The gut-brain axis (GBA) refers to the link between the human brain with its various cognitive and affective functions and the gastrointestinal (GI) system, which includes the enteric nervous system and the diverse microbiome inhabiting the gut lumen. The neurochemical aspects of the GBA have been studied in germ-free mice; these studies demonstrate how absence or derangement of this microbiome can cause significant alterations in levels of serotonin, brain-derived neurotrophic factor, tryptophan, and other neurocompounds.^1,2 These neurotransmitter alterations have demonstrable effects on anxiety, cognition, socialization, and neuronal development in mice.^1,2

Current evidence suggests that the GBA works through a combination of both fast-acting neural and delayed immune-mediated mechanisms in a bidirectional manner with feedback on and from both systems.³ In addition to their direct effects on neural pathways and immune modulation, intestinal microbiota are essential in the production of a vast array of vitamins, cofactors, and nutrients required for optimal health and metabolism.⁴ Existing research on the GBA demonstrates the direct functional impact of the intestinal microbiome on neurologic and psychiatric health.

We will review current knowledge regarding this intriguing relationship. In doing so, we take a closer look at several specific genera and families of intestinal microbiota, review the microbiome’s effects on immune function, and examine the relationship between this microbiome and mental disease, using specific examples such as generalized anxiety disorder (GAD) and major depressive disorder (MDD). We seek to consolidate existing knowledge on the intricacies of the GBA in the hope that it may promote individual health and become a standard component in the treatment of mental illness.

Direct Activation of Neuronal Pathways

Vagal and spinal afferent nerve pathways convey information regarding hormonal, chemical, and mechanical stimuli from the intestines to the brain.³ These afferent neurons have been shown to be responsive to microbial signals and cytokines as well as to gut hormones. This provides the basis for research that presumes that neurobehavioral change may ensue from manipulating the gut microbes emitting these chemical signals to which these afferent neurons respond.³ Using these same pathways, efferent neurons of the parasympathetic and sympathetic nervous systems can modulate the intestinal environment by altering acid and bile secretion, mucous production, and motility. This modulation can directly impact the relative diversity of intestinal flora, and in more extreme states, may result in bacterial overgrowth.⁵ Of particular relevance to mental health (MH) is that the frequency of migrating motor complexes that promote peristalsis can be directly influenced by readily modifiable behaviors such as sleep and food intake, which can cause one bacterial species to dominate in a higher percentage.⁵ This imbalance of gut microbes has been implicated in contributing to somatic conditions, such as irritable bowel syndrome (IBS), which the literature has shown is related to psychiatric conditions such as anxiety. ⁵

The Microbiome and Host Immunity

The GI tract is colonized with commensal microorganisms from dozens of bacterial, archaeal, fungal, and protozoal groups.⁶ This relationship has its most classical immunologic interaction in the toll-like receptors. These receptors are on the lymphoid Peyer patches of the GI tract, which sample microorganisms and develop immunoglobulin (IgA) antibodies to them. Evidence exists that commensal microflora play a critical role in the regulation of host inflammatory response.⁷

The relationship between the microbiome and the immune system remains poorly understood, yet evidence has shown that the use of probiotics may reduce inflammation and its sequelae. Probiotics have been shown to have a beneficial effect on autoimmune diseases, such as Crohn disease and ulcerative colitis, specifically with certain strains of Escherichia coli (E coli) and a proprietary probiotic from VSL pharmaceuticals.^8,9 However, these interventions are not without risk. Fecal microbiota transplants have a risk of transferring unwanted organisms, potentially including COVID-19.¹⁰ Additionally, the use of probiotics is generally discouraged in immunocompromised, chronically ill, and/or hospitalized patients, as these patients may be at greater risk of developing probiotic bacteremia and sepsis.¹¹

Studies have also demonstrated that ingesting probiotics may decrease the expression of pro-inflammatory cytokines.¹¹ In a study comparing patients with ulcerative colitis who were prescribed both sulfasalazine and probiotic supplements vs sulfasalazine alone, patients who took the probiotic supplements were shown to have less colonic inflammation and decreased expression of cytokines such as IL-6, tumor necrosis factor-α (TNF-α), and nuclear factor-κβ.¹²

Gut-Specific Bacterial Phyla

Over the past decade, much attention has been paid toward 2 bacterial phyla that compromise a large proportion of the human gut microbiome: Firmicutes and Bacteroidetes. Intestinal Firmicutes species are predominantly Gram positive and are found as both cocci and bacilli. Well-known classes within the phylum Firmicutes include Bacilli (orders Bacillales and Lactobacillales) and Clostridia. The phylum Bacteroidetes is composed of Gram-negative rods and includes the genus Bacteroides—a substantial component of mammalian gut biomes. The ratio of Firmicutes to Bacteroidetes, also known as the F/B ratio, have shown fascinating patterns in certain psychiatric conditions. This knowledge may be applied to better identify, treat, and manage such patients.

Regarding bacterial phyla and their relationship to mood disorders, interesting patterns have been observed. In one population of patients with anorexia nervosa (AN) lower diversity within classes of Firmicutes bacteria was observed compared with age- and sex-matched controls without AN.¹³ As patients were re-fed and treated in this study, there was a significant corresponding increase in microbiome diversity; however, the level of bacterial diversity in re-fed patients with AN was still far less than that of patients in the control group. In patients with AN with comorbid depression, diversity was noted to be exceptionally reduced. Similarly, patients with AN with a more severe eating disorder psychopathology demonstrated decreased microbial diversity.¹³

The impact of intestinal microbiome diversity and relative bacterial population density in MH conditions such as anxiety, depression, and eating disorders remains an intriguing avenue worth further exploring. Modulating these phenomena may reduce overall dysfunction and serve as a possible treatment modality.

Anxiety and the Microbiome

GAD is characterized by decreased social and occupational functioning. Anxiolytic pharmacotherapy combined with psychotherapy are the current mainstays of GAD treatment. Given the interplay of the gut microbiome and MH, probiotics may prove to be a promising alternative or adjunct treatment option.

The human stress response is enacted largely through the hypothalamus-pituitary-adrenal (HPA) axis. Anxiety and situational fear trigger a stress response that results in increased cortisol being released from the adrenal glands, thereby disrupting typical GI function by modifying the frequency of migrating motor complexes, the electromechanical impulses within the smooth muscle of the stomach and small bowel that allow for propagation of chyme. This, in turn, has downstream consequences on the composition of the intestinal microbiome.¹⁴ Patients with GAD have a lower prevalence of Faecalibacterium, Eubacterium rectale, Lachnospira, Butyricioccus, and Sutterella, all important producers of short-chain fatty acids (SCFA).^15,16 Diminished SCFA production has been linked to intestinal barrier dysfunction, contributing to increases in gut endothelial permeability and facilitating a proinflammatory response with resultant neural feedback loops.^17,18 Indeed, proinflammatory cytokines, namely C-reactive protein (CRP), interleukin 6 (IL-6), and TNF-α were found to be elevated in patients with diagnosed GAD.¹⁹ These proinflammatory cytokines are critical in neurochemical modulation as they inhibit the essential enzyme tetrahydrobiopterin, a cofactor of monoamine synthesis, thereby decreasing the monoamine neurotransmitters serotonin, dopamine, and norepinephrine.²⁰ Decrease in the monoamine neurotransmitters serves as the lynchpin for the monoamine hypothesis of both anxiety and depression and currently guides our choice in pharmacotherapy.²¹

Anxiolytic pharmacotherapy targets the neurochemical consequences of GAD to ameliorate social, functional, and emotional impairment. However, the physiology of the gut-brain feedback loop in GAD is an attractive target for the creation and trialing of probiotics, which can rebalance intestinal flora, reduce inflammation, and allow for increased synthesis of monoamine neurotransmitters. Indeed, Lactobacillus and Bifidobacterium have been shown to possess anxiolytic properties by increasing serotonin and SCFAs while reducing the HPA adrenergic response.²²

Depression and the Microbiome

MDD significantly diminishes quality of life and is the leading cause of disability worldwide, affecting nearly 350 million individuals.²³ Psychotherapy in conjunction with pharmacotherapy aimed at increasing cerebral serotonin availability are the current mainstays of MDD treatment. Yet the brain does not exist in isolation: It has 3 known methods of bidirectional communication with the GI tract via the vagus nerve, immune mediators, and bacterial metabolites.^24,25

The vagus nerve (vagus means wandering in Latin), is the longest nerve of the autonomic nervous system (ANS) and historically has been called the pneumogastric nerve for its parasympathetic innervation of the heart, lungs, and digestive tract. Current research supports that up to 80% of the fibers within the vagus nerve are afferent, relaying signals from the GI tract to the brain.²⁶ Therefore, modulation of vagus nerve signaling may theoretically impact mental health. Indeed, studies have demonstrated clinically significant improvement in patients with treatment-resistant depression who underwent vagal nerve stimulation (VNS).²⁷ Although the mechanism by which it exerts its mood-modulating activity is not well understood, recent human and animal studies indicate that VNS may alter central neurotransmitter levels, having demonstrated the ability to increase serotonin levels.²⁵ Also the vagus nerve possesses the ability to differentiate between pathogenic and nonpathogenic gut microorganisms; beneficial gut flora emit signals within the gut lumen, which in turn, are transmitted through afferent vagus nerve fibers to the brain, effecting both anti-inflammatory and mood-modulating responses.^25,28

Immunomediators involving intestinal microbiota also are known to play a critical role in the pathophysiology of MDD. Depression is closely tied to systemic inflammation; both are hypothesized to have played a role in the evolutionary response to fighting infection and healing wounds.²⁹ With regard to the gut, MDD is associated with increased GI permeability, which allows for microorganisms to leak through the intestinal mucosa into the systemic circulation and stimulate an inflammatory response.¹⁸ Levels of IgM and IgA against enterobacteria lipopolysaccharides (LPS) were found to be markedly greater in patients with MDD vs those of nondepressed controls.³⁰ Current research indicates that IgM and IgA against LPS of translocated bacteria serve to amplify immune pathways seen in the pathophysiology of chronic MDD.^30,31 Further research is indicated to deduce whether bacterial translocation with subsequent immune response induces MDD in susceptible individuals, or whether translocation occurs secondary to the systemic inflammation seen in MDD.

The makeup of the GI microbiome is fundamentally altered in patients with MDD, with a marked reduction in both microorganism diversity and density.³⁰ Patients with MDD have been shown to have increased levels of Alistipes, a bacterium that also is elevated in chronic fatigue syndrome and irritable bowel syndrome (IBS), diagnoses that are associated with MDD.^32-34 Lower counts of Bifidobacterium and Lactobacillus are documented in both MDD and IBS patients as well.³⁵ Decreased Bifidobacterium and Lactobacillus might indicate a causal rather than correlative relationship as these bacterium take the precursor monosodium glutamate to create γ-aminobutyric acid (GABA).³⁶

Psychobiotics and Mental Health

The pathophysiology of the bidirectional communication between the gut and the brain offers an attractive approach for treatment modalities. Currently, the research into probiotic supplementation to treat mental disorders, such as anxiety and depression, is still in its infancy, and treatment guidelines do not support their routine administration. There is great promise in the use of probiotics to ameliorate psychiatric symptomatology, referred to by many in the field as psychobiotics.

One pathophysiology of the stress response seen in anxiety can be traced to the HPA axis and increased cortisol levels, with downstream effects on the microbiome through modification of the migrating motor complexes. Healthy volunteers tasked with taking a trademarked galactooligosaccharide prebiotic daily for 3 weeks had a reduced salivary cortisol awakening response compared with that of a placebo (maltodextrin). The same group demonstrated decreased attentional vigilance to negative information in a dot-probe task compared with attentional vigilance with positive information.³⁷ It is possible that this was due to the decreased stress response secondary to probiotic consumption. In mice models, a probiotic consisting of Lactobacillus helveticus and Bifidobacterium longum (B longum) (bacterium that are decreased in GAD and MDD) demonstrated anxiolytic-like behavior. The same formulation also demonstrated beneficial psychological effects in healthy human volunteers.²² In mice models, Lactobacillus feeding was superior to citalopram in anxiolysis and in cognitive functioning.³⁸

Like GAD, the pathophysiology of the GBA in MDD is an attractive target for psychobiotic therapy. Although current research is not yet sufficient to create general guidelines or recommendations for the routine administration of psychobiotics, it holds significant promise as an effective primary and/or adjunct treatment. In patients with IBS, administration of B longum reduced depression and increased quality of life. This same study demonstrated that probiotic administration was associated with reduced limbic activity in the brain.³⁹ In MDD, the hippocampus demonstrates altered expression of various transcription factors and cellular metabolism.⁴⁰ In a double-blind placebo-controlled trial, Lactobaccillus rhamnosus supplementation in postnatal mothers resulted in less severe depressive symptoms reported.⁴¹ Furthermore, probiotic supplementation consisting of Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum in patients with MDD for 8 weeks had significant decreases in score on the Beck Depression Inventory scale.⁴² Also, a meta-analysis of probiotic administration on depression scales demonstrated appreciably lower scores after administration in both patients with MDD and healthy patients aged 60 years, although these results were found to be correlative.⁴³ However, while promising, another meta-analysis of 10 randomized controlled trials found probiotic supplementation had no significant effect on mood.⁴⁴

The Role of Diet

Although there has been tremendous focus on new and improved therapeutics to address MH conditions, such as depression and anxiety, there also has been renewed interest in the fundamental importance and benefit of a wholesome diet. Recent literature has shown how diet may play a pivotal role in the development and severity of mental illness and holds promise as another potential target for treatment. A 2010 cross-sectional population study of more than 1000 adult women aged 20 to 93 years demonstrated that women with a largely Western dietary pattern (ie, largely composed of processed meats, pizza, chips, hamburgers, white bread, sugar, flavored milk drinks, and beer) were more likely to have dysthymic disorder or major depression, whereas women in this same cohort with a more traditional dietary pattern (ie, composed mainly of vegetables, fruit, lamb, beef, fish, and whole grains) were found to have significantly reduced odds for depression or dysthymic disorder as well as anxiety disorders.⁴⁵

Several other large-scale population studies such as the SUN cohort study, Hordaland Health study, Whitehall II cohort study, and RHEA mother and baby cohort study have demonstrated similar findings: that a more wholesome diet composed mainly of lean meats, vegetables, fruits, and whole grains was associated with significantly reduced risk of depression compared with a largely processed, high fat, and high sugar diet. This trend also has been observed in children and adolescents and is of particular importance when considering that many psychological and psychiatric problems tend to arise in the formative and often turbulent years prior to adulthood.⁴⁶

The causal relationship between diet and MH may be better understood by taking a closer look at a crucial intermediate factor: the gut microbiome. The interplay between diet and intestinal microbiome was well elucidated in a landmark 2010 study by De Filippo and colleagues.⁴⁷ In this study, the microbiota of 14 healthy children from a small village in Burkina Faso (BF) were compared with those of 15 healthy children from an urban area of Florence, Italy (EU). The BF children were reported to consume a traditional rural African diet that is primarily vegetarian, rich in fiber, and low in animal protein and fat, whereas the EU children were noted as consuming a typical Western diet low in fiber but rich in animal protein, fat, sugar, and starch. Comparison revealed that EU children had a higher F/B ratio than their BF counterparts, a metric that has been associated with obesity.⁴⁷ Furthermore, increased exposure to environmental microbes associated with a fiber-rich diet has been postulated to increase the richness of intestinal flora and serve as a protective factor against noninfectious and inflammatory colonic diseases, which are found to be more prevalent in Western nations whose diets lack fiber. BF children were found to have increased microbial diversity and increased abundance of bacteria capable of producing SCFA relative to their EU counterparts, both of which have a positive influence on the gut, systemic inflammation, and MH.⁴⁷

Conclusions

Diet has a powerful impact on the intestinal microbiome, which in turn directly impacts our physical and MH in myriad ways. The well-known benefits of a wholesome, nutritious, and well-varied diet include reduced cardiovascular risk, improved glycemic control, GI regularity, and decreased depression. Along with a balanced diet, patients may achieve further benefit with the addition of probiotics.

