and efficacy were evaluated over 12 weeks. In a second extension phase, placebo patients were rerandomized to one of the fezolinetant study doses. Those on active therapy remained in their assigned groups. All patients were then followed for an additional 40 weeks.

The coprimary endpoints were frequency and severity of moderate to severe vasomotor symptoms as reported by patients using an electronic diary. There were several secondary endpoints, including patient-reported outcomes regarding sleep quality.

As expected from other controlled trials, placebo patients achieved about a 40% reduction in moderate to severe vasomotor symptom frequency over the first 12 weeks. Relative to placebo, symptom frequency declined more quickly and steeply on fezolinetant. By week 12, both achieved reductions of about 60%. Statistical P values for the differences in the three arms were not provided, but Dr. Neal-Perry reported they were significant.

Vasomotor severity, like frequency, is reduced

The change in vasomotor severity, which subjects in the trial rated as better or worse, was also significant. The differences in the severity curves were less, but they separated in favor of the two active treatment arms by about 2 weeks, and the curves continued to show an advantage for fezolinetant over both the first 12 weeks and then the remaining 40 weeks.

Overall, the decline in vasomotor symptom frequency remained on a persistent downward slope on both doses of fezolinetant for the full 52 weeks of the study, so that the reduction at 52 weeks was on the order of 25% greater than that seen at 12 weeks.

At 52 weeks, “you can see that individuals on placebo who were crossed over to an active treatment had a significant reduction in their hot flashes and look very much like those who were randomized to fezolinetant at the beginning of the study,” said Dr. Neal-Perry, who is chair of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.

Other outcomes also favored fezolinetant over placebo. For example, a reduction in sleep disturbance observed at 12 weeks was sustained over the full 52 weeks of the study. The reduction in sleep symptoms appeared to be slightly greater on the higher dose, but the benefit at 52 weeks among patients after the crossover was similar on either active arm.

No serious side effects identified

There were no serious drug-related treatment-emergent adverse events in any treatment group. One patient in the placebo arm (< 1%), two patients in the 30-mg fezolinetant arm (1.2%), and five patients in the 45-mg arm (3%) discontinued therapy for an adverse event considered to be treatment related.

“The most common side effect associated with fezolinetant was headache. There were no other side effects that led patients to pull out of the study,” Dr. Neal-Perry reported at the meeting, which was held in Atlanta and virtually.

According to Dr. Neal-Perry the vasomotor symptoms relative to menopause, which occur in almost all women, are moderate to severe in an estimated 35%-45%. Some groups, such as those with an elevated body mass index and African Americans, appear to be at even greater risk. Study enrollment was specifically designed to include these high-risk groups, but the subgroup efficacy data have not yet been analyzed.

Other drugs with a similar mechanism of action have not been brought forward because of concern about elevated liver enzymes, but Dr. Neal-Perry said that this does not appear to be an issue for fezolinetant, which was designed with greater specificity for the NK3 target than previous treatments.

If fezolinetant is approved, Dr. Neal-Perry expects this agent to fulfill an important unmet need because of the limitations of other nonhormonal solutions for control of menopause symptoms.

HT alternatives limited

For control of many menopause symptoms, particularly hot flashes, hormone therapy (HT) is the most efficacious, but Richard J. Santen, MD, emeritus professor and an endocrinologist at the University of Virginia, Charlottesville, agreed there is a need for alternatives.

In addition to those who have contraindications for HT, Dr. Santen said in an interview that this option is not acceptable to others “for a variety of reasons.” The problem is that the alternatives are limited.

“The SSRI agents and gabapentin are alternative nonhormonal agents, but they have side effects and are not as effective,” he said. Hot flashes “can be a major disruptor of quality of life,” so he is intrigued with the positive results achieved with fezolinetant.

“A new drug such as reported at the Endocrine Society meeting would be an important new addition to the armamentarium,” he said.

Dr. Neal-Perry reports no conflicts of interest.

A phase 3 trial has associated the neurokinin-3 (NK3)–receptor inhibitor fezolinetant, an oral therapy taken once daily, with substantial control over the symptoms of menopause, according to results of the randomized SKYLIGHT 2 trial.

The nonhormonal therapy has the potential to address an important unmet need, Genevieve Neal-Perry, MD, PhD, said at the annual meeting of the Endocrine Society.

The health risks of hormone therapy (HT) have “caused quite a few women to consider whether hormone replacement is right for them, and, in addition, there are other individuals who have hormone-responsive cancers or other disorders that might prohibit them [from using HT],” Dr. Neal-Perry said.

The NK3 receptor stimulates the thermoregulatory center in the hypothalamus. By blocking the NK3 receptor, vasodilation and other downstream effects are inhibited, explained Dr. Neal-Perry. She credited relatively recent advances in understanding the mechanisms of menopausal symptoms for identifying this and other potentially targetable mediators.