With regard to psychiatry in particular, increased awareness of the intimate relationship between the gut and the brain is expected to have profound implications for the field. Given this mounting data, immunology, microbiology, and GI pathophysiology should be included in future discussions regarding MH. Their application will likely improve both somatic and mental well-being. We anticipate that newly discovered probiotics and other psychobiotic formulations will be routinely included in a psychiatrist’s pharmacopeia in the near future. Unfortunately, as is clear from our review of the current literature, we do not yet have specific interventions targeting the intestinal microbiome to recommend for the management of specific psychiatric conditions. However, this should not deter further exploring diet modification and psychobiotic supplementation as a means of impacting the intestinal microbiome in the pursuit of psychiatric symptom relief.

Dietary modification is already a standard component of sound primary care medicine, designed to mitigate risk for cardiovascular disease. This exploration can occur as part of otherwise standard psychiatric care and be used as a form of behavioral activation for the patient. Furthermore, explaining the interconnectedness of the mind, brain, and body along with the rationale for experimentation could further help destigmatize the experience of mental illness.

The gut-brain axis (GBA) refers to the link between the human brain with its various cognitive and affective functions and the gastrointestinal (GI) system, which includes the enteric nervous system and the diverse microbiome inhabiting the gut lumen. The neurochemical aspects of the GBA have been studied in germ-free mice; these studies demonstrate how absence or derangement of this microbiome can cause significant alterations in levels of serotonin, brain-derived neurotrophic factor, tryptophan, and other neurocompounds.^1,2 These neurotransmitter alterations have demonstrable effects on anxiety, cognition, socialization, and neuronal development in mice.^1,2

Current evidence suggests that the GBA works through a combination of both fast-acting neural and delayed immune-mediated mechanisms in a bidirectional manner with feedback on and from both systems.³ In addition to their direct effects on neural pathways and immune modulation, intestinal microbiota are essential in the production of a vast array of vitamins, cofactors, and nutrients required for optimal health and metabolism.⁴ Existing research on the GBA demonstrates the direct functional impact of the intestinal microbiome on neurologic and psychiatric health.

We will review current knowledge regarding this intriguing relationship. In doing so, we take a closer look at several specific genera and families of intestinal microbiota, review the microbiome’s effects on immune function, and examine the relationship between this microbiome and mental disease, using specific examples such as generalized anxiety disorder (GAD) and major depressive disorder (MDD). We seek to consolidate existing knowledge on the intricacies of the GBA in the hope that it may promote individual health and become a standard component in the treatment of mental illness.

Direct Activation of Neuronal Pathways

Vagal and spinal afferent nerve pathways convey information regarding hormonal, chemical, and mechanical stimuli from the intestines to the brain.³ These afferent neurons have been shown to be responsive to microbial signals and cytokines as well as to gut hormones. This provides the basis for research that presumes that neurobehavioral change may ensue from manipulating the gut microbes emitting these chemical signals to which these afferent neurons respond.³ Using these same pathways, efferent neurons of the parasympathetic and sympathetic nervous systems can modulate the intestinal environment by altering acid and bile secretion, mucous production, and motility. This modulation can directly impact the relative diversity of intestinal flora, and in more extreme states, may result in bacterial overgrowth.⁵ Of particular relevance to mental health (MH) is that the frequency of migrating motor complexes that promote peristalsis can be directly influenced by readily modifiable behaviors such as sleep and food intake, which can cause one bacterial species to dominate in a higher percentage.⁵ This imbalance of gut microbes has been implicated in contributing to somatic conditions, such as irritable bowel syndrome (IBS), which the literature has shown is related to psychiatric conditions such as anxiety. ⁵

The Microbiome and Host Immunity

The GI tract is colonized with commensal microorganisms from dozens of bacterial, archaeal, fungal, and protozoal groups.⁶ This relationship has its most classical immunologic interaction in the toll-like receptors. These receptors are on the lymphoid Peyer patches of the GI tract, which sample microorganisms and develop immunoglobulin (IgA) antibodies to them. Evidence exists that commensal microflora play a critical role in the regulation of host inflammatory response.⁷

The relationship between the microbiome and the immune system remains poorly understood, yet evidence has shown that the use of probiotics may reduce inflammation and its sequelae. Probiotics have been shown to have a beneficial effect on autoimmune diseases, such as Crohn disease and ulcerative colitis, specifically with certain strains of Escherichia coli (E coli) and a proprietary probiotic from VSL pharmaceuticals.^8,9 However, these interventions are not without risk. Fecal microbiota transplants have a risk of transferring unwanted organisms, potentially including COVID-19.¹⁰ Additionally, the use of probiotics is generally discouraged in immunocompromised, chronically ill, and/or hospitalized patients, as these patients may be at greater risk of developing probiotic bacteremia and sepsis.¹¹

Studies have also demonstrated that ingesting probiotics may decrease the expression of pro-inflammatory cytokines.¹¹ In a study comparing patients with ulcerative colitis who were prescribed both sulfasalazine and probiotic supplements vs sulfasalazine alone, patients who took the probiotic supplements were shown to have less colonic inflammation and decreased expression of cytokines such as IL-6, tumor necrosis factor-α (TNF-α), and nuclear factor-κβ.¹²

Gut-Specific Bacterial Phyla

Over the past decade, much attention has been paid toward 2 bacterial phyla that compromise a large proportion of the human gut microbiome: Firmicutes and Bacteroidetes. Intestinal Firmicutes species are predominantly Gram positive and are found as both cocci and bacilli. Well-known classes within the phylum Firmicutes include Bacilli (orders Bacillales and Lactobacillales) and Clostridia. The phylum Bacteroidetes is composed of Gram-negative rods and includes the genus Bacteroides—a substantial component of mammalian gut biomes. The ratio of Firmicutes to Bacteroidetes, also known as the F/B ratio, have shown fascinating patterns in certain psychiatric conditions. This knowledge may be applied to better identify, treat, and manage such patients.

Regarding bacterial phyla and their relationship to mood disorders, interesting patterns have been observed. In one population of patients with anorexia nervosa (AN) lower diversity within classes of Firmicutes bacteria was observed compared with age- and sex-matched controls without AN.¹³ As patients were re-fed and treated in this study, there was a significant corresponding increase in microbiome diversity; however, the level of bacterial diversity in re-fed patients with AN was still far less than that of patients in the control group. In patients with AN with comorbid depression, diversity was noted to be exceptionally reduced. Similarly, patients with AN with a more severe eating disorder psychopathology demonstrated decreased microbial diversity.¹³

The impact of intestinal microbiome diversity and relative bacterial population density in MH conditions such as anxiety, depression, and eating disorders remains an intriguing avenue worth further exploring. Modulating these phenomena may reduce overall dysfunction and serve as a possible treatment modality.

Anxiety and the Microbiome

GAD is characterized by decreased social and occupational functioning. Anxiolytic pharmacotherapy combined with psychotherapy are the current mainstays of GAD treatment. Given the interplay of the gut microbiome and MH, probiotics may prove to be a promising alternative or adjunct treatment option.

The human stress response is enacted largely through the hypothalamus-pituitary-adrenal (HPA) axis. Anxiety and situational fear trigger a stress response that results in increased cortisol being released from the adrenal glands, thereby disrupting typical GI function by modifying the frequency of migrating motor complexes, the electromechanical impulses within the smooth muscle of the stomach and small bowel that allow for propagation of chyme. This, in turn, has downstream consequences on the composition of the intestinal microbiome.¹⁴ Patients with GAD have a lower prevalence of Faecalibacterium, Eubacterium rectale, Lachnospira, Butyricioccus, and Sutterella, all important producers of short-chain fatty acids (SCFA).^15,16 Diminished SCFA production has been linked to intestinal barrier dysfunction, contributing to increases in gut endothelial permeability and facilitating a proinflammatory response with resultant neural feedback loops.^17,18 Indeed, proinflammatory cytokines, namely C-reactive protein (CRP), interleukin 6 (IL-6), and TNF-α were found to be elevated in patients with diagnosed GAD.¹⁹ These proinflammatory cytokines are critical in neurochemical modulation as they inhibit the essential enzyme tetrahydrobiopterin, a cofactor of monoamine synthesis, thereby decreasing the monoamine neurotransmitters serotonin, dopamine, and norepinephrine.²⁰ Decrease in the monoamine neurotransmitters serves as the lynchpin for the monoamine hypothesis of both anxiety and depression and currently guides our choice in pharmacotherapy.²¹

Anxiolytic pharmacotherapy targets the neurochemical consequences of GAD to ameliorate social, functional, and emotional impairment. However, the physiology of the gut-brain feedback loop in GAD is an attractive target for the creation and trialing of probiotics, which can rebalance intestinal flora, reduce inflammation, and allow for increased synthesis of monoamine neurotransmitters. Indeed, Lactobacillus and Bifidobacterium have been shown to possess anxiolytic properties by increasing serotonin and SCFAs while reducing the HPA adrenergic response.²²

Depression and the Microbiome

MDD significantly diminishes quality of life and is the leading cause of disability worldwide, affecting nearly 350 million individuals.²³ Psychotherapy in conjunction with pharmacotherapy aimed at increasing cerebral serotonin availability are the current mainstays of MDD treatment. Yet the brain does not exist in isolation: It has 3 known methods of bidirectional communication with the GI tract via the vagus nerve, immune mediators, and bacterial metabolites.^24,25

The vagus nerve (vagus means wandering in Latin), is the longest nerve of the autonomic nervous system (ANS) and historically has been called the pneumogastric nerve for its parasympathetic innervation of the heart, lungs, and digestive tract. Current research supports that up to 80% of the fibers within the vagus nerve are afferent, relaying signals from the GI tract to the brain.²⁶ Therefore, modulation of vagus nerve signaling may theoretically impact mental health. Indeed, studies have demonstrated clinically significant improvement in patients with treatment-resistant depression who underwent vagal nerve stimulation (VNS).²⁷ Although the mechanism by which it exerts its mood-modulating activity is not well understood, recent human and animal studies indicate that VNS may alter central neurotransmitter levels, having demonstrated the ability to increase serotonin levels.²⁵ Also the vagus nerve possesses the ability to differentiate between pathogenic and nonpathogenic gut microorganisms; beneficial gut flora emit signals within the gut lumen, which in turn, are transmitted through afferent vagus nerve fibers to the brain, effecting both anti-inflammatory and mood-modulating responses.^25,28

Immunomediators involving intestinal microbiota also are known to play a critical role in the pathophysiology of MDD. Depression is closely tied to systemic inflammation; both are hypothesized to have played a role in the evolutionary response to fighting infection and healing wounds.²⁹ With regard to the gut, MDD is associated with increased GI permeability, which allows for microorganisms to leak through the intestinal mucosa into the systemic circulation and stimulate an inflammatory response.¹⁸ Levels of IgM and IgA against enterobacteria lipopolysaccharides (LPS) were found to be markedly greater in patients with MDD vs those of nondepressed controls.³⁰ Current research indicates that IgM and IgA against LPS of translocated bacteria serve to amplify immune pathways seen in the pathophysiology of chronic MDD.^30,31 Further research is indicated to deduce whether bacterial translocation with subsequent immune response induces MDD in susceptible individuals, or whether translocation occurs secondary to the systemic inflammation seen in MDD.

The makeup of the GI microbiome is fundamentally altered in patients with MDD, with a marked reduction in both microorganism diversity and density.³⁰ Patients with MDD have been shown to have increased levels of Alistipes, a bacterium that also is elevated in chronic fatigue syndrome and irritable bowel syndrome (IBS), diagnoses that are associated with MDD.^32-34 Lower counts of Bifidobacterium and Lactobacillus are documented in both MDD and IBS patients as well.³⁵ Decreased Bifidobacterium and Lactobacillus might indicate a causal rather than correlative relationship as these bacterium take the precursor monosodium glutamate to create γ-aminobutyric acid (GABA).³⁶

Psychobiotics and Mental Health

The pathophysiology of the bidirectional communication between the gut and the brain offers an attractive approach for treatment modalities. Currently, the research into probiotic supplementation to treat mental disorders, such as anxiety and depression, is still in its infancy, and treatment guidelines do not support their routine administration. There is great promise in the use of probiotics to ameliorate psychiatric symptomatology, referred to by many in the field as psychobiotics.

One pathophysiology of the stress response seen in anxiety can be traced to the HPA axis and increased cortisol levels, with downstream effects on the microbiome through modification of the migrating motor complexes. Healthy volunteers tasked with taking a trademarked galactooligosaccharide prebiotic daily for 3 weeks had a reduced salivary cortisol awakening response compared with that of a placebo (maltodextrin). The same group demonstrated decreased attentional vigilance to negative information in a dot-probe task compared with attentional vigilance with positive information.³⁷ It is possible that this was due to the decreased stress response secondary to probiotic consumption. In mice models, a probiotic consisting of Lactobacillus helveticus and Bifidobacterium longum (B longum) (bacterium that are decreased in GAD and MDD) demonstrated anxiolytic-like behavior. The same formulation also demonstrated beneficial psychological effects in healthy human volunteers.²² In mice models, Lactobacillus feeding was superior to citalopram in anxiolysis and in cognitive functioning.³⁸

Like GAD, the pathophysiology of the GBA in MDD is an attractive target for psychobiotic therapy. Although current research is not yet sufficient to create general guidelines or recommendations for the routine administration of psychobiotics, it holds significant promise as an effective primary and/or adjunct treatment. In patients with IBS, administration of B longum reduced depression and increased quality of life. This same study demonstrated that probiotic administration was associated with reduced limbic activity in the brain.³⁹ In MDD, the hippocampus demonstrates altered expression of various transcription factors and cellular metabolism.⁴⁰ In a double-blind placebo-controlled trial, Lactobaccillus rhamnosus supplementation in postnatal mothers resulted in less severe depressive symptoms reported.⁴¹ Furthermore, probiotic supplementation consisting of Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum in patients with MDD for 8 weeks had significant decreases in score on the Beck Depression Inventory scale.⁴² Also, a meta-analysis of probiotic administration on depression scales demonstrated appreciably lower scores after administration in both patients with MDD and healthy patients aged 60 years, although these results were found to be correlative.⁴³ However, while promising, another meta-analysis of 10 randomized controlled trials found probiotic supplementation had no significant effect on mood.⁴⁴

The Role of Diet

Although there has been tremendous focus on new and improved therapeutics to address MH conditions, such as depression and anxiety, there also has been renewed interest in the fundamental importance and benefit of a wholesome diet. Recent literature has shown how diet may play a pivotal role in the development and severity of mental illness and holds promise as another potential target for treatment. A 2010 cross-sectional population study of more than 1000 adult women aged 20 to 93 years demonstrated that women with a largely Western dietary pattern (ie, largely composed of processed meats, pizza, chips, hamburgers, white bread, sugar, flavored milk drinks, and beer) were more likely to have dysthymic disorder or major depression, whereas women in this same cohort with a more traditional dietary pattern (ie, composed mainly of vegetables, fruit, lamb, beef, fish, and whole grains) were found to have significantly reduced odds for depression or dysthymic disorder as well as anxiety disorders.⁴⁵

Several other large-scale population studies such as the SUN cohort study, Hordaland Health study, Whitehall II cohort study, and RHEA mother and baby cohort study have demonstrated similar findings: that a more wholesome diet composed mainly of lean meats, vegetables, fruits, and whole grains was associated with significantly reduced risk of depression compared with a largely processed, high fat, and high sugar diet. This trend also has been observed in children and adolescents and is of particular importance when considering that many psychological and psychiatric problems tend to arise in the formative and often turbulent years prior to adulthood.⁴⁶

The causal relationship between diet and MH may be better understood by taking a closer look at a crucial intermediate factor: the gut microbiome. The interplay between diet and intestinal microbiome was well elucidated in a landmark 2010 study by De Filippo and colleagues.⁴⁷ In this study, the microbiota of 14 healthy children from a small village in Burkina Faso (BF) were compared with those of 15 healthy children from an urban area of Florence, Italy (EU). The BF children were reported to consume a traditional rural African diet that is primarily vegetarian, rich in fiber, and low in animal protein and fat, whereas the EU children were noted as consuming a typical Western diet low in fiber but rich in animal protein, fat, sugar, and starch. Comparison revealed that EU children had a higher F/B ratio than their BF counterparts, a metric that has been associated with obesity.⁴⁷ Furthermore, increased exposure to environmental microbes associated with a fiber-rich diet has been postulated to increase the richness of intestinal flora and serve as a protective factor against noninfectious and inflammatory colonic diseases, which are found to be more prevalent in Western nations whose diets lack fiber. BF children were found to have increased microbial diversity and increased abundance of bacteria capable of producing SCFA relative to their EU counterparts, both of which have a positive influence on the gut, systemic inflammation, and MH.⁴⁷

Conclusions

Diet has a powerful impact on the intestinal microbiome, which in turn directly impacts our physical and MH in myriad ways. The well-known benefits of a wholesome, nutritious, and well-varied diet include reduced cardiovascular risk, improved glycemic control, GI regularity, and decreased depression. Along with a balanced diet, patients may achieve further benefit with the addition of probiotics.

With regard to psychiatry in particular, increased awareness of the intimate relationship between the gut and the brain is expected to have profound implications for the field. Given this mounting data, immunology, microbiology, and GI pathophysiology should be included in future discussions regarding MH. Their application will likely improve both somatic and mental well-being. We anticipate that newly discovered probiotics and other psychobiotic formulations will be routinely included in a psychiatrist’s pharmacopeia in the near future. Unfortunately, as is clear from our review of the current literature, we do not yet have specific interventions targeting the intestinal microbiome to recommend for the management of specific psychiatric conditions. However, this should not deter further exploring diet modification and psychobiotic supplementation as a means of impacting the intestinal microbiome in the pursuit of psychiatric symptom relief.

Dietary modification is already a standard component of sound primary care medicine, designed to mitigate risk for cardiovascular disease. This exploration can occur as part of otherwise standard psychiatric care and be used as a form of behavioral activation for the patient. Furthermore, explaining the interconnectedness of the mind, brain, and body along with the rationale for experimentation could further help destigmatize the experience of mental illness.

The gut-brain axis (GBA) refers to the link between the human brain with its various cognitive and affective functions and the gastrointestinal (GI) system, which includes the enteric nervous system and the diverse microbiome inhabiting the gut lumen. The neurochemical aspects of the GBA have been studied in germ-free mice; these studies demonstrate how absence or derangement of this microbiome can cause significant alterations in levels of serotonin, brain-derived neurotrophic factor, tryptophan, and other neurocompounds.^1,2 These neurotransmitter alterations have demonstrable effects on anxiety, cognition, socialization, and neuronal development in mice.^1,2

Current evidence suggests that the GBA works through a combination of both fast-acting neural and delayed immune-mediated mechanisms in a bidirectional manner with feedback on and from both systems.³ In addition to their direct effects on neural pathways and immune modulation, intestinal microbiota are essential in the production of a vast array of vitamins, cofactors, and nutrients required for optimal health and metabolism.⁴ Existing research on the GBA demonstrates the direct functional impact of the intestinal microbiome on neurologic and psychiatric health.

We will review current knowledge regarding this intriguing relationship. In doing so, we take a closer look at several specific genera and families of intestinal microbiota, review the microbiome’s effects on immune function, and examine the relationship between this microbiome and mental disease, using specific examples such as generalized anxiety disorder (GAD) and major depressive disorder (MDD). We seek to consolidate existing knowledge on the intricacies of the GBA in the hope that it may promote individual health and become a standard component in the treatment of mental illness.

Direct Activation of Neuronal Pathways

Vagal and spinal afferent nerve pathways convey information regarding hormonal, chemical, and mechanical stimuli from the intestines to the brain.³ These afferent neurons have been shown to be responsive to microbial signals and cytokines as well as to gut hormones. This provides the basis for research that presumes that neurobehavioral change may ensue from manipulating the gut microbes emitting these chemical signals to which these afferent neurons respond.³ Using these same pathways, efferent neurons of the parasympathetic and sympathetic nervous systems can modulate the intestinal environment by altering acid and bile secretion, mucous production, and motility. This modulation can directly impact the relative diversity of intestinal flora, and in more extreme states, may result in bacterial overgrowth.⁵ Of particular relevance to mental health (MH) is that the frequency of migrating motor complexes that promote peristalsis can be directly influenced by readily modifiable behaviors such as sleep and food intake, which can cause one bacterial species to dominate in a higher percentage.⁵ This imbalance of gut microbes has been implicated in contributing to somatic conditions, such as irritable bowel syndrome (IBS), which the literature has shown is related to psychiatric conditions such as anxiety. ⁵

The Microbiome and Host Immunity

The GI tract is colonized with commensal microorganisms from dozens of bacterial, archaeal, fungal, and protozoal groups.⁶ This relationship has its most classical immunologic interaction in the toll-like receptors. These receptors are on the lymphoid Peyer patches of the GI tract, which sample microorganisms and develop immunoglobulin (IgA) antibodies to them. Evidence exists that commensal microflora play a critical role in the regulation of host inflammatory response.⁷

The relationship between the microbiome and the immune system remains poorly understood, yet evidence has shown that the use of probiotics may reduce inflammation and its sequelae. Probiotics have been shown to have a beneficial effect on autoimmune diseases, such as Crohn disease and ulcerative colitis, specifically with certain strains of Escherichia coli (E coli) and a proprietary probiotic from VSL pharmaceuticals.^8,9 However, these interventions are not without risk. Fecal microbiota transplants have a risk of transferring unwanted organisms, potentially including COVID-19.¹⁰ Additionally, the use of probiotics is generally discouraged in immunocompromised, chronically ill, and/or hospitalized patients, as these patients may be at greater risk of developing probiotic bacteremia and sepsis.¹¹

Studies have also demonstrated that ingesting probiotics may decrease the expression of pro-inflammatory cytokines.¹¹ In a study comparing patients with ulcerative colitis who were prescribed both sulfasalazine and probiotic supplements vs sulfasalazine alone, patients who took the probiotic supplements were shown to have less colonic inflammation and decreased expression of cytokines such as IL-6, tumor necrosis factor-α (TNF-α), and nuclear factor-κβ.¹²

Gut-Specific Bacterial Phyla

Over the past decade, much attention has been paid toward 2 bacterial phyla that compromise a large proportion of the human gut microbiome: Firmicutes and Bacteroidetes. Intestinal Firmicutes species are predominantly Gram positive and are found as both cocci and bacilli. Well-known classes within the phylum Firmicutes include Bacilli (orders Bacillales and Lactobacillales) and Clostridia. The phylum Bacteroidetes is composed of Gram-negative rods and includes the genus Bacteroides—a substantial component of mammalian gut biomes. The ratio of Firmicutes to Bacteroidetes, also known as the F/B ratio, have shown fascinating patterns in certain psychiatric conditions. This knowledge may be applied to better identify, treat, and manage such patients.

Regarding bacterial phyla and their relationship to mood disorders, interesting patterns have been observed. In one population of patients with anorexia nervosa (AN) lower diversity within classes of Firmicutes bacteria was observed compared with age- and sex-matched controls without AN.¹³ As patients were re-fed and treated in this study, there was a significant corresponding increase in microbiome diversity; however, the level of bacterial diversity in re-fed patients with AN was still far less than that of patients in the control group. In patients with AN with comorbid depression, diversity was noted to be exceptionally reduced. Similarly, patients with AN with a more severe eating disorder psychopathology demonstrated decreased microbial diversity.¹³

The impact of intestinal microbiome diversity and relative bacterial population density in MH conditions such as anxiety, depression, and eating disorders remains an intriguing avenue worth further exploring. Modulating these phenomena may reduce overall dysfunction and serve as a possible treatment modality.

Anxiety and the Microbiome

GAD is characterized by decreased social and occupational functioning. Anxiolytic pharmacotherapy combined with psychotherapy are the current mainstays of GAD treatment. Given the interplay of the gut microbiome and MH, probiotics may prove to be a promising alternative or adjunct treatment option.

The human stress response is enacted largely through the hypothalamus-pituitary-adrenal (HPA) axis. Anxiety and situational fear trigger a stress response that results in increased cortisol being released from the adrenal glands, thereby disrupting typical GI function by modifying the frequency of migrating motor complexes, the electromechanical impulses within the smooth muscle of the stomach and small bowel that allow for propagation of chyme. This, in turn, has downstream consequences on the composition of the intestinal microbiome.¹⁴ Patients with GAD have a lower prevalence of Faecalibacterium, Eubacterium rectale, Lachnospira, Butyricioccus, and Sutterella, all important producers of short-chain fatty acids (SCFA).^15,16 Diminished SCFA production has been linked to intestinal barrier dysfunction, contributing to increases in gut endothelial permeability and facilitating a proinflammatory response with resultant neural feedback loops.^17,18 Indeed, proinflammatory cytokines, namely C-reactive protein (CRP), interleukin 6 (IL-6), and TNF-α were found to be elevated in patients with diagnosed GAD.¹⁹ These proinflammatory cytokines are critical in neurochemical modulation as they inhibit the essential enzyme tetrahydrobiopterin, a cofactor of monoamine synthesis, thereby decreasing the monoamine neurotransmitters serotonin, dopamine, and norepinephrine.²⁰ Decrease in the monoamine neurotransmitters serves as the lynchpin for the monoamine hypothesis of both anxiety and depression and currently guides our choice in pharmacotherapy.²¹

Anxiolytic pharmacotherapy targets the neurochemical consequences of GAD to ameliorate social, functional, and emotional impairment. However, the physiology of the gut-brain feedback loop in GAD is an attractive target for the creation and trialing of probiotics, which can rebalance intestinal flora, reduce inflammation, and allow for increased synthesis of monoamine neurotransmitters. Indeed, Lactobacillus and Bifidobacterium have been shown to possess anxiolytic properties by increasing serotonin and SCFAs while reducing the HPA adrenergic response.²²

Depression and the Microbiome

MDD significantly diminishes quality of life and is the leading cause of disability worldwide, affecting nearly 350 million individuals.²³ Psychotherapy in conjunction with pharmacotherapy aimed at increasing cerebral serotonin availability are the current mainstays of MDD treatment. Yet the brain does not exist in isolation: It has 3 known methods of bidirectional communication with the GI tract via the vagus nerve, immune mediators, and bacterial metabolites.^24,25

The vagus nerve (vagus means wandering in Latin), is the longest nerve of the autonomic nervous system (ANS) and historically has been called the pneumogastric nerve for its parasympathetic innervation of the heart, lungs, and digestive tract. Current research supports that up to 80% of the fibers within the vagus nerve are afferent, relaying signals from the GI tract to the brain.²⁶ Therefore, modulation of vagus nerve signaling may theoretically impact mental health. Indeed, studies have demonstrated clinically significant improvement in patients with treatment-resistant depression who underwent vagal nerve stimulation (VNS).²⁷ Although the mechanism by which it exerts its mood-modulating activity is not well understood, recent human and animal studies indicate that VNS may alter central neurotransmitter levels, having demonstrated the ability to increase serotonin levels.²⁵ Also the vagus nerve possesses the ability to differentiate between pathogenic and nonpathogenic gut microorganisms; beneficial gut flora emit signals within the gut lumen, which in turn, are transmitted through afferent vagus nerve fibers to the brain, effecting both anti-inflammatory and mood-modulating responses.^25,28

Immunomediators involving intestinal microbiota also are known to play a critical role in the pathophysiology of MDD. Depression is closely tied to systemic inflammation; both are hypothesized to have played a role in the evolutionary response to fighting infection and healing wounds.²⁹ With regard to the gut, MDD is associated with increased GI permeability, which allows for microorganisms to leak through the intestinal mucosa into the systemic circulation and stimulate an inflammatory response.¹⁸ Levels of IgM and IgA against enterobacteria lipopolysaccharides (LPS) were found to be markedly greater in patients with MDD vs those of nondepressed controls.³⁰ Current research indicates that IgM and IgA against LPS of translocated bacteria serve to amplify immune pathways seen in the pathophysiology of chronic MDD.^30,31 Further research is indicated to deduce whether bacterial translocation with subsequent immune response induces MDD in susceptible individuals, or whether translocation occurs secondary to the systemic inflammation seen in MDD.

The makeup of the GI microbiome is fundamentally altered in patients with MDD, with a marked reduction in both microorganism diversity and density.³⁰ Patients with MDD have been shown to have increased levels of Alistipes, a bacterium that also is elevated in chronic fatigue syndrome and irritable bowel syndrome (IBS), diagnoses that are associated with MDD.^32-34 Lower counts of Bifidobacterium and Lactobacillus are documented in both MDD and IBS patients as well.³⁵ Decreased Bifidobacterium and Lactobacillus might indicate a causal rather than correlative relationship as these bacterium take the precursor monosodium glutamate to create γ-aminobutyric acid (GABA).³⁶

Psychobiotics and Mental Health

The pathophysiology of the bidirectional communication between the gut and the brain offers an attractive approach for treatment modalities. Currently, the research into probiotic supplementation to treat mental disorders, such as anxiety and depression, is still in its infancy, and treatment guidelines do not support their routine administration. There is great promise in the use of probiotics to ameliorate psychiatric symptomatology, referred to by many in the field as psychobiotics.