SKYLIGHT 2 trial: Two phases

In the double-blind multinational phase 3 SKYLIGHT 2 trial, 484 otherwise healthy symptomatic menopausal women were randomized to 30 mg of fezolinetant, 45 mg of fezolinetant, or placebo. The 120 participating centers were in North American and Europe.

In the first phase, safety and efficacy were evaluated over 12 weeks. In a second extension phase, placebo patients were rerandomized to one of the fezolinetant study doses. Those on active therapy remained in their assigned groups. All patients were then followed for an additional 40 weeks.

The coprimary endpoints were frequency and severity of moderate to severe vasomotor symptoms as reported by patients using an electronic diary. There were several secondary endpoints, including patient-reported outcomes regarding sleep quality.

As expected from other controlled trials, placebo patients achieved about a 40% reduction in moderate to severe vasomotor symptom frequency over the first 12 weeks. Relative to placebo, symptom frequency declined more quickly and steeply on fezolinetant. By week 12, both achieved reductions of about 60%. Statistical P values for the differences in the three arms were not provided, but Dr. Neal-Perry reported they were significant.

Vasomotor severity, like frequency, is reduced

The change in vasomotor severity, which subjects in the trial rated as better or worse, was also significant. The differences in the severity curves were less, but they separated in favor of the two active treatment arms by about 2 weeks, and the curves continued to show an advantage for fezolinetant over both the first 12 weeks and then the remaining 40 weeks.

Overall, the decline in vasomotor symptom frequency remained on a persistent downward slope on both doses of fezolinetant for the full 52 weeks of the study, so that the reduction at 52 weeks was on the order of 25% greater than that seen at 12 weeks.

At 52 weeks, “you can see that individuals on placebo who were crossed over to an active treatment had a significant reduction in their hot flashes and look very much like those who were randomized to fezolinetant at the beginning of the study,” said Dr. Neal-Perry, who is chair of the department of obstetrics and gynecology at the University of North Carolina at Chapel Hill.

Other outcomes also favored fezolinetant over placebo. For example, a reduction in sleep disturbance observed at 12 weeks was sustained over the full 52 weeks of the study. The reduction in sleep symptoms appeared to be slightly greater on the higher dose, but the benefit at 52 weeks among patients after the crossover was similar on either active arm.

No serious side effects identified

There were no serious drug-related treatment-emergent adverse events in any treatment group. One patient in the placebo arm (< 1%), two patients in the 30-mg fezolinetant arm (1.2%), and five patients in the 45-mg arm (3%) discontinued therapy for an adverse event considered to be treatment related.

“The most common side effect associated with fezolinetant was headache. There were no other side effects that led patients to pull out of the study,” Dr. Neal-Perry reported at the meeting, which was held in Atlanta and virtually.

According to Dr. Neal-Perry the vasomotor symptoms relative to menopause, which occur in almost all women, are moderate to severe in an estimated 35%-45%. Some groups, such as those with an elevated body mass index and African Americans, appear to be at even greater risk. Study enrollment was specifically designed to include these high-risk groups, but the subgroup efficacy data have not yet been analyzed.

Other drugs with a similar mechanism of action have not been brought forward because of concern about elevated liver enzymes, but Dr. Neal-Perry said that this does not appear to be an issue for fezolinetant, which was designed with greater specificity for the NK3 target than previous treatments.

If fezolinetant is approved, Dr. Neal-Perry expects this agent to fulfill an important unmet need because of the limitations of other nonhormonal solutions for control of menopause symptoms.

HT alternatives limited

For control of many menopause symptoms, particularly hot flashes, hormone therapy (HT) is the most efficacious, but Richard J. Santen, MD, emeritus professor and an endocrinologist at the University of Virginia, Charlottesville, agreed there is a need for alternatives.

In addition to those who have contraindications for HT, Dr. Santen said in an interview that this option is not acceptable to others “for a variety of reasons.” The problem is that the alternatives are limited.

“The SSRI agents and gabapentin are alternative nonhormonal agents, but they have side effects and are not as effective,” he said. Hot flashes “can be a major disruptor of quality of life,” so he is intrigued with the positive results achieved with fezolinetant.

“A new drug such as reported at the Endocrine Society meeting would be an important new addition to the armamentarium,” he said.

Dr. Neal-Perry reports no conflicts of interest.

Prediabetes is not only a predictor of diabetes and the cardiovascular complications that ensue, but it is also a risk factor by itself for myocardial infarction, according to data drawn from almost 1.8 million patients hospitalized for MI.

“Our study serves as a wakeup call for clinicians and patients to shift the focus to preventing prediabetes, and not just diabetes, said Geethika Thota, MD, at the annual meeting of the Endocrine Society.

There are plenty of data suggesting that prediabetes places patients on a trajectory toward cardiovascular disease. In a meta-analysis of 129 studies published 2 years ago, prediabetes was not only associated with a statistically significant 16% increase in coronary heart disease, but also a 13% increased risk of all-cause mortality relative to those with normoglycemia.
 

Data drawn from 1.8 million patients

In this study, 1,794,149 weighted patient hospitalizations for MI were drawn from the National Inpatient Sample database. Excluding patients who eventually developed diabetes, roughly 1% of these patients had a history of prediabetes in the past, according to a search of ICD-10 codes.

Before adjustment for other risk factors, prediabetes was linked to a greater than 40% increased odds of MI (odds ratio, 1.41; P < .01). After adjustment for a large array of known MI risk factors – including prior history of MI, dyslipidemia, hypertension, nicotine dependence, and obesity – prediabetes remained an independent risk factor, corresponding with a 25% increased risk of MI (OR, 1.25; P < .01).

A history of prediabetes was also an independent risk factor for percutaneous intervention and coronary artery bypass grafting, with increased risk of 45% and 95%, respectively.

As a retrospective study looking at prediabetes as a risk factor in those who already had a MI, it is possible that not all patients with prediabetes were properly coded, but Dr. Thota said that was unlikely to have been an issue of sufficient magnitude to have affected the major conclusions.
 

Relevance seen for community care

Although the study was drawn from hospitalized patients, its relevance is for the community setting, where screening and intervention for prediabetes has the potential to alter the risk, according to Dr. Thota.

Most clinicians are likely aware of the value of screening for prediabetes, which was defined in this study as a hemoglobin A1c of 5.7%-6.4%, but Dr. Thota suggested that many might not fully grasp the full scope of goals. Early detection and prevention will prevent diabetes and, by extension, cardiovascular disease, but her data suggest that control of prediabetes with lower cardiovascular risk by a more direct route.

“Despite mounting evidence, many clinicians are unaware that prediabetes is also a major risk factor for atherosclerotic cardiovascular disease,” said Dr. Thota, an internal medicine resident at Saint Peter’s University Hospital, New Brunswick, N.J.

Like diabetes, the prevalence of prediabetes is growing rapidly, according to data from the Centers for Disease Control that Dr. Thota cited. In 2020, the Centers for Disease Control and Prevention estimated that 38% of the adult population have prediabetes. By 2030, one model predicts a further 25% growth.

Screening for hyperglycemia is part of routine patient evaluations at Dr. Thota’s center. In an interview, she said that once a diagnosis of prediabetes is entered in the electronic medical record, the history is carried forward so that changes in status are continually monitored.
 

Worsening prediabetes should be addressed

“Prediabetes is not treated with medication, at least initially,” Dr. Thota explained. Rather, patients are educated about important lifestyle changes, such as diet and physical activity, that can reverse the diagnosis. However, patients who remain on a path of worsening hyperglycemia are candidates for more intensive lifestyle intervention and might be considered selectively for metformin.

“Early recognition of prediabetes through screening is important,” Dr. Thota emphasized. The benefit for preventing patients from progressing to diabetes is well recognized, but these data provide the basis for incentivizing lifestyle changes in patients with prediabetes by telling them that it can reduce their risk for MI.

These data have an important message, but they are not surprising, according to Deepak L. Bhatt, MD, executive director, interventional cardiovascular programs, Brigham and Women’s Hospital Heart & Vascular Center, Boston.

“In fact, in daily practice we see a substantial percentage of patients with MI who have prediabetes that had not been previously recognized or formally diagnosed,” Dr. Bhatt said in an interview.

“Identifying these patients – preferably prior to coming in with cardiovascular complications – is important both to reduce cardiovascular risk but also to try and prevent progression at diabetes,” he added.

Dr. Bhatt went on to say that this large analysis, confirming that prediabetes is independently associated with MI, should prompt clinicians to screen patients rigorously for this condition.

“At a minimum, such patients would be candidates for intensive lifestyle modification aimed at weight loss and treatment of frequent coexistent conditions, such as hypertension and dyslipidemia,” Dr. Bhatt said.

Dr. Thota reports no potential conflicts of interest. Dr. Bhatt has financial relationships with more than 30 pharmaceutical companies, many of which make products relevant to the management of diabetes and cardiovascular disease.

Prediabetes is not only a predictor of diabetes and the cardiovascular complications that ensue, but it is also a risk factor by itself for myocardial infarction, according to data drawn from almost 1.8 million patients hospitalized for MI.

“Our study serves as a wakeup call for clinicians and patients to shift the focus to preventing prediabetes, and not just diabetes, said Geethika Thota, MD, at the annual meeting of the Endocrine Society.

There are plenty of data suggesting that prediabetes places patients on a trajectory toward cardiovascular disease. In a meta-analysis of 129 studies published 2 years ago, prediabetes was not only associated with a statistically significant 16% increase in coronary heart disease, but also a 13% increased risk of all-cause mortality relative to those with normoglycemia.
 

Data drawn from 1.8 million patients

In this study, 1,794,149 weighted patient hospitalizations for MI were drawn from the National Inpatient Sample database. Excluding patients who eventually developed diabetes, roughly 1% of these patients had a history of prediabetes in the past, according to a search of ICD-10 codes.