One pathophysiology of the stress response seen in anxiety can be traced to the HPA axis and increased cortisol levels, with downstream effects on the microbiome through modification of the migrating motor complexes. Healthy volunteers tasked with taking a trademarked galactooligosaccharide prebiotic daily for 3 weeks had a reduced salivary cortisol awakening response compared with that of a placebo (maltodextrin). The same group demonstrated decreased attentional vigilance to negative information in a dot-probe task compared with attentional vigilance with positive information.³⁷ It is possible that this was due to the decreased stress response secondary to probiotic consumption. In mice models, a probiotic consisting of Lactobacillus helveticus and Bifidobacterium longum (B longum) (bacterium that are decreased in GAD and MDD) demonstrated anxiolytic-like behavior. The same formulation also demonstrated beneficial psychological effects in healthy human volunteers.²² In mice models, Lactobacillus feeding was superior to citalopram in anxiolysis and in cognitive functioning.³⁸

Like GAD, the pathophysiology of the GBA in MDD is an attractive target for psychobiotic therapy. Although current research is not yet sufficient to create general guidelines or recommendations for the routine administration of psychobiotics, it holds significant promise as an effective primary and/or adjunct treatment. In patients with IBS, administration of B longum reduced depression and increased quality of life. This same study demonstrated that probiotic administration was associated with reduced limbic activity in the brain.³⁹ In MDD, the hippocampus demonstrates altered expression of various transcription factors and cellular metabolism.⁴⁰ In a double-blind placebo-controlled trial, Lactobaccillus rhamnosus supplementation in postnatal mothers resulted in less severe depressive symptoms reported.⁴¹ Furthermore, probiotic supplementation consisting of Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum in patients with MDD for 8 weeks had significant decreases in score on the Beck Depression Inventory scale.⁴² Also, a meta-analysis of probiotic administration on depression scales demonstrated appreciably lower scores after administration in both patients with MDD and healthy patients aged 60 years, although these results were found to be correlative.⁴³ However, while promising, another meta-analysis of 10 randomized controlled trials found probiotic supplementation had no significant effect on mood.⁴⁴

The Role of Diet

Although there has been tremendous focus on new and improved therapeutics to address MH conditions, such as depression and anxiety, there also has been renewed interest in the fundamental importance and benefit of a wholesome diet. Recent literature has shown how diet may play a pivotal role in the development and severity of mental illness and holds promise as another potential target for treatment. A 2010 cross-sectional population study of more than 1000 adult women aged 20 to 93 years demonstrated that women with a largely Western dietary pattern (ie, largely composed of processed meats, pizza, chips, hamburgers, white bread, sugar, flavored milk drinks, and beer) were more likely to have dysthymic disorder or major depression, whereas women in this same cohort with a more traditional dietary pattern (ie, composed mainly of vegetables, fruit, lamb, beef, fish, and whole grains) were found to have significantly reduced odds for depression or dysthymic disorder as well as anxiety disorders.⁴⁵

Several other large-scale population studies such as the SUN cohort study, Hordaland Health study, Whitehall II cohort study, and RHEA mother and baby cohort study have demonstrated similar findings: that a more wholesome diet composed mainly of lean meats, vegetables, fruits, and whole grains was associated with significantly reduced risk of depression compared with a largely processed, high fat, and high sugar diet. This trend also has been observed in children and adolescents and is of particular importance when considering that many psychological and psychiatric problems tend to arise in the formative and often turbulent years prior to adulthood.⁴⁶

The causal relationship between diet and MH may be better understood by taking a closer look at a crucial intermediate factor: the gut microbiome. The interplay between diet and intestinal microbiome was well elucidated in a landmark 2010 study by De Filippo and colleagues.⁴⁷ In this study, the microbiota of 14 healthy children from a small village in Burkina Faso (BF) were compared with those of 15 healthy children from an urban area of Florence, Italy (EU). The BF children were reported to consume a traditional rural African diet that is primarily vegetarian, rich in fiber, and low in animal protein and fat, whereas the EU children were noted as consuming a typical Western diet low in fiber but rich in animal protein, fat, sugar, and starch. Comparison revealed that EU children had a higher F/B ratio than their BF counterparts, a metric that has been associated with obesity.⁴⁷ Furthermore, increased exposure to environmental microbes associated with a fiber-rich diet has been postulated to increase the richness of intestinal flora and serve as a protective factor against noninfectious and inflammatory colonic diseases, which are found to be more prevalent in Western nations whose diets lack fiber. BF children were found to have increased microbial diversity and increased abundance of bacteria capable of producing SCFA relative to their EU counterparts, both of which have a positive influence on the gut, systemic inflammation, and MH.⁴⁷

Conclusions

Diet has a powerful impact on the intestinal microbiome, which in turn directly impacts our physical and MH in myriad ways. The well-known benefits of a wholesome, nutritious, and well-varied diet include reduced cardiovascular risk, improved glycemic control, GI regularity, and decreased depression. Along with a balanced diet, patients may achieve further benefit with the addition of probiotics.

With regard to psychiatry in particular, increased awareness of the intimate relationship between the gut and the brain is expected to have profound implications for the field. Given this mounting data, immunology, microbiology, and GI pathophysiology should be included in future discussions regarding MH. Their application will likely improve both somatic and mental well-being. We anticipate that newly discovered probiotics and other psychobiotic formulations will be routinely included in a psychiatrist’s pharmacopeia in the near future. Unfortunately, as is clear from our review of the current literature, we do not yet have specific interventions targeting the intestinal microbiome to recommend for the management of specific psychiatric conditions. However, this should not deter further exploring diet modification and psychobiotic supplementation as a means of impacting the intestinal microbiome in the pursuit of psychiatric symptom relief.

Dietary modification is already a standard component of sound primary care medicine, designed to mitigate risk for cardiovascular disease. This exploration can occur as part of otherwise standard psychiatric care and be used as a form of behavioral activation for the patient. Furthermore, explaining the interconnectedness of the mind, brain, and body along with the rationale for experimentation could further help destigmatize the experience of mental illness.

The American Medical Association publicly acknowledged in November 2020 that race is a social construct without biological basis, with many other leading medical organizations following suit.¹ Historically, biased science based on observed human physical differences has incorrectly asserted a racial biological hierarchy.^2,3 Today, leading health care organizations recognize that the effects of racist policies in housing, education, employment, and the criminal justice system contribute to health disparities and have a disproportionately negative impact on Black, Indigenous, and People of Color.^3,4 

Racial classification systems are fraught with bias. Trying to classify a complex and nuanced identity such as race into discrete categories does not capture the extensive heterogeneity at the individual level or within the increasingly diverse, multiracial population.⁵ Racial and ethnic categories used in collecting census data and research, as defined by the US Office of Management and Budget, have evolved over time.⁶ These changes in classification are a reflection of changes in the political environment, not changes in scientific knowledge of race and ethnicity.⁶

The Use of Race in Research and Practice

In the United States, racial minorities bear a disproportionate burden of morbidity and mortality across all major disease categories.³ These disparities cannot be explained by genetics.⁴ The Human Genome Project in 2003 confirmed that racial categories have no biologic or genetic basis and that there is more intraracial than interracial genetic variation.³ Nevertheless, significant misapplication of race in medical research and clinical practice remains. Instead of attributing observed differences in health outcomes between racial groups to innate physiological differences between the groups, clinicians and researchers must carefully consider the impact of racism.⁷ This includes considering the complex interactions between socioeconomic, political, and environmental factors, and how they affect health.³

While race is not biologic, the effects of racism can have biologic effects, and advocates appropriately cite the need to collect race as an important category in epidemiological analysis. When race and ethnicity are used as a study variable, bioethicists Kaplan and Bennett recommend that researchers: (1) account for limitations due to imprecision of racial categories; (2) avoid attributing causality when there is an association between race/ethnicity and a health outcome; and (3) refrain from exacerbating racial disparities.⁶

At the bedside, race has become embedded in clinical, seemingly objective, decision-making tools used across medical specialties.⁸ These algorithms often use observational outcomes data and draw conclusions by explicitly or implicitly assuming biological differences among races. By crudely adjusting for race without identifying the root cause for observed racial differences, these tools can further magnify health inequities.⁸ With the increased recognition that race cannot be used as a proxy for genetic ancestry, and that racial and ethnic categories are complex sociopolitical constructs that have changed over time, the practice of race-based medicine is increasingly being criticized.⁸

This article presents a case for the removal of the race coefficient from estimated glomerular filtration rate (eGFR) calculations that exacerbate disparities in kidney health by overestimating kidney function in Black patients.⁸ The main justification for using the race coefficient stems from the disproven assumption that Black people have more muscle mass compared with non-Black people.⁹  The questioning of this racist assertion has led to a national movement to reevaluate the use of race in eGFR calculations.

Racial Disparities in Kidney Disease

According to epidemiological data published by the National Kidney Foundation (NKF) and American Society of Nephrology (ASN), 37 million people in the United States have chronic kidney disease (CKD).¹⁰ Black Americans make up 13% of the US population yet they account for more than 30% of patients with end-stage kidney disease (ESKD) and 35% of those on dialysis.^10,11 There is a 3 times greater risk for progression from early-stage CKD to ESKD in Black Americans when compared to the risk for White Americans.¹¹ Black patients are younger at the time of CKD diagnosis and, once diagnosed, experience a faster progression to ESKD.¹² These disparities are partially attributable to delays in diagnosis, preventative measures, and referrals to nephrology care.¹²  

In a VA medical center study, although Black patients were referred to nephrology care at higher rates than White patients, Black patients had faster progression to CKD stage 5.¹³ An earlier study showed that, at any given eGFR, Black patients have higher levels of albuminuria compared to White patients.¹⁴ While the reasons behind this observation are likely complex and multifactorial, one hypothesis is that Black patients were already at a more advanced stage of kidney disease at the time of referral as a result of the overestimation of eGFR calculations related to the use of a race coefficient.

Additionally, numerous analyses have revealed that Black patients are less likely to be identified as transplant candidates, less likely to be referred for transplant evaluation and, once on the waiting list, wait longer than do White patients.^11,15

Estimated Glomerular Filtration Rate

It is imperative that clinicians have the most accurate measure of GFR to ensure timely diagnosis and appropriate management in patients with CKD. The gold standard for determining renal function requires measuring GFR using an ideal, exogenous, filtration marker such as iothalamate. However, this process is complex and time-consuming, rendering it infeasible in routine care. As a result, we usually estimate GFR using endogenous serum markers such as creatinine and cystatin C. Due to availability and cost, serum creatinine (SCr) is the most widely used marker for estimating kidney function. However, many pitfalls are inherent in its use, including the effects of tubular secretion, extrarenal clearance, and day-to-day variability in creatinine generation related to muscle mass, diet, and activity.¹⁶ The 2 most widely used estimation equations are the Modification of Diet in Renal Disease (MDRD) study equation and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation; both equations incorporate correction factors for age, sex, and race. 

The VA uses MDRD, which was derived and validated in a cohort of 1628 patients that included only 197 Black patients (12%), resulting in an eGFR for Black patients that is 21% higher than is the eGFR for non-Black patients with the same SCr value.⁹ In the VA electronic health record, the race coefficient is incorporated directly into eGFR laboratory calculations based on the race that the veteran self-identified during intake. Because the laboratory reports only a race-adjusted eGFR, there is a lack of transparency as many health care providers and patients are unaware that a race coefficient is used in eGFR calculations at the VA.  

Case for Removing Race Coefficient

When applied to cohorts outside the original study, both the MDRD and CKD-EPI equations have proved to be highly biased, imprecise, and inaccurate when compared to measured GFR (mGFR).^15,17 For any given eGFR, the possible mGFR may span 3 stages of CKD, underscoring the limitations of using such a crude estimate in clinical decision making.¹⁷ 

Current Kidney Estimation Pitfalls

A recent cohort study by Zelnick and colleagues that included 1658 self-identified Black adults showed less bias between mGFR and eGFR without the use of a race coefficient, and a shorter median time to transplant eligibility by 1.9 years.¹⁵ This study provides further evidence that these equations were derived from a biased observational data set that overestimates eGFR in Black patients living with CKD. This overestimation is particularly egregious for frail or malnourished patients with CKD and multiple comorbidities, with many potential harmful clinical consequences.

In addition, multiple international studies in African countries have demonstrated worse performance of eGFR calculations when using the race coefficient than without it. In the Democratic Republic of the Congo, eGFR was calculated for adults using MDRD with and without the race coefficient, as well as CKD-EPI with and without the race coefficient, and then compared to mGFR. Both the MDRD and the CKD-EPI equations overestimated GFR when using the race coefficient, and notably the equations without the race coefficient had better correlation to mGFR.¹⁸ Similar data were also found in studies from South Africa, the Ivory Coast, Brazil, and Europe.^19-22

Clinical Consequences of Race Coefficient Use

The use of a race coefficient in these estimation equations causes adverse clinical outcomes. In early stages of CKD, overestimation of eGFR using the race coefficient can cause an under-recognition of CKD, and can lead to delays in diagnosis and failure to implement measures to slow its progression, such as minimizing drug-related nephrotoxic injury and iatrogenic acute kidney injury. Consequently, a patient with an overestimated eGFR may suffer an accelerated progression to ESKD and premature mortality from cardiovascular disease.²³ 

In advanced CKD stages, eGFR overestimation may result in delayed referral to a nephrologist (recommended at eGFR < 30mL/min/1.73 m²), nutrition counseling, renal replacement therapy education, timely referral for renal replacement therapy access placement, and transplant evaluation (can be listed when eGFR < 20 mL/min/1.73 m²).^16,24,25 

In the Clinical Vignette, it is clear from the information presented that Mr. C’s concerns are well-founded. Table 1 presents the impact on eGFR caused by the race coefficient using the MDRD and CKD-EPI equations. In many VA systems, this overestimation would prevent him from being referred for a kidney transplant at this visit, thereby perpetuating racial health disparities in kidney transplantation. 

Concerns About Removal of Race From eGFR Calculations

Opponents of removing the race coefficient assert that a lower eGFR will preclude some patients from qualifying for medications such as metformin and certain anticoagulants, or that it may result in subtherapeutic dosing of drugs such as antibiotics and chemotherapeutic agents.²⁶ These recommendations are in place for patient safety, so conversely maintaining the race coefficient and overestimating eGFR will expose some patients to medication toxicity. Another fear is that lower eGFRs will have the unintended consequence of limiting the kidney donor pool. However, this can be prevented by following current guidelines to use mGFR in settings where accurate GFR is imperative.¹⁶ Additionally, some nephrologists have expressed concern that diagnosing more patients with advanced stages of CKD will result in inappropriately early initiation of dialysis. Again, this risk can be mitigated by ensuring that nephrologists consider multiple clinical factors and data points, not simply eGFR when deciding to initiate dialysis. Also, an increase in referrals to nephrology may occur when the race coefficient is removed and increased wait times at some VA medical centers could be a concern. An increase in appropriate referrals would show that removing the race coefficient was having its intended effect—more veterans with advanced CKD being seen by nephrologists.

When considering the lack of biological plausibility, inaccuracy, and the clinical harms associated with the use of the race coefficient in eGFR calculations, the benefits of removing the race coefficient from eGFR calculations within the VA far outweigh any potential risks.  

A Call for Equity

The National Conversation on Race and eGFR

To advance health equity, members of the medical community have advocated for the removal of the race coefficient from eGFR calculations for years. Beth Israel Deaconess Medical Center was the first establishment to institute this change in 2017. Since then, many health systems across the country that are affiliated with Veterans Health Administration (VHA) medical centers have removed the race coefficient from eGFR equations (Table 2). Many other hospital systems are contemplating this change. 