Before adjustment for other risk factors, prediabetes was linked to a greater than 40% increased odds of MI (odds ratio, 1.41; P < .01). After adjustment for a large array of known MI risk factors – including prior history of MI, dyslipidemia, hypertension, nicotine dependence, and obesity – prediabetes remained an independent risk factor, corresponding with a 25% increased risk of MI (OR, 1.25; P < .01).

A history of prediabetes was also an independent risk factor for percutaneous intervention and coronary artery bypass grafting, with increased risk of 45% and 95%, respectively.

As a retrospective study looking at prediabetes as a risk factor in those who already had a MI, it is possible that not all patients with prediabetes were properly coded, but Dr. Thota said that was unlikely to have been an issue of sufficient magnitude to have affected the major conclusions.
 

Relevance seen for community care

Although the study was drawn from hospitalized patients, its relevance is for the community setting, where screening and intervention for prediabetes has the potential to alter the risk, according to Dr. Thota.

Most clinicians are likely aware of the value of screening for prediabetes, which was defined in this study as a hemoglobin A1c of 5.7%-6.4%, but Dr. Thota suggested that many might not fully grasp the full scope of goals. Early detection and prevention will prevent diabetes and, by extension, cardiovascular disease, but her data suggest that control of prediabetes with lower cardiovascular risk by a more direct route.

“Despite mounting evidence, many clinicians are unaware that prediabetes is also a major risk factor for atherosclerotic cardiovascular disease,” said Dr. Thota, an internal medicine resident at Saint Peter’s University Hospital, New Brunswick, N.J.

Like diabetes, the prevalence of prediabetes is growing rapidly, according to data from the Centers for Disease Control that Dr. Thota cited. In 2020, the Centers for Disease Control and Prevention estimated that 38% of the adult population have prediabetes. By 2030, one model predicts a further 25% growth.

Screening for hyperglycemia is part of routine patient evaluations at Dr. Thota’s center. In an interview, she said that once a diagnosis of prediabetes is entered in the electronic medical record, the history is carried forward so that changes in status are continually monitored.
 

Worsening prediabetes should be addressed

“Prediabetes is not treated with medication, at least initially,” Dr. Thota explained. Rather, patients are educated about important lifestyle changes, such as diet and physical activity, that can reverse the diagnosis. However, patients who remain on a path of worsening hyperglycemia are candidates for more intensive lifestyle intervention and might be considered selectively for metformin.

“Early recognition of prediabetes through screening is important,” Dr. Thota emphasized. The benefit for preventing patients from progressing to diabetes is well recognized, but these data provide the basis for incentivizing lifestyle changes in patients with prediabetes by telling them that it can reduce their risk for MI.

These data have an important message, but they are not surprising, according to Deepak L. Bhatt, MD, executive director, interventional cardiovascular programs, Brigham and Women’s Hospital Heart & Vascular Center, Boston.

“In fact, in daily practice we see a substantial percentage of patients with MI who have prediabetes that had not been previously recognized or formally diagnosed,” Dr. Bhatt said in an interview.

“Identifying these patients – preferably prior to coming in with cardiovascular complications – is important both to reduce cardiovascular risk but also to try and prevent progression at diabetes,” he added.

Dr. Bhatt went on to say that this large analysis, confirming that prediabetes is independently associated with MI, should prompt clinicians to screen patients rigorously for this condition.

“At a minimum, such patients would be candidates for intensive lifestyle modification aimed at weight loss and treatment of frequent coexistent conditions, such as hypertension and dyslipidemia,” Dr. Bhatt said.

Dr. Thota reports no potential conflicts of interest. Dr. Bhatt has financial relationships with more than 30 pharmaceutical companies, many of which make products relevant to the management of diabetes and cardiovascular disease.

Prediabetes is not only a predictor of diabetes and the cardiovascular complications that ensue, but it is also a risk factor by itself for myocardial infarction, according to data drawn from almost 1.8 million patients hospitalized for MI.

“Our study serves as a wakeup call for clinicians and patients to shift the focus to preventing prediabetes, and not just diabetes, said Geethika Thota, MD, at the annual meeting of the Endocrine Society.

There are plenty of data suggesting that prediabetes places patients on a trajectory toward cardiovascular disease. In a meta-analysis of 129 studies published 2 years ago, prediabetes was not only associated with a statistically significant 16% increase in coronary heart disease, but also a 13% increased risk of all-cause mortality relative to those with normoglycemia.
 

Data drawn from 1.8 million patients

In this study, 1,794,149 weighted patient hospitalizations for MI were drawn from the National Inpatient Sample database. Excluding patients who eventually developed diabetes, roughly 1% of these patients had a history of prediabetes in the past, according to a search of ICD-10 codes.

Before adjustment for other risk factors, prediabetes was linked to a greater than 40% increased odds of MI (odds ratio, 1.41; P < .01). After adjustment for a large array of known MI risk factors – including prior history of MI, dyslipidemia, hypertension, nicotine dependence, and obesity – prediabetes remained an independent risk factor, corresponding with a 25% increased risk of MI (OR, 1.25; P < .01).

A history of prediabetes was also an independent risk factor for percutaneous intervention and coronary artery bypass grafting, with increased risk of 45% and 95%, respectively.

As a retrospective study looking at prediabetes as a risk factor in those who already had a MI, it is possible that not all patients with prediabetes were properly coded, but Dr. Thota said that was unlikely to have been an issue of sufficient magnitude to have affected the major conclusions.
 

Relevance seen for community care

Although the study was drawn from hospitalized patients, its relevance is for the community setting, where screening and intervention for prediabetes has the potential to alter the risk, according to Dr. Thota.

Most clinicians are likely aware of the value of screening for prediabetes, which was defined in this study as a hemoglobin A1c of 5.7%-6.4%, but Dr. Thota suggested that many might not fully grasp the full scope of goals. Early detection and prevention will prevent diabetes and, by extension, cardiovascular disease, but her data suggest that control of prediabetes with lower cardiovascular risk by a more direct route.

“Despite mounting evidence, many clinicians are unaware that prediabetes is also a major risk factor for atherosclerotic cardiovascular disease,” said Dr. Thota, an internal medicine resident at Saint Peter’s University Hospital, New Brunswick, N.J.

Like diabetes, the prevalence of prediabetes is growing rapidly, according to data from the Centers for Disease Control that Dr. Thota cited. In 2020, the Centers for Disease Control and Prevention estimated that 38% of the adult population have prediabetes. By 2030, one model predicts a further 25% growth.

Screening for hyperglycemia is part of routine patient evaluations at Dr. Thota’s center. In an interview, she said that once a diagnosis of prediabetes is entered in the electronic medical record, the history is carried forward so that changes in status are continually monitored.
 

Worsening prediabetes should be addressed

“Prediabetes is not treated with medication, at least initially,” Dr. Thota explained. Rather, patients are educated about important lifestyle changes, such as diet and physical activity, that can reverse the diagnosis. However, patients who remain on a path of worsening hyperglycemia are candidates for more intensive lifestyle intervention and might be considered selectively for metformin.

“Early recognition of prediabetes through screening is important,” Dr. Thota emphasized. The benefit for preventing patients from progressing to diabetes is well recognized, but these data provide the basis for incentivizing lifestyle changes in patients with prediabetes by telling them that it can reduce their risk for MI.

These data have an important message, but they are not surprising, according to Deepak L. Bhatt, MD, executive director, interventional cardiovascular programs, Brigham and Women’s Hospital Heart & Vascular Center, Boston.

“In fact, in daily practice we see a substantial percentage of patients with MI who have prediabetes that had not been previously recognized or formally diagnosed,” Dr. Bhatt said in an interview.

“Identifying these patients – preferably prior to coming in with cardiovascular complications – is important both to reduce cardiovascular risk but also to try and prevent progression at diabetes,” he added.

Dr. Bhatt went on to say that this large analysis, confirming that prediabetes is independently associated with MI, should prompt clinicians to screen patients rigorously for this condition.

“At a minimum, such patients would be candidates for intensive lifestyle modification aimed at weight loss and treatment of frequent coexistent conditions, such as hypertension and dyslipidemia,” Dr. Bhatt said.

Dr. Thota reports no potential conflicts of interest. Dr. Bhatt has financial relationships with more than 30 pharmaceutical companies, many of which make products relevant to the management of diabetes and cardiovascular disease.

ATLANTA – Potential once-daily male oral contraceptives have passed a first clinical hurdle, showing a degree of testosterone suppression that should be sufficient for a contraceptive effect without causing symptomatic hypogonadism, according to phase 1 study results to be presented at the annual meeting of the Endocrine Society.

Credit: Flickr/Marco Verch Professional Photographer/CC by 2.0

There are two pills in development and the studies so far suggest that both or a combination might be able to provide an acceptable balance of efficacy and tolerability, according to Tamar Jacobsohn, a researcher in the Contraceptive Development Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md.

The two drugs evaluated in this study are dimethandrolone undecanoate (DMAU) and 11b-methyl-19-nortestosterone-17b-dodecylcarbonate (11b-MNTDC). Both are bifunctional prodrugs with androgenic and progestogenic effects. The prodrugs are designed to be cleaved after ingestion so that the active hormones are released over 24 hours, permitting once-daily dosing.

“As potent androgens, these steroids suppress gonadotropin secretion, leading to markedly decreased serum testosterone production,” explained Ms. Jacobsohn in an interview.

However, she noted that there is still a long way to go on this research path. While the phase 1 studies have shown tolerability, the biology involved in suppressing sperm production suggests that men would need to take these pills daily for about 3 months at the very beginning of contraceptive treatment, until adequate sperm suppression is achieved to prevent pregnancy.

“We are working toward a phase 2 trial that will include a contraceptive efficacy endpoint, but there are lots of steps to get there, including more early phase studies,” she noted.