In July 2020, the NKF and the ASN established a joint task force dedicated to reassessing the inclusion of race in eGFR calculations. This task force acknowledges that race is a social, not biological, construct.¹² The NKF/ASN task force is now in the second of its 3-phase process. In March 2021, prior to publication of their phase 1 findings, they announced “(1) race modifiers should not be included in equations to estimate kidney function; and (2) current race-based equations should be replaced by a suitable approach that is accurate, inclusive, and standardized in every laboratory in the United States. Any such approach must not differentially introduce bias, inaccuracy, or inequalities.”²⁷

Health Equity in the VHA

In January 2021, President Biden issued an executive order to advance racial equity and support underserved communities through the federal government and its agencies. The VHA is the largest integrated health care system in the United States serving 9 million veterans and is one of the largest federal agencies. As VA clinicians, it is our responsibility to examine the evidence, consider national guidance, and ensure health equity for veterans by practicing unbiased medicine. The evidence and the interim guidance from the NKF-ASN task force clearly indicate that the race coefficient should no longer be used.²⁷ It is imperative that we make these changes immediately knowing that the use of race in kidney function calculators is harming Black veterans. Similar to finding evidence of harm in a treatment group in a clinical trial, it is unethical to wait. Removal of the race coefficient in eGFR calculations will allow VHA clinicians to provide timely and high-quality care to our patients as well as establish the VHA as a national leader in health equity.

VISN 12 Leads the Way

On May 11, 2021, the VA Great Lakes Health Care System, Veterans Integrated Service Network (VISN) 12, leaders responded to this author group’s call to advance health equity and voted to remove the race coefficient from eGFR calculations. Other VISNs should follow, and the VHA should continue to work with national leaders and experts to establish and implement superior tools to ensure the highest quality of kidney health care for all veterans.  

Acknowledgments
The authors would like to thank the medical students across the nation who have been leading the charge on this important issue. The authors are also thankful for the collaboration and support of all members of the Jesse Brown for Black Lives (JB4BL) Task Force. 

The American Medical Association publicly acknowledged in November 2020 that race is a social construct without biological basis, with many other leading medical organizations following suit.¹ Historically, biased science based on observed human physical differences has incorrectly asserted a racial biological hierarchy.^2,3 Today, leading health care organizations recognize that the effects of racist policies in housing, education, employment, and the criminal justice system contribute to health disparities and have a disproportionately negative impact on Black, Indigenous, and People of Color.^3,4 

Racial classification systems are fraught with bias. Trying to classify a complex and nuanced identity such as race into discrete categories does not capture the extensive heterogeneity at the individual level or within the increasingly diverse, multiracial population.⁵ Racial and ethnic categories used in collecting census data and research, as defined by the US Office of Management and Budget, have evolved over time.⁶ These changes in classification are a reflection of changes in the political environment, not changes in scientific knowledge of race and ethnicity.⁶

The Use of Race in Research and Practice

In the United States, racial minorities bear a disproportionate burden of morbidity and mortality across all major disease categories.³ These disparities cannot be explained by genetics.⁴ The Human Genome Project in 2003 confirmed that racial categories have no biologic or genetic basis and that there is more intraracial than interracial genetic variation.³ Nevertheless, significant misapplication of race in medical research and clinical practice remains. Instead of attributing observed differences in health outcomes between racial groups to innate physiological differences between the groups, clinicians and researchers must carefully consider the impact of racism.⁷ This includes considering the complex interactions between socioeconomic, political, and environmental factors, and how they affect health.³

While race is not biologic, the effects of racism can have biologic effects, and advocates appropriately cite the need to collect race as an important category in epidemiological analysis. When race and ethnicity are used as a study variable, bioethicists Kaplan and Bennett recommend that researchers: (1) account for limitations due to imprecision of racial categories; (2) avoid attributing causality when there is an association between race/ethnicity and a health outcome; and (3) refrain from exacerbating racial disparities.⁶

At the bedside, race has become embedded in clinical, seemingly objective, decision-making tools used across medical specialties.⁸ These algorithms often use observational outcomes data and draw conclusions by explicitly or implicitly assuming biological differences among races. By crudely adjusting for race without identifying the root cause for observed racial differences, these tools can further magnify health inequities.⁸ With the increased recognition that race cannot be used as a proxy for genetic ancestry, and that racial and ethnic categories are complex sociopolitical constructs that have changed over time, the practice of race-based medicine is increasingly being criticized.⁸

This article presents a case for the removal of the race coefficient from estimated glomerular filtration rate (eGFR) calculations that exacerbate disparities in kidney health by overestimating kidney function in Black patients.⁸ The main justification for using the race coefficient stems from the disproven assumption that Black people have more muscle mass compared with non-Black people.⁹  The questioning of this racist assertion has led to a national movement to reevaluate the use of race in eGFR calculations.

Racial Disparities in Kidney Disease

According to epidemiological data published by the National Kidney Foundation (NKF) and American Society of Nephrology (ASN), 37 million people in the United States have chronic kidney disease (CKD).¹⁰ Black Americans make up 13% of the US population yet they account for more than 30% of patients with end-stage kidney disease (ESKD) and 35% of those on dialysis.^10,11 There is a 3 times greater risk for progression from early-stage CKD to ESKD in Black Americans when compared to the risk for White Americans.¹¹ Black patients are younger at the time of CKD diagnosis and, once diagnosed, experience a faster progression to ESKD.¹² These disparities are partially attributable to delays in diagnosis, preventative measures, and referrals to nephrology care.¹²  

In a VA medical center study, although Black patients were referred to nephrology care at higher rates than White patients, Black patients had faster progression to CKD stage 5.¹³ An earlier study showed that, at any given eGFR, Black patients have higher levels of albuminuria compared to White patients.¹⁴ While the reasons behind this observation are likely complex and multifactorial, one hypothesis is that Black patients were already at a more advanced stage of kidney disease at the time of referral as a result of the overestimation of eGFR calculations related to the use of a race coefficient.

Additionally, numerous analyses have revealed that Black patients are less likely to be identified as transplant candidates, less likely to be referred for transplant evaluation and, once on the waiting list, wait longer than do White patients.^11,15

Estimated Glomerular Filtration Rate

It is imperative that clinicians have the most accurate measure of GFR to ensure timely diagnosis and appropriate management in patients with CKD. The gold standard for determining renal function requires measuring GFR using an ideal, exogenous, filtration marker such as iothalamate. However, this process is complex and time-consuming, rendering it infeasible in routine care. As a result, we usually estimate GFR using endogenous serum markers such as creatinine and cystatin C. Due to availability and cost, serum creatinine (SCr) is the most widely used marker for estimating kidney function. However, many pitfalls are inherent in its use, including the effects of tubular secretion, extrarenal clearance, and day-to-day variability in creatinine generation related to muscle mass, diet, and activity.¹⁶ The 2 most widely used estimation equations are the Modification of Diet in Renal Disease (MDRD) study equation and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation; both equations incorporate correction factors for age, sex, and race. 

The VA uses MDRD, which was derived and validated in a cohort of 1628 patients that included only 197 Black patients (12%), resulting in an eGFR for Black patients that is 21% higher than is the eGFR for non-Black patients with the same SCr value.⁹ In the VA electronic health record, the race coefficient is incorporated directly into eGFR laboratory calculations based on the race that the veteran self-identified during intake. Because the laboratory reports only a race-adjusted eGFR, there is a lack of transparency as many health care providers and patients are unaware that a race coefficient is used in eGFR calculations at the VA.  

Case for Removing Race Coefficient

When applied to cohorts outside the original study, both the MDRD and CKD-EPI equations have proved to be highly biased, imprecise, and inaccurate when compared to measured GFR (mGFR).^15,17 For any given eGFR, the possible mGFR may span 3 stages of CKD, underscoring the limitations of using such a crude estimate in clinical decision making.¹⁷ 

Current Kidney Estimation Pitfalls

A recent cohort study by Zelnick and colleagues that included 1658 self-identified Black adults showed less bias between mGFR and eGFR without the use of a race coefficient, and a shorter median time to transplant eligibility by 1.9 years.¹⁵ This study provides further evidence that these equations were derived from a biased observational data set that overestimates eGFR in Black patients living with CKD. This overestimation is particularly egregious for frail or malnourished patients with CKD and multiple comorbidities, with many potential harmful clinical consequences.

In addition, multiple international studies in African countries have demonstrated worse performance of eGFR calculations when using the race coefficient than without it. In the Democratic Republic of the Congo, eGFR was calculated for adults using MDRD with and without the race coefficient, as well as CKD-EPI with and without the race coefficient, and then compared to mGFR. Both the MDRD and the CKD-EPI equations overestimated GFR when using the race coefficient, and notably the equations without the race coefficient had better correlation to mGFR.¹⁸ Similar data were also found in studies from South Africa, the Ivory Coast, Brazil, and Europe.^19-22

Clinical Consequences of Race Coefficient Use

The use of a race coefficient in these estimation equations causes adverse clinical outcomes. In early stages of CKD, overestimation of eGFR using the race coefficient can cause an under-recognition of CKD, and can lead to delays in diagnosis and failure to implement measures to slow its progression, such as minimizing drug-related nephrotoxic injury and iatrogenic acute kidney injury. Consequently, a patient with an overestimated eGFR may suffer an accelerated progression to ESKD and premature mortality from cardiovascular disease.²³ 

In advanced CKD stages, eGFR overestimation may result in delayed referral to a nephrologist (recommended at eGFR < 30mL/min/1.73 m²), nutrition counseling, renal replacement therapy education, timely referral for renal replacement therapy access placement, and transplant evaluation (can be listed when eGFR < 20 mL/min/1.73 m²).^16,24,25 

In the Clinical Vignette, it is clear from the information presented that Mr. C’s concerns are well-founded. Table 1 presents the impact on eGFR caused by the race coefficient using the MDRD and CKD-EPI equations. In many VA systems, this overestimation would prevent him from being referred for a kidney transplant at this visit, thereby perpetuating racial health disparities in kidney transplantation. 

Concerns About Removal of Race From eGFR Calculations

Opponents of removing the race coefficient assert that a lower eGFR will preclude some patients from qualifying for medications such as metformin and certain anticoagulants, or that it may result in subtherapeutic dosing of drugs such as antibiotics and chemotherapeutic agents.²⁶ These recommendations are in place for patient safety, so conversely maintaining the race coefficient and overestimating eGFR will expose some patients to medication toxicity. Another fear is that lower eGFRs will have the unintended consequence of limiting the kidney donor pool. However, this can be prevented by following current guidelines to use mGFR in settings where accurate GFR is imperative.¹⁶ Additionally, some nephrologists have expressed concern that diagnosing more patients with advanced stages of CKD will result in inappropriately early initiation of dialysis. Again, this risk can be mitigated by ensuring that nephrologists consider multiple clinical factors and data points, not simply eGFR when deciding to initiate dialysis. Also, an increase in referrals to nephrology may occur when the race coefficient is removed and increased wait times at some VA medical centers could be a concern. An increase in appropriate referrals would show that removing the race coefficient was having its intended effect—more veterans with advanced CKD being seen by nephrologists.

When considering the lack of biological plausibility, inaccuracy, and the clinical harms associated with the use of the race coefficient in eGFR calculations, the benefits of removing the race coefficient from eGFR calculations within the VA far outweigh any potential risks.  

A Call for Equity

The National Conversation on Race and eGFR

To advance health equity, members of the medical community have advocated for the removal of the race coefficient from eGFR calculations for years. Beth Israel Deaconess Medical Center was the first establishment to institute this change in 2017. Since then, many health systems across the country that are affiliated with Veterans Health Administration (VHA) medical centers have removed the race coefficient from eGFR equations (Table 2). Many other hospital systems are contemplating this change. 

In July 2020, the NKF and the ASN established a joint task force dedicated to reassessing the inclusion of race in eGFR calculations. This task force acknowledges that race is a social, not biological, construct.¹² The NKF/ASN task force is now in the second of its 3-phase process. In March 2021, prior to publication of their phase 1 findings, they announced “(1) race modifiers should not be included in equations to estimate kidney function; and (2) current race-based equations should be replaced by a suitable approach that is accurate, inclusive, and standardized in every laboratory in the United States. Any such approach must not differentially introduce bias, inaccuracy, or inequalities.”²⁷

Health Equity in the VHA

In January 2021, President Biden issued an executive order to advance racial equity and support underserved communities through the federal government and its agencies. The VHA is the largest integrated health care system in the United States serving 9 million veterans and is one of the largest federal agencies. As VA clinicians, it is our responsibility to examine the evidence, consider national guidance, and ensure health equity for veterans by practicing unbiased medicine. The evidence and the interim guidance from the NKF-ASN task force clearly indicate that the race coefficient should no longer be used.²⁷ It is imperative that we make these changes immediately knowing that the use of race in kidney function calculators is harming Black veterans. Similar to finding evidence of harm in a treatment group in a clinical trial, it is unethical to wait. Removal of the race coefficient in eGFR calculations will allow VHA clinicians to provide timely and high-quality care to our patients as well as establish the VHA as a national leader in health equity.

VISN 12 Leads the Way

On May 11, 2021, the VA Great Lakes Health Care System, Veterans Integrated Service Network (VISN) 12, leaders responded to this author group’s call to advance health equity and voted to remove the race coefficient from eGFR calculations. Other VISNs should follow, and the VHA should continue to work with national leaders and experts to establish and implement superior tools to ensure the highest quality of kidney health care for all veterans.  

Acknowledgments
The authors would like to thank the medical students across the nation who have been leading the charge on this important issue. The authors are also thankful for the collaboration and support of all members of the Jesse Brown for Black Lives (JB4BL) Task Force. 

The American Medical Association publicly acknowledged in November 2020 that race is a social construct without biological basis, with many other leading medical organizations following suit.¹ Historically, biased science based on observed human physical differences has incorrectly asserted a racial biological hierarchy.^2,3 Today, leading health care organizations recognize that the effects of racist policies in housing, education, employment, and the criminal justice system contribute to health disparities and have a disproportionately negative impact on Black, Indigenous, and People of Color.^3,4 

Racial classification systems are fraught with bias. Trying to classify a complex and nuanced identity such as race into discrete categories does not capture the extensive heterogeneity at the individual level or within the increasingly diverse, multiracial population.⁵ Racial and ethnic categories used in collecting census data and research, as defined by the US Office of Management and Budget, have evolved over time.⁶ These changes in classification are a reflection of changes in the political environment, not changes in scientific knowledge of race and ethnicity.⁶

The Use of Race in Research and Practice

In the United States, racial minorities bear a disproportionate burden of morbidity and mortality across all major disease categories.³ These disparities cannot be explained by genetics.⁴ The Human Genome Project in 2003 confirmed that racial categories have no biologic or genetic basis and that there is more intraracial than interracial genetic variation.³ Nevertheless, significant misapplication of race in medical research and clinical practice remains. Instead of attributing observed differences in health outcomes between racial groups to innate physiological differences between the groups, clinicians and researchers must carefully consider the impact of racism.⁷ This includes considering the complex interactions between socioeconomic, political, and environmental factors, and how they affect health.³

While race is not biologic, the effects of racism can have biologic effects, and advocates appropriately cite the need to collect race as an important category in epidemiological analysis. When race and ethnicity are used as a study variable, bioethicists Kaplan and Bennett recommend that researchers: (1) account for limitations due to imprecision of racial categories; (2) avoid attributing causality when there is an association between race/ethnicity and a health outcome; and (3) refrain from exacerbating racial disparities.⁶

At the bedside, race has become embedded in clinical, seemingly objective, decision-making tools used across medical specialties.⁸ These algorithms often use observational outcomes data and draw conclusions by explicitly or implicitly assuming biological differences among races. By crudely adjusting for race without identifying the root cause for observed racial differences, these tools can further magnify health inequities.⁸ With the increased recognition that race cannot be used as a proxy for genetic ancestry, and that racial and ethnic categories are complex sociopolitical constructs that have changed over time, the practice of race-based medicine is increasingly being criticized.⁸

This article presents a case for the removal of the race coefficient from estimated glomerular filtration rate (eGFR) calculations that exacerbate disparities in kidney health by overestimating kidney function in Black patients.⁸ The main justification for using the race coefficient stems from the disproven assumption that Black people have more muscle mass compared with non-Black people.⁹  The questioning of this racist assertion has led to a national movement to reevaluate the use of race in eGFR calculations.