“There is a huge unmet need in terms of male contraceptive methods,” said Arthi Thirumalai, MBBS, an endocrinologist and assistant professor of medicine at the University of Washington School of Medicine in Seattle.

Senior author of a 2020 review article on male contraception, Dr. Thirumalai said in an interview that prodrugs and other hormonal methods to lower testosterone and suppress sperm production are attractive because of convenience, efficacy, and reversibility,

“We hope that oral formulations can be used to address this need,” said Dr. Thirumalai, who has participated in several experimental and clinical studies of male contraception methods. She is, in fact, one of the many coauthors of the data presented by Ms. Jacobsohn.

Ms. Jacobsohn emphasized: “Development of an effective, reversible male contraceptive method will improve reproductive options for men and women, have a major impact on public health by decreasing unintended pregnancy, and allow men to have an increasingly active role in family planning.”

Phase 1 results with DMAU and MNTDC

The work that led to phase 1 studies suggested that each of the drugs — DMAU and MNTDC — might provide adequate hormone suppression to reduce sperm counts without inducing unacceptable symptoms of hypogonadism. To test this potential, dose-ranging phase 1 studies with an endpoint of testosterone suppression were conducted with each one.

In the two placebo-controlled phase 1a studies, which are to be presented in a poster on June 13, healthy male subjects were randomly assigned to two pills of active therapy, four pills of active therapy, or placebo. In the two studies combined, 39 subjects received DMAU, 30 received 11b-MNTDC, and 28 received placebo.

Efficacy was evaluated by measuring testosterone levels. Tolerability was largely based on patient questionnaires.

At the end of 7 days, testosterone levels remained at reference levels (400 to 600 ng/dL) in those who received placebo. The levels fell to less than 100 ng/dL in all subjects assigned to an active agent regardless of which agent or dose was used.

From day 7 to 28, there was less median suppression of testosterone on 200 mg than 400 mg daily (92.7 ng/dL vs. 49.6 ng/dL; P < .001), but both remained below the target of 100 ng/dL, Ms. Jacobsohn reported.

The difference in degree of testosterone suppression did not appear to influence tolerability.

Subjects on four vs. two daily pills “did not report a significant difference in general satisfaction or their willingness to use the pills in the future or recommend them to other men,” said Ms. Jacobson, presenting P values for these outcomes among subjects on active therapy relative to placebo that were not significant, ranging from 0.48 to 0.85.

Overall, there were no serious adverse events. Mild side effects associated with hypogonadism did occur, but “all resolved by the end of the study,” she said.

Zero sperm production is not the goal. Lowering it sufficiently is

Dr. Thirumalai said the need for a male contraceptive is strong. While condoms have a substantial failure rate, vasectomy is not reliably reversible even though the majority of men agree that the responsibility for preventing pregnancy should be shared, she said.

Dr. Thirumalai’s earlier review article found that clinical trials of hormonal suppression to provide male contraception have been conducted for at least 30 years. The challenge has been finding an effective therapy that is well tolerated.

Drugs that combine both androgenic and progestogenic activity might be the answer. By manipulating hormones that lower testosterone, sperm production is reduced without eliminating a man’s ability to ejaculate. Zero sperm production is not the goal, according to data in Dr. Thirumalai’s review article.

Rather, studies suggest that when ejaculate contains less than 1 million sperm per mL (levels typically range from 15 to 200 million sperm/mL), the antipregnancy efficacy is similar to that achieved with female oral contraceptives.

However, clinical trials to demonstrate that this can be achieved safely have yet to be conducted.

Ms. Jacobsohn said that sperm half-life is about 3 months. This means that patients would need to be on hormonal therapy for a period of about this duration before reliable contraception is achieved.

In other words, the efficacy endpoint used in this current study [of 28 days duration] does not ensure effective contraception, but Ms. Jacobsohn suggested this is nevertheless an important step forward in clinical development.

Ms. Jacobsohn and Dr. Thirumalai report no relevant financial relationships.

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

ATLANTA – Potential once-daily male oral contraceptives have passed a first clinical hurdle, showing a degree of testosterone suppression that should be sufficient for a contraceptive effect without causing symptomatic hypogonadism, according to phase 1 study results to be presented at the annual meeting of the Endocrine Society.

Credit: Flickr/Marco Verch Professional Photographer/CC by 2.0

There are two pills in development and the studies so far suggest that both or a combination might be able to provide an acceptable balance of efficacy and tolerability, according to Tamar Jacobsohn, a researcher in the Contraceptive Development Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md.

The two drugs evaluated in this study are dimethandrolone undecanoate (DMAU) and 11b-methyl-19-nortestosterone-17b-dodecylcarbonate (11b-MNTDC). Both are bifunctional prodrugs with androgenic and progestogenic effects. The prodrugs are designed to be cleaved after ingestion so that the active hormones are released over 24 hours, permitting once-daily dosing.

“As potent androgens, these steroids suppress gonadotropin secretion, leading to markedly decreased serum testosterone production,” explained Ms. Jacobsohn in an interview.

However, she noted that there is still a long way to go on this research path. While the phase 1 studies have shown tolerability, the biology involved in suppressing sperm production suggests that men would need to take these pills daily for about 3 months at the very beginning of contraceptive treatment, until adequate sperm suppression is achieved to prevent pregnancy.

“We are working toward a phase 2 trial that will include a contraceptive efficacy endpoint, but there are lots of steps to get there, including more early phase studies,” she noted.

“There is a huge unmet need in terms of male contraceptive methods,” said Arthi Thirumalai, MBBS, an endocrinologist and assistant professor of medicine at the University of Washington School of Medicine in Seattle.

Senior author of a 2020 review article on male contraception, Dr. Thirumalai said in an interview that prodrugs and other hormonal methods to lower testosterone and suppress sperm production are attractive because of convenience, efficacy, and reversibility,

“We hope that oral formulations can be used to address this need,” said Dr. Thirumalai, who has participated in several experimental and clinical studies of male contraception methods. She is, in fact, one of the many coauthors of the data presented by Ms. Jacobsohn.

Ms. Jacobsohn emphasized: “Development of an effective, reversible male contraceptive method will improve reproductive options for men and women, have a major impact on public health by decreasing unintended pregnancy, and allow men to have an increasingly active role in family planning.”

Phase 1 results with DMAU and MNTDC

The work that led to phase 1 studies suggested that each of the drugs — DMAU and MNTDC — might provide adequate hormone suppression to reduce sperm counts without inducing unacceptable symptoms of hypogonadism. To test this potential, dose-ranging phase 1 studies with an endpoint of testosterone suppression were conducted with each one.

In the two placebo-controlled phase 1a studies, which are to be presented in a poster on June 13, healthy male subjects were randomly assigned to two pills of active therapy, four pills of active therapy, or placebo. In the two studies combined, 39 subjects received DMAU, 30 received 11b-MNTDC, and 28 received placebo.

Efficacy was evaluated by measuring testosterone levels. Tolerability was largely based on patient questionnaires.

At the end of 7 days, testosterone levels remained at reference levels (400 to 600 ng/dL) in those who received placebo. The levels fell to less than 100 ng/dL in all subjects assigned to an active agent regardless of which agent or dose was used.

From day 7 to 28, there was less median suppression of testosterone on 200 mg than 400 mg daily (92.7 ng/dL vs. 49.6 ng/dL; P < .001), but both remained below the target of 100 ng/dL, Ms. Jacobsohn reported.

The difference in degree of testosterone suppression did not appear to influence tolerability.

Subjects on four vs. two daily pills “did not report a significant difference in general satisfaction or their willingness to use the pills in the future or recommend them to other men,” said Ms. Jacobson, presenting P values for these outcomes among subjects on active therapy relative to placebo that were not significant, ranging from 0.48 to 0.85.

Overall, there were no serious adverse events. Mild side effects associated with hypogonadism did occur, but “all resolved by the end of the study,” she said.

Zero sperm production is not the goal. Lowering it sufficiently is

Dr. Thirumalai said the need for a male contraceptive is strong. While condoms have a substantial failure rate, vasectomy is not reliably reversible even though the majority of men agree that the responsibility for preventing pregnancy should be shared, she said.

Dr. Thirumalai’s earlier review article found that clinical trials of hormonal suppression to provide male contraception have been conducted for at least 30 years. The challenge has been finding an effective therapy that is well tolerated.

Drugs that combine both androgenic and progestogenic activity might be the answer. By manipulating hormones that lower testosterone, sperm production is reduced without eliminating a man’s ability to ejaculate. Zero sperm production is not the goal, according to data in Dr. Thirumalai’s review article.

Rather, studies suggest that when ejaculate contains less than 1 million sperm per mL (levels typically range from 15 to 200 million sperm/mL), the antipregnancy efficacy is similar to that achieved with female oral contraceptives.

However, clinical trials to demonstrate that this can be achieved safely have yet to be conducted.

Ms. Jacobsohn said that sperm half-life is about 3 months. This means that patients would need to be on hormonal therapy for a period of about this duration before reliable contraception is achieved.

In other words, the efficacy endpoint used in this current study [of 28 days duration] does not ensure effective contraception, but Ms. Jacobsohn suggested this is nevertheless an important step forward in clinical development.

Ms. Jacobsohn and Dr. Thirumalai report no relevant financial relationships.

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

ATLANTA – Potential once-daily male oral contraceptives have passed a first clinical hurdle, showing a degree of testosterone suppression that should be sufficient for a contraceptive effect without causing symptomatic hypogonadism, according to phase 1 study results to be presented at the annual meeting of the Endocrine Society.

Credit: Flickr/Marco Verch Professional Photographer/CC by 2.0

There are two pills in development and the studies so far suggest that both or a combination might be able to provide an acceptable balance of efficacy and tolerability, according to Tamar Jacobsohn, a researcher in the Contraceptive Development Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Md.