Racial Disparities in Kidney Disease

According to epidemiological data published by the National Kidney Foundation (NKF) and American Society of Nephrology (ASN), 37 million people in the United States have chronic kidney disease (CKD).¹⁰ Black Americans make up 13% of the US population yet they account for more than 30% of patients with end-stage kidney disease (ESKD) and 35% of those on dialysis.^10,11 There is a 3 times greater risk for progression from early-stage CKD to ESKD in Black Americans when compared to the risk for White Americans.¹¹ Black patients are younger at the time of CKD diagnosis and, once diagnosed, experience a faster progression to ESKD.¹² These disparities are partially attributable to delays in diagnosis, preventative measures, and referrals to nephrology care.¹²  

In a VA medical center study, although Black patients were referred to nephrology care at higher rates than White patients, Black patients had faster progression to CKD stage 5.¹³ An earlier study showed that, at any given eGFR, Black patients have higher levels of albuminuria compared to White patients.¹⁴ While the reasons behind this observation are likely complex and multifactorial, one hypothesis is that Black patients were already at a more advanced stage of kidney disease at the time of referral as a result of the overestimation of eGFR calculations related to the use of a race coefficient.

Additionally, numerous analyses have revealed that Black patients are less likely to be identified as transplant candidates, less likely to be referred for transplant evaluation and, once on the waiting list, wait longer than do White patients.^11,15

Estimated Glomerular Filtration Rate

It is imperative that clinicians have the most accurate measure of GFR to ensure timely diagnosis and appropriate management in patients with CKD. The gold standard for determining renal function requires measuring GFR using an ideal, exogenous, filtration marker such as iothalamate. However, this process is complex and time-consuming, rendering it infeasible in routine care. As a result, we usually estimate GFR using endogenous serum markers such as creatinine and cystatin C. Due to availability and cost, serum creatinine (SCr) is the most widely used marker for estimating kidney function. However, many pitfalls are inherent in its use, including the effects of tubular secretion, extrarenal clearance, and day-to-day variability in creatinine generation related to muscle mass, diet, and activity.¹⁶ The 2 most widely used estimation equations are the Modification of Diet in Renal Disease (MDRD) study equation and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation; both equations incorporate correction factors for age, sex, and race. 

The VA uses MDRD, which was derived and validated in a cohort of 1628 patients that included only 197 Black patients (12%), resulting in an eGFR for Black patients that is 21% higher than is the eGFR for non-Black patients with the same SCr value.⁹ In the VA electronic health record, the race coefficient is incorporated directly into eGFR laboratory calculations based on the race that the veteran self-identified during intake. Because the laboratory reports only a race-adjusted eGFR, there is a lack of transparency as many health care providers and patients are unaware that a race coefficient is used in eGFR calculations at the VA.  

Case for Removing Race Coefficient

When applied to cohorts outside the original study, both the MDRD and CKD-EPI equations have proved to be highly biased, imprecise, and inaccurate when compared to measured GFR (mGFR).^15,17 For any given eGFR, the possible mGFR may span 3 stages of CKD, underscoring the limitations of using such a crude estimate in clinical decision making.¹⁷ 

Current Kidney Estimation Pitfalls

A recent cohort study by Zelnick and colleagues that included 1658 self-identified Black adults showed less bias between mGFR and eGFR without the use of a race coefficient, and a shorter median time to transplant eligibility by 1.9 years.¹⁵ This study provides further evidence that these equations were derived from a biased observational data set that overestimates eGFR in Black patients living with CKD. This overestimation is particularly egregious for frail or malnourished patients with CKD and multiple comorbidities, with many potential harmful clinical consequences.

In addition, multiple international studies in African countries have demonstrated worse performance of eGFR calculations when using the race coefficient than without it. In the Democratic Republic of the Congo, eGFR was calculated for adults using MDRD with and without the race coefficient, as well as CKD-EPI with and without the race coefficient, and then compared to mGFR. Both the MDRD and the CKD-EPI equations overestimated GFR when using the race coefficient, and notably the equations without the race coefficient had better correlation to mGFR.¹⁸ Similar data were also found in studies from South Africa, the Ivory Coast, Brazil, and Europe.^19-22

Clinical Consequences of Race Coefficient Use

The use of a race coefficient in these estimation equations causes adverse clinical outcomes. In early stages of CKD, overestimation of eGFR using the race coefficient can cause an under-recognition of CKD, and can lead to delays in diagnosis and failure to implement measures to slow its progression, such as minimizing drug-related nephrotoxic injury and iatrogenic acute kidney injury. Consequently, a patient with an overestimated eGFR may suffer an accelerated progression to ESKD and premature mortality from cardiovascular disease.²³ 

In advanced CKD stages, eGFR overestimation may result in delayed referral to a nephrologist (recommended at eGFR < 30mL/min/1.73 m²), nutrition counseling, renal replacement therapy education, timely referral for renal replacement therapy access placement, and transplant evaluation (can be listed when eGFR < 20 mL/min/1.73 m²).^16,24,25 

In the Clinical Vignette, it is clear from the information presented that Mr. C’s concerns are well-founded. Table 1 presents the impact on eGFR caused by the race coefficient using the MDRD and CKD-EPI equations. In many VA systems, this overestimation would prevent him from being referred for a kidney transplant at this visit, thereby perpetuating racial health disparities in kidney transplantation. 

Concerns About Removal of Race From eGFR Calculations

Opponents of removing the race coefficient assert that a lower eGFR will preclude some patients from qualifying for medications such as metformin and certain anticoagulants, or that it may result in subtherapeutic dosing of drugs such as antibiotics and chemotherapeutic agents.²⁶ These recommendations are in place for patient safety, so conversely maintaining the race coefficient and overestimating eGFR will expose some patients to medication toxicity. Another fear is that lower eGFRs will have the unintended consequence of limiting the kidney donor pool. However, this can be prevented by following current guidelines to use mGFR in settings where accurate GFR is imperative.¹⁶ Additionally, some nephrologists have expressed concern that diagnosing more patients with advanced stages of CKD will result in inappropriately early initiation of dialysis. Again, this risk can be mitigated by ensuring that nephrologists consider multiple clinical factors and data points, not simply eGFR when deciding to initiate dialysis. Also, an increase in referrals to nephrology may occur when the race coefficient is removed and increased wait times at some VA medical centers could be a concern. An increase in appropriate referrals would show that removing the race coefficient was having its intended effect—more veterans with advanced CKD being seen by nephrologists.

When considering the lack of biological plausibility, inaccuracy, and the clinical harms associated with the use of the race coefficient in eGFR calculations, the benefits of removing the race coefficient from eGFR calculations within the VA far outweigh any potential risks.  

A Call for Equity

The National Conversation on Race and eGFR

To advance health equity, members of the medical community have advocated for the removal of the race coefficient from eGFR calculations for years. Beth Israel Deaconess Medical Center was the first establishment to institute this change in 2017. Since then, many health systems across the country that are affiliated with Veterans Health Administration (VHA) medical centers have removed the race coefficient from eGFR equations (Table 2). Many other hospital systems are contemplating this change. 

In July 2020, the NKF and the ASN established a joint task force dedicated to reassessing the inclusion of race in eGFR calculations. This task force acknowledges that race is a social, not biological, construct.¹² The NKF/ASN task force is now in the second of its 3-phase process. In March 2021, prior to publication of their phase 1 findings, they announced “(1) race modifiers should not be included in equations to estimate kidney function; and (2) current race-based equations should be replaced by a suitable approach that is accurate, inclusive, and standardized in every laboratory in the United States. Any such approach must not differentially introduce bias, inaccuracy, or inequalities.”²⁷

Health Equity in the VHA

In January 2021, President Biden issued an executive order to advance racial equity and support underserved communities through the federal government and its agencies. The VHA is the largest integrated health care system in the United States serving 9 million veterans and is one of the largest federal agencies. As VA clinicians, it is our responsibility to examine the evidence, consider national guidance, and ensure health equity for veterans by practicing unbiased medicine. The evidence and the interim guidance from the NKF-ASN task force clearly indicate that the race coefficient should no longer be used.²⁷ It is imperative that we make these changes immediately knowing that the use of race in kidney function calculators is harming Black veterans. Similar to finding evidence of harm in a treatment group in a clinical trial, it is unethical to wait. Removal of the race coefficient in eGFR calculations will allow VHA clinicians to provide timely and high-quality care to our patients as well as establish the VHA as a national leader in health equity.

VISN 12 Leads the Way

On May 11, 2021, the VA Great Lakes Health Care System, Veterans Integrated Service Network (VISN) 12, leaders responded to this author group’s call to advance health equity and voted to remove the race coefficient from eGFR calculations. Other VISNs should follow, and the VHA should continue to work with national leaders and experts to establish and implement superior tools to ensure the highest quality of kidney health care for all veterans.  

Acknowledgments
The authors would like to thank the medical students across the nation who have been leading the charge on this important issue. The authors are also thankful for the collaboration and support of all members of the Jesse Brown for Black Lives (JB4BL) Task Force. 

Amid the parades and speeches that commemorate Pride Month across the United States, a remarkable event occurred in Florida at the Orlando Veterans Affairs Healthcare System. At the 11th annual celebration of Pride on June 21, US Department of Veterans Affairs (VA) Secretary Denis R. McDonough made a historic announcement, “We are taking the first necessary steps to expand VA’s care to include gender-confirmation surgery, thus allowing transgender vets to go through the full gender-confirmation process with VA by their side.”²

The proclamation reflected the results of a review of VA transgender policies that McDonough had ordered in February 2021 to coordinate VA policies with those of the US Department of Defense (DoD) and to actualize President Biden’s January 2021 executive order that prohibited discrimination on the basis of sexual orientation or gender identity.^3,4 In an interview with NPR shortly after the Orlando commemoration, Secretary McDonough reported that the governing body overseeing VA health care services unanimously endorsed the proposal.⁵ The National Center for Transgender Equity estimates there are 134,000 transgender veterans.⁶ VA authorities believe 4000 transgender veterans may be interested in obtaining the new gender-affirming benefit when it is available, and Secretary McDonough indicated that about 543 veterans a year soon might be eligible.^5,7

Transgender veterans and their supporters along with many of the VA practitioners who care for them had long waited and hoped for this announcement. The Secretary ended a too-long period in which transgender veterans encountered enormous practical, financial, and personal obstacles, causing frustration and despair on their journey to becoming who they knew they are. Although VA previously did not provide gender-affirmation surgery, it did deliver other forms of transgender care to veterans, such as hormone therapy and other transition-related services. Yet it was painful for transgender veterans and their health care professionals (HCPs) to see that under the VA medical benefits package prior to Secretary McDonough’s historic announcement, gender-affirmation surgery was not deemed care “to promote, preserve, or restore the health of the individual.”⁸

Similarly, the decision is the beginning of the end of an ethical dilemma with which many VA clinicians struggled: They had the competence to perform gender-affirming surgery, but VA policy prohibited them from providing it to their patients.^9,10 The 2013 directive issued under the Obama administration made the ethics of gender-confirmation surgery even more complex. A VA surgeon could perform “medically-indicated procedures” or treat “other medical conditions” even if it simultaneously furthered gender transition. What the surgeon could not perform was a procedure solely for the purpose of gender transition. Because transgender veterans seeking gender-affirmation surgery were forced to go outside the VA system and use their resources to pay for the surgery, VA did permit practitioners to perform preoperative and postoperative treatment, including treating surgical complications of an outside gender-affirmation surgery. VA HCPs were placed in a catch-22 situation that pitted their duty to care in accordance with the preferences and interests of the veteran against their obligation to practice and adhere to VA policy and federal regulation.⁸ With his Pride-month speech, Secretary McDonough resolved this conflict for VA HCPs and made a strong public declaration VA should and will provide gender-affirming surgery that can promote, preserve, and restore the health of transgender veterans.

Secretary McDonough called the move to formally change the rule regarding gender-affirming surgery “the right thing to do” and emphasized that it was “life-saving.”⁷ This last remark was in recognition of the strong evidence demonstrating the adverse psychological impact on transgender veterans of the previous position.²

Denial of gender-confirmation surgery was not the only health care inequity identified among transgender veterans. Research inside and outside VA has found significant health disparities between transgender and nontransgender veterans, including higher rates of depression, suicidality, serious mental illness, posttraumatic stress disorder, military sexual trauma, and homelessness.¹¹ The provision of gender-affirming surgery to transgender veterans whether through VA hospitals or through partnerships with academic affiliates and the community is a major step to remedy these disparities. A 2019 systematic review found that gender-affirming surgery is far from cosmetic: It leads to marked improvement in many of the mental health problems transgender persons experience.¹²

Anyone who has experienced the snail’s pace of change in the behemoth VA bureaucracy knows that this initial movement is only the beginning of the laborious federal process of changing the regulation that currently prohibits VA from offering and paying for gender-confirmation surgery under the VA medical benefits package. Once the regulation is changed, then VA will be empowered to establish policy that in Secretary McDonough’s words, “will ensure the equitable treatment and safety of transgender veterans.”² The decision to eventually provide gender-confirmation surgery as part of VA care was an important aspect of the agency’s overall attempt to make VA more welcome to lesbian, gay, bisexual, transgender, and queer (LGBTQ) veterans. During the Orlando speech, Secretary McDonough also announced that VA was changing the name of its LGBT program to LGBTQ+ to clearly communicate that all veterans are included in VA care.²

The announcement sends a powerful message of hope, which was a central theme of slain San Francisco supervisor, Harvey Milk, an early and influential LGBTQ activist and advocate.¹ But as always in our polarized country, there was immediate opposition to the proposal arguing that the surgery would place transgender veterans at greater risk of depression and suicide, was not compatible with the VA mission and diverts VA funding from meeting more legitimate care needs in a timely manner.¹¹ It is a sad irony that transgender veterans defended the freedom of their opponents to express their opinion and had to fight this long and hard for their liberty to live as they choose.