The two drugs evaluated in this study are dimethandrolone undecanoate (DMAU) and 11b-methyl-19-nortestosterone-17b-dodecylcarbonate (11b-MNTDC). Both are bifunctional prodrugs with androgenic and progestogenic effects. The prodrugs are designed to be cleaved after ingestion so that the active hormones are released over 24 hours, permitting once-daily dosing.

“As potent androgens, these steroids suppress gonadotropin secretion, leading to markedly decreased serum testosterone production,” explained Ms. Jacobsohn in an interview.

However, she noted that there is still a long way to go on this research path. While the phase 1 studies have shown tolerability, the biology involved in suppressing sperm production suggests that men would need to take these pills daily for about 3 months at the very beginning of contraceptive treatment, until adequate sperm suppression is achieved to prevent pregnancy.

“We are working toward a phase 2 trial that will include a contraceptive efficacy endpoint, but there are lots of steps to get there, including more early phase studies,” she noted.

“There is a huge unmet need in terms of male contraceptive methods,” said Arthi Thirumalai, MBBS, an endocrinologist and assistant professor of medicine at the University of Washington School of Medicine in Seattle.

Senior author of a 2020 review article on male contraception, Dr. Thirumalai said in an interview that prodrugs and other hormonal methods to lower testosterone and suppress sperm production are attractive because of convenience, efficacy, and reversibility,

“We hope that oral formulations can be used to address this need,” said Dr. Thirumalai, who has participated in several experimental and clinical studies of male contraception methods. She is, in fact, one of the many coauthors of the data presented by Ms. Jacobsohn.

Ms. Jacobsohn emphasized: “Development of an effective, reversible male contraceptive method will improve reproductive options for men and women, have a major impact on public health by decreasing unintended pregnancy, and allow men to have an increasingly active role in family planning.”

Phase 1 results with DMAU and MNTDC

The work that led to phase 1 studies suggested that each of the drugs — DMAU and MNTDC — might provide adequate hormone suppression to reduce sperm counts without inducing unacceptable symptoms of hypogonadism. To test this potential, dose-ranging phase 1 studies with an endpoint of testosterone suppression were conducted with each one.

In the two placebo-controlled phase 1a studies, which are to be presented in a poster on June 13, healthy male subjects were randomly assigned to two pills of active therapy, four pills of active therapy, or placebo. In the two studies combined, 39 subjects received DMAU, 30 received 11b-MNTDC, and 28 received placebo.

Efficacy was evaluated by measuring testosterone levels. Tolerability was largely based on patient questionnaires.

At the end of 7 days, testosterone levels remained at reference levels (400 to 600 ng/dL) in those who received placebo. The levels fell to less than 100 ng/dL in all subjects assigned to an active agent regardless of which agent or dose was used.

From day 7 to 28, there was less median suppression of testosterone on 200 mg than 400 mg daily (92.7 ng/dL vs. 49.6 ng/dL; P < .001), but both remained below the target of 100 ng/dL, Ms. Jacobsohn reported.

The difference in degree of testosterone suppression did not appear to influence tolerability.

Subjects on four vs. two daily pills “did not report a significant difference in general satisfaction or their willingness to use the pills in the future or recommend them to other men,” said Ms. Jacobson, presenting P values for these outcomes among subjects on active therapy relative to placebo that were not significant, ranging from 0.48 to 0.85.

Overall, there were no serious adverse events. Mild side effects associated with hypogonadism did occur, but “all resolved by the end of the study,” she said.

Zero sperm production is not the goal. Lowering it sufficiently is

Dr. Thirumalai said the need for a male contraceptive is strong. While condoms have a substantial failure rate, vasectomy is not reliably reversible even though the majority of men agree that the responsibility for preventing pregnancy should be shared, she said.

Dr. Thirumalai’s earlier review article found that clinical trials of hormonal suppression to provide male contraception have been conducted for at least 30 years. The challenge has been finding an effective therapy that is well tolerated.

Drugs that combine both androgenic and progestogenic activity might be the answer. By manipulating hormones that lower testosterone, sperm production is reduced without eliminating a man’s ability to ejaculate. Zero sperm production is not the goal, according to data in Dr. Thirumalai’s review article.

Rather, studies suggest that when ejaculate contains less than 1 million sperm per mL (levels typically range from 15 to 200 million sperm/mL), the antipregnancy efficacy is similar to that achieved with female oral contraceptives.

However, clinical trials to demonstrate that this can be achieved safely have yet to be conducted.

Ms. Jacobsohn said that sperm half-life is about 3 months. This means that patients would need to be on hormonal therapy for a period of about this duration before reliable contraception is achieved.

In other words, the efficacy endpoint used in this current study [of 28 days duration] does not ensure effective contraception, but Ms. Jacobsohn suggested this is nevertheless an important step forward in clinical development.

Ms. Jacobsohn and Dr. Thirumalai report no relevant financial relationships.

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