Amid the parades and speeches that commemorate Pride Month across the United States, a remarkable event occurred in Florida at the Orlando Veterans Affairs Healthcare System. At the 11th annual celebration of Pride on June 21, US Department of Veterans Affairs (VA) Secretary Denis R. McDonough made a historic announcement, “We are taking the first necessary steps to expand VA’s care to include gender-confirmation surgery, thus allowing transgender vets to go through the full gender-confirmation process with VA by their side.”²

The proclamation reflected the results of a review of VA transgender policies that McDonough had ordered in February 2021 to coordinate VA policies with those of the US Department of Defense (DoD) and to actualize President Biden’s January 2021 executive order that prohibited discrimination on the basis of sexual orientation or gender identity.^3,4 In an interview with NPR shortly after the Orlando commemoration, Secretary McDonough reported that the governing body overseeing VA health care services unanimously endorsed the proposal.⁵ The National Center for Transgender Equity estimates there are 134,000 transgender veterans.⁶ VA authorities believe 4000 transgender veterans may be interested in obtaining the new gender-affirming benefit when it is available, and Secretary McDonough indicated that about 543 veterans a year soon might be eligible.^5,7

Transgender veterans and their supporters along with many of the VA practitioners who care for them had long waited and hoped for this announcement. The Secretary ended a too-long period in which transgender veterans encountered enormous practical, financial, and personal obstacles, causing frustration and despair on their journey to becoming who they knew they are. Although VA previously did not provide gender-affirmation surgery, it did deliver other forms of transgender care to veterans, such as hormone therapy and other transition-related services. Yet it was painful for transgender veterans and their health care professionals (HCPs) to see that under the VA medical benefits package prior to Secretary McDonough’s historic announcement, gender-affirmation surgery was not deemed care “to promote, preserve, or restore the health of the individual.”⁸

Similarly, the decision is the beginning of the end of an ethical dilemma with which many VA clinicians struggled: They had the competence to perform gender-affirming surgery, but VA policy prohibited them from providing it to their patients.^9,10 The 2013 directive issued under the Obama administration made the ethics of gender-confirmation surgery even more complex. A VA surgeon could perform “medically-indicated procedures” or treat “other medical conditions” even if it simultaneously furthered gender transition. What the surgeon could not perform was a procedure solely for the purpose of gender transition. Because transgender veterans seeking gender-affirmation surgery were forced to go outside the VA system and use their resources to pay for the surgery, VA did permit practitioners to perform preoperative and postoperative treatment, including treating surgical complications of an outside gender-affirmation surgery. VA HCPs were placed in a catch-22 situation that pitted their duty to care in accordance with the preferences and interests of the veteran against their obligation to practice and adhere to VA policy and federal regulation.⁸ With his Pride-month speech, Secretary McDonough resolved this conflict for VA HCPs and made a strong public declaration VA should and will provide gender-affirming surgery that can promote, preserve, and restore the health of transgender veterans.

Secretary McDonough called the move to formally change the rule regarding gender-affirming surgery “the right thing to do” and emphasized that it was “life-saving.”⁷ This last remark was in recognition of the strong evidence demonstrating the adverse psychological impact on transgender veterans of the previous position.²

Denial of gender-confirmation surgery was not the only health care inequity identified among transgender veterans. Research inside and outside VA has found significant health disparities between transgender and nontransgender veterans, including higher rates of depression, suicidality, serious mental illness, posttraumatic stress disorder, military sexual trauma, and homelessness.¹¹ The provision of gender-affirming surgery to transgender veterans whether through VA hospitals or through partnerships with academic affiliates and the community is a major step to remedy these disparities. A 2019 systematic review found that gender-affirming surgery is far from cosmetic: It leads to marked improvement in many of the mental health problems transgender persons experience.¹²

Anyone who has experienced the snail’s pace of change in the behemoth VA bureaucracy knows that this initial movement is only the beginning of the laborious federal process of changing the regulation that currently prohibits VA from offering and paying for gender-confirmation surgery under the VA medical benefits package. Once the regulation is changed, then VA will be empowered to establish policy that in Secretary McDonough’s words, “will ensure the equitable treatment and safety of transgender veterans.”² The decision to eventually provide gender-confirmation surgery as part of VA care was an important aspect of the agency’s overall attempt to make VA more welcome to lesbian, gay, bisexual, transgender, and queer (LGBTQ) veterans. During the Orlando speech, Secretary McDonough also announced that VA was changing the name of its LGBT program to LGBTQ+ to clearly communicate that all veterans are included in VA care.²

The announcement sends a powerful message of hope, which was a central theme of slain San Francisco supervisor, Harvey Milk, an early and influential LGBTQ activist and advocate.¹ But as always in our polarized country, there was immediate opposition to the proposal arguing that the surgery would place transgender veterans at greater risk of depression and suicide, was not compatible with the VA mission and diverts VA funding from meeting more legitimate care needs in a timely manner.¹¹ It is a sad irony that transgender veterans defended the freedom of their opponents to express their opinion and had to fight this long and hard for their liberty to live as they choose.

Amid the parades and speeches that commemorate Pride Month across the United States, a remarkable event occurred in Florida at the Orlando Veterans Affairs Healthcare System. At the 11th annual celebration of Pride on June 21, US Department of Veterans Affairs (VA) Secretary Denis R. McDonough made a historic announcement, “We are taking the first necessary steps to expand VA’s care to include gender-confirmation surgery, thus allowing transgender vets to go through the full gender-confirmation process with VA by their side.”²

The proclamation reflected the results of a review of VA transgender policies that McDonough had ordered in February 2021 to coordinate VA policies with those of the US Department of Defense (DoD) and to actualize President Biden’s January 2021 executive order that prohibited discrimination on the basis of sexual orientation or gender identity.^3,4 In an interview with NPR shortly after the Orlando commemoration, Secretary McDonough reported that the governing body overseeing VA health care services unanimously endorsed the proposal.⁵ The National Center for Transgender Equity estimates there are 134,000 transgender veterans.⁶ VA authorities believe 4000 transgender veterans may be interested in obtaining the new gender-affirming benefit when it is available, and Secretary McDonough indicated that about 543 veterans a year soon might be eligible.^5,7

Transgender veterans and their supporters along with many of the VA practitioners who care for them had long waited and hoped for this announcement. The Secretary ended a too-long period in which transgender veterans encountered enormous practical, financial, and personal obstacles, causing frustration and despair on their journey to becoming who they knew they are. Although VA previously did not provide gender-affirmation surgery, it did deliver other forms of transgender care to veterans, such as hormone therapy and other transition-related services. Yet it was painful for transgender veterans and their health care professionals (HCPs) to see that under the VA medical benefits package prior to Secretary McDonough’s historic announcement, gender-affirmation surgery was not deemed care “to promote, preserve, or restore the health of the individual.”⁸

Similarly, the decision is the beginning of the end of an ethical dilemma with which many VA clinicians struggled: They had the competence to perform gender-affirming surgery, but VA policy prohibited them from providing it to their patients.^9,10 The 2013 directive issued under the Obama administration made the ethics of gender-confirmation surgery even more complex. A VA surgeon could perform “medically-indicated procedures” or treat “other medical conditions” even if it simultaneously furthered gender transition. What the surgeon could not perform was a procedure solely for the purpose of gender transition. Because transgender veterans seeking gender-affirmation surgery were forced to go outside the VA system and use their resources to pay for the surgery, VA did permit practitioners to perform preoperative and postoperative treatment, including treating surgical complications of an outside gender-affirmation surgery. VA HCPs were placed in a catch-22 situation that pitted their duty to care in accordance with the preferences and interests of the veteran against their obligation to practice and adhere to VA policy and federal regulation.⁸ With his Pride-month speech, Secretary McDonough resolved this conflict for VA HCPs and made a strong public declaration VA should and will provide gender-affirming surgery that can promote, preserve, and restore the health of transgender veterans.

Secretary McDonough called the move to formally change the rule regarding gender-affirming surgery “the right thing to do” and emphasized that it was “life-saving.”⁷ This last remark was in recognition of the strong evidence demonstrating the adverse psychological impact on transgender veterans of the previous position.²

Denial of gender-confirmation surgery was not the only health care inequity identified among transgender veterans. Research inside and outside VA has found significant health disparities between transgender and nontransgender veterans, including higher rates of depression, suicidality, serious mental illness, posttraumatic stress disorder, military sexual trauma, and homelessness.¹¹ The provision of gender-affirming surgery to transgender veterans whether through VA hospitals or through partnerships with academic affiliates and the community is a major step to remedy these disparities. A 2019 systematic review found that gender-affirming surgery is far from cosmetic: It leads to marked improvement in many of the mental health problems transgender persons experience.¹²

Anyone who has experienced the snail’s pace of change in the behemoth VA bureaucracy knows that this initial movement is only the beginning of the laborious federal process of changing the regulation that currently prohibits VA from offering and paying for gender-confirmation surgery under the VA medical benefits package. Once the regulation is changed, then VA will be empowered to establish policy that in Secretary McDonough’s words, “will ensure the equitable treatment and safety of transgender veterans.”² The decision to eventually provide gender-confirmation surgery as part of VA care was an important aspect of the agency’s overall attempt to make VA more welcome to lesbian, gay, bisexual, transgender, and queer (LGBTQ) veterans. During the Orlando speech, Secretary McDonough also announced that VA was changing the name of its LGBT program to LGBTQ+ to clearly communicate that all veterans are included in VA care.²

The announcement sends a powerful message of hope, which was a central theme of slain San Francisco supervisor, Harvey Milk, an early and influential LGBTQ activist and advocate.¹ But as always in our polarized country, there was immediate opposition to the proposal arguing that the surgery would place transgender veterans at greater risk of depression and suicide, was not compatible with the VA mission and diverts VA funding from meeting more legitimate care needs in a timely manner.¹¹ It is a sad irony that transgender veterans defended the freedom of their opponents to express their opinion and had to fight this long and hard for their liberty to live as they choose.

What do you want to be when you grow up? What kind of doctor do you want to be? These are common conversation starters that we probably have all heard at some point in our lives.

But perhaps these are not the most thought-provoking or insightful questions to ask or be asked.

Instead, “What is your passion?” or “What inspires/motivates you?” or “What makes you want to get out of bed in the morning?” or “What creates flow for you?” may be more thoughtful questions that encourage greater self-reflection.

There is a Japanese concept called ikigai that loosely translates to “a reason for being.” This framework suggests that one should attempt to find the intersection of four things:

• One’s interests.
• One’s abilities/talents.
• What the world needs.
• What one can be paid for.

When any two of these intersect, you will have the following:

A passion: something that interests you and you excel at.

A profession: something that you excel at and are paid for.

A vocation: something that the world needs and that you’re paid for.

A mission: something that interests you and that the world needs.

Finding that “sweet spot” that intersects all four is the ideal prescribed by ikigai.

Ultimately, ikigai challenges us to find purpose, and finding this alignment of purpose can subsequently help us plan our professional and personal lives.

Of note, several of the world’s communities that are known for longevity/higher proportion of centenarians are linked by the common concept of ikigai. While there isn’t strong evidence that this phenomenon is correlated with or predictive of longevity, I believe we can all agree that finding purpose can lead to increased satisfaction, happiness, and perhaps less stress.

Achieving this sweet spot that satisfies all conditions above is undoubtedly easier said than done when placed in the context of real life, as there are often competing interests. Your purpose may align with a job that doesn’t pay the bills, or the job that provides financial stability may be uninteresting work to you. The path there may be winding, but eventually, with enough trial and error, I think we can all carve out a version of ikigai for ourselves.

I’ve had conversations with more senior physicians who have made a great impact in their fields and could certainly retire yesterday if they desired. When asked why they keep showing up, it is usually some version of “this is what I’m meant to do” or “this is my purpose” or “this is my joy.” In some ways, if you find true joy in what you do, it becomes part of your identity (in a positive way).

Though our health care system and culture are certainly far from perfect, many of us went to medical school because this was/is our “calling” – vocational, if you will. For me personally, it was a unique intersection of being able to serve others, use my abilities in math/science, and make a living.

In some ways, being a physician or health care worker puts us in a unique position to serve and provide services that the world needs. But with burnout rampant within the physician community, it is even more important to understand ourselves, work out our own version of ikigai, and make sure that we are living it daily.

Dr Thachil is a noninvasive cardiologist and assistant professor of medicine at the Albert Einstein College of Medicine, New York. She is a graduate of Jefferson Medical College and completed cardiology training at Mount Sinai Hospital. She is a fellow of the American College of Cardiology.

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

What do you want to be when you grow up? What kind of doctor do you want to be? These are common conversation starters that we probably have all heard at some point in our lives.

But perhaps these are not the most thought-provoking or insightful questions to ask or be asked.

Instead, “What is your passion?” or “What inspires/motivates you?” or “What makes you want to get out of bed in the morning?” or “What creates flow for you?” may be more thoughtful questions that encourage greater self-reflection.

There is a Japanese concept called ikigai that loosely translates to “a reason for being.” This framework suggests that one should attempt to find the intersection of four things:

• One’s interests.
• One’s abilities/talents.
• What the world needs.
• What one can be paid for.

When any two of these intersect, you will have the following:

A passion: something that interests you and you excel at.

A profession: something that you excel at and are paid for.

A vocation: something that the world needs and that you’re paid for.

A mission: something that interests you and that the world needs.

Finding that “sweet spot” that intersects all four is the ideal prescribed by ikigai.

Ultimately, ikigai challenges us to find purpose, and finding this alignment of purpose can subsequently help us plan our professional and personal lives.

Of note, several of the world’s communities that are known for longevity/higher proportion of centenarians are linked by the common concept of ikigai. While there isn’t strong evidence that this phenomenon is correlated with or predictive of longevity, I believe we can all agree that finding purpose can lead to increased satisfaction, happiness, and perhaps less stress.

Achieving this sweet spot that satisfies all conditions above is undoubtedly easier said than done when placed in the context of real life, as there are often competing interests. Your purpose may align with a job that doesn’t pay the bills, or the job that provides financial stability may be uninteresting work to you. The path there may be winding, but eventually, with enough trial and error, I think we can all carve out a version of ikigai for ourselves.

I’ve had conversations with more senior physicians who have made a great impact in their fields and could certainly retire yesterday if they desired. When asked why they keep showing up, it is usually some version of “this is what I’m meant to do” or “this is my purpose” or “this is my joy.” In some ways, if you find true joy in what you do, it becomes part of your identity (in a positive way).

Though our health care system and culture are certainly far from perfect, many of us went to medical school because this was/is our “calling” – vocational, if you will. For me personally, it was a unique intersection of being able to serve others, use my abilities in math/science, and make a living.

In some ways, being a physician or health care worker puts us in a unique position to serve and provide services that the world needs. But with burnout rampant within the physician community, it is even more important to understand ourselves, work out our own version of ikigai, and make sure that we are living it daily.

Dr Thachil is a noninvasive cardiologist and assistant professor of medicine at the Albert Einstein College of Medicine, New York. She is a graduate of Jefferson Medical College and completed cardiology training at Mount Sinai Hospital. She is a fellow of the American College of Cardiology.

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

What do you want to be when you grow up? What kind of doctor do you want to be? These are common conversation starters that we probably have all heard at some point in our lives.

But perhaps these are not the most thought-provoking or insightful questions to ask or be asked.

Instead, “What is your passion?” or “What inspires/motivates you?” or “What makes you want to get out of bed in the morning?” or “What creates flow for you?” may be more thoughtful questions that encourage greater self-reflection.

There is a Japanese concept called ikigai that loosely translates to “a reason for being.” This framework suggests that one should attempt to find the intersection of four things:

• One’s interests.
• One’s abilities/talents.
• What the world needs.
• What one can be paid for.

When any two of these intersect, you will have the following:

A passion: something that interests you and you excel at.

A profession: something that you excel at and are paid for.

A vocation: something that the world needs and that you’re paid for.

A mission: something that interests you and that the world needs.

Finding that “sweet spot” that intersects all four is the ideal prescribed by ikigai.

Ultimately, ikigai challenges us to find purpose, and finding this alignment of purpose can subsequently help us plan our professional and personal lives.

Of note, several of the world’s communities that are known for longevity/higher proportion of centenarians are linked by the common concept of ikigai. While there isn’t strong evidence that this phenomenon is correlated with or predictive of longevity, I believe we can all agree that finding purpose can lead to increased satisfaction, happiness, and perhaps less stress.

Achieving this sweet spot that satisfies all conditions above is undoubtedly easier said than done when placed in the context of real life, as there are often competing interests. Your purpose may align with a job that doesn’t pay the bills, or the job that provides financial stability may be uninteresting work to you. The path there may be winding, but eventually, with enough trial and error, I think we can all carve out a version of ikigai for ourselves.

I’ve had conversations with more senior physicians who have made a great impact in their fields and could certainly retire yesterday if they desired. When asked why they keep showing up, it is usually some version of “this is what I’m meant to do” or “this is my purpose” or “this is my joy.” In some ways, if you find true joy in what you do, it becomes part of your identity (in a positive way).

Though our health care system and culture are certainly far from perfect, many of us went to medical school because this was/is our “calling” – vocational, if you will. For me personally, it was a unique intersection of being able to serve others, use my abilities in math/science, and make a living.

In some ways, being a physician or health care worker puts us in a unique position to serve and provide services that the world needs. But with burnout rampant within the physician community, it is even more important to understand ourselves, work out our own version of ikigai, and make sure that we are living it daily.

Dr Thachil is a noninvasive cardiologist and assistant professor of medicine at the Albert Einstein College of Medicine, New York. She is a graduate of Jefferson Medical College and completed cardiology training at Mount Sinai Hospital. She is a fellow of the American College of Cardiology.

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

Anna Suk-Fong Lok, M.D., is assistant dean for clinical research, a post she has held since March 2016. She also is the Alice Lohrman Andrews Research Professor in Hepatology and director of clinical hepatology. Her research focuses on the natural history and treatment of hepatitis B and C, and the prevention of liver cancer.

Q: Are there any unique operative or preparation steps required for this type of transplant regarding the donor, recipient, or both? Walk us through any differences from standard transplant procedures.

Dr. Lok: There’s nothing special about the surgical operation itself other than the surgeon’s need to remember that the organs came from an HCV+ donor, so they should be a little bit more careful. This procedure should only be done within a protocol where the possibility of putting in an organ from an HCV+ to HCV- recipient is being discussed ahead of time and agreed to by both the transplant team within the institute, and with the potential recipients.

Currently, all donors in the U.S. are tested for hepatitis C antibody and also for hepatitis C RNA using what we call nucleic acid (NAT or PCR) test. It is important to differentiate between a donor who is anti-HCV+ but NAT negative, versus someone who is anti-HCV+ and NAT positive. Someone who is anti-HCV+ and NAT or PCR positive is capable of transmitting the infection, whereas someone who is anti-HCV+ but NAT or PCR negative, had a prior infection, is no longer infected, and is not going to transmit the infection.

It is important to have a discussion with the recipient ahead of time. The recipients will most likely be HCV-, so we are going to be giving them an infection, because we are transplanting an organ from an HCV-infected donor. It is best to have the discussion at the time of listing, with written consent, and rediscuss as the patients get closer to the top of the list.  It can be several years before they move to the top and receive a transplant. What was discussed and agreed on with the patient 2 or 3 years ago might be forgotten, and it is important to bring it up again as the patients get closer to their transplant date. In addition, we need to reverify the consent when it is time for the actual transplant. The surgery itself is similar, whether the donor is HCV+ or HCV-, but the transplant center needs to have a protocol ahead of time. There are several ways to minimize the impact on the recipient. How do we monitor for infection in the recipient? When do we start HCV direct-acting antiviral (DAA) therapy? Who is going to pay for it? What about insurance coverage? The answers to all these questions need to be in place.

During the early post-transplant period, doctors place patients on many different medications, which can cause interference with the DAAs, so we need to be cautious about potential drug-drug interactions. Some programs start in the first few days post-transplant, others start the day before transplant and continue through the transplant period, yet others start only after the patient is stable post-transplant, which can vary from a few days to a few weeks. Some patients are not ready to take oral medications right after the transplant because they just had a major operation. Debate continues over whether we can crush these pills and put them down a feeding tube. The manufacturers of these medications have not provided the data to show how well these drugs are absorbed when crushed. Still, limited data appear to suggest that some DAAs can be crushed and are effective when put down the feeding tube. 

Q: In addition to increasing the donor pool, what are other benefits of this manner of transplantation?

Dr. Lok: Some patients may be sick, going in and out of the hospital because of the underlying end-organ damage, and it is getting worse. The willingness to accept an HCV+ organ might mean that they can get transplanted sooner. There are also some data to suggest that HCV+ donors tend to be younger, with fewer comorbidities, and potentially the organ quality could be better.

Q: Do the risks and possible side effects outweigh the potential benefits of this type of transplantation?

Dr. Lok: Overall, the benefits outweigh the risk, in my opinion. There are several reasons: 1) it allows the recipient to have an earlier transplant. So, they do not have to continue to suffer from the end-organ damage; and 2) the success rate of HCV cure with the DAA drugs is very high. And we certainly know that even when we administer it post-transplant, most of the regimens have been 95% to 100% successful.

A wide range of regimens are currently in practice. Many transplant centers use the classical regimen of 8 to 12 weeks of treatment. We know that some transplant programs have shortened the duration of treatment to 4 weeks or even shorter. But some of the ultra-short regimens may be associated with a lower rate of success. And that is why it is important for people to really think through what protocols would be most cost-effective.

The key thing here is to really ensure success. We are introducing a new infection; many of us would consider even a drop from a success rate of 98% to 90% to be unacceptable. There are times when a success rate is lower because patients encounter complications after the transplant operation that results in interruption of treatment. This is one reason why, I think, that if the patients cannot take the pills by mouth, we should consider administering the medications through the feeding tube rather than stopping the treatment.

We certainly know that when we start, DAAs can affect the success rate. If we wait until the patient is truly stable post-transplant, and if the patient did have postoperative complications lasting more than a couple of weeks, the delay would be too long. There have been occasional reports of these patients suffering adverse consequences, including kidney injury related to HCV glomerulonephritis, or Fibrosing cholestatic hepatitis (FCH)—a severe and rapidly progressive form of liver damage.

Thus, it is very important to make sure that we start the treatment as soon as possible and that is why some of the programs have moved to starting one day before a patient has transplant surgery.

Another aspect that should be considered is that some of the HCV+ donors might have underlying liver disease. When HCV+ livers are being used, a liver biopsy should be performed to ensure there is no significant liver damage. This is, generally speaking, not a problem because many of the HCV+ donors are young and likely have been infected for a short period of time. The use ofHCV+ organs in HCV- recipients is relatively new. We know that the risk is short-term, but we do not know what the long-term risk is. The data we have so far extends to one-year post-transplant and shows no negative impact, but a longer follow-up is needed.

Q: How reluctant have insurance companies been to lower treatment barriers, such as cost and coverage approvals?

Dr. Lok: There were many concerns early on, but now this procedure has become more common. This is an accepted practice within the transplant community and has been endorsed by professional societies. We also know that the cost of the DAAs has been greatly reduced. And it is certainly shown to be cost-effective and cost-saving. If it allows us to get these patients transplanted sooner, if we can save one hospital admission because of cirrhosis complications prior to transplant, it is a win for the patient, who will save money as a result.

Q: This transplantation method started with kidneys. How have other organs fared such as liver, heart, and lungs?

Dr. Lok: Yes, this procedure started with the kidneys, but is now widely accepted for liver, lung, heart, pancreas, and even some of the combined transplants such as kidney and pancreas. The good news is that the success rate of the DAA is similar whether you had a kidney or heart transplant. The willingness to accept HCV+ organs in 2018 had increased by about 30% to 40% for all organs compared to 2015, except for intestines, but intestinal transplant is rare. So, the increase has occurred for all organs.

Anna Suk-Fong Lok, M.D., is assistant dean for clinical research, a post she has held since March 2016. She also is the Alice Lohrman Andrews Research Professor in Hepatology and director of clinical hepatology. Her research focuses on the natural history and treatment of hepatitis B and C, and the prevention of liver cancer.

Q: Are there any unique operative or preparation steps required for this type of transplant regarding the donor, recipient, or both? Walk us through any differences from standard transplant procedures.

Dr. Lok: There’s nothing special about the surgical operation itself other than the surgeon’s need to remember that the organs came from an HCV+ donor, so they should be a little bit more careful. This procedure should only be done within a protocol where the possibility of putting in an organ from an HCV+ to HCV- recipient is being discussed ahead of time and agreed to by both the transplant team within the institute, and with the potential recipients.

Currently, all donors in the U.S. are tested for hepatitis C antibody and also for hepatitis C RNA using what we call nucleic acid (NAT or PCR) test. It is important to differentiate between a donor who is anti-HCV+ but NAT negative, versus someone who is anti-HCV+ and NAT positive. Someone who is anti-HCV+ and NAT or PCR positive is capable of transmitting the infection, whereas someone who is anti-HCV+ but NAT or PCR negative, had a prior infection, is no longer infected, and is not going to transmit the infection.

It is important to have a discussion with the recipient ahead of time. The recipients will most likely be HCV-, so we are going to be giving them an infection, because we are transplanting an organ from an HCV-infected donor. It is best to have the discussion at the time of listing, with written consent, and rediscuss as the patients get closer to the top of the list.  It can be several years before they move to the top and receive a transplant. What was discussed and agreed on with the patient 2 or 3 years ago might be forgotten, and it is important to bring it up again as the patients get closer to their transplant date. In addition, we need to reverify the consent when it is time for the actual transplant. The surgery itself is similar, whether the donor is HCV+ or HCV-, but the transplant center needs to have a protocol ahead of time. There are several ways to minimize the impact on the recipient. How do we monitor for infection in the recipient? When do we start HCV direct-acting antiviral (DAA) therapy? Who is going to pay for it? What about insurance coverage? The answers to all these questions need to be in place.

During the early post-transplant period, doctors place patients on many different medications, which can cause interference with the DAAs, so we need to be cautious about potential drug-drug interactions. Some programs start in the first few days post-transplant, others start the day before transplant and continue through the transplant period, yet others start only after the patient is stable post-transplant, which can vary from a few days to a few weeks. Some patients are not ready to take oral medications right after the transplant because they just had a major operation. Debate continues over whether we can crush these pills and put them down a feeding tube. The manufacturers of these medications have not provided the data to show how well these drugs are absorbed when crushed. Still, limited data appear to suggest that some DAAs can be crushed and are effective when put down the feeding tube. 

Q: In addition to increasing the donor pool, what are other benefits of this manner of transplantation?

Dr. Lok: Some patients may be sick, going in and out of the hospital because of the underlying end-organ damage, and it is getting worse. The willingness to accept an HCV+ organ might mean that they can get transplanted sooner. There are also some data to suggest that HCV+ donors tend to be younger, with fewer comorbidities, and potentially the organ quality could be better.

Q: Do the risks and possible side effects outweigh the potential benefits of this type of transplantation?

Dr. Lok: Overall, the benefits outweigh the risk, in my opinion. There are several reasons: 1) it allows the recipient to have an earlier transplant. So, they do not have to continue to suffer from the end-organ damage; and 2) the success rate of HCV cure with the DAA drugs is very high. And we certainly know that even when we administer it post-transplant, most of the regimens have been 95% to 100% successful.

A wide range of regimens are currently in practice. Many transplant centers use the classical regimen of 8 to 12 weeks of treatment. We know that some transplant programs have shortened the duration of treatment to 4 weeks or even shorter. But some of the ultra-short regimens may be associated with a lower rate of success. And that is why it is important for people to really think through what protocols would be most cost-effective.

The key thing here is to really ensure success. We are introducing a new infection; many of us would consider even a drop from a success rate of 98% to 90% to be unacceptable. There are times when a success rate is lower because patients encounter complications after the transplant operation that results in interruption of treatment. This is one reason why, I think, that if the patients cannot take the pills by mouth, we should consider administering the medications through the feeding tube rather than stopping the treatment.

We certainly know that when we start, DAAs can affect the success rate. If we wait until the patient is truly stable post-transplant, and if the patient did have postoperative complications lasting more than a couple of weeks, the delay would be too long. There have been occasional reports of these patients suffering adverse consequences, including kidney injury related to HCV glomerulonephritis, or Fibrosing cholestatic hepatitis (FCH)—a severe and rapidly progressive form of liver damage.

Thus, it is very important to make sure that we start the treatment as soon as possible and that is why some of the programs have moved to starting one day before a patient has transplant surgery.

Another aspect that should be considered is that some of the HCV+ donors might have underlying liver disease. When HCV+ livers are being used, a liver biopsy should be performed to ensure there is no significant liver damage. This is, generally speaking, not a problem because many of the HCV+ donors are young and likely have been infected for a short period of time. The use ofHCV+ organs in HCV- recipients is relatively new. We know that the risk is short-term, but we do not know what the long-term risk is. The data we have so far extends to one-year post-transplant and shows no negative impact, but a longer follow-up is needed.

Q: How reluctant have insurance companies been to lower treatment barriers, such as cost and coverage approvals?

Dr. Lok: There were many concerns early on, but now this procedure has become more common. This is an accepted practice within the transplant community and has been endorsed by professional societies. We also know that the cost of the DAAs has been greatly reduced. And it is certainly shown to be cost-effective and cost-saving. If it allows us to get these patients transplanted sooner, if we can save one hospital admission because of cirrhosis complications prior to transplant, it is a win for the patient, who will save money as a result.

Q: This transplantation method started with kidneys. How have other organs fared such as liver, heart, and lungs?

Dr. Lok: Yes, this procedure started with the kidneys, but is now widely accepted for liver, lung, heart, pancreas, and even some of the combined transplants such as kidney and pancreas. The good news is that the success rate of the DAA is similar whether you had a kidney or heart transplant. The willingness to accept HCV+ organs in 2018 had increased by about 30% to 40% for all organs compared to 2015, except for intestines, but intestinal transplant is rare. So, the increase has occurred for all organs.

Anna Suk-Fong Lok, M.D., is assistant dean for clinical research, a post she has held since March 2016. She also is the Alice Lohrman Andrews Research Professor in Hepatology and director of clinical hepatology. Her research focuses on the natural history and treatment of hepatitis B and C, and the prevention of liver cancer.

Q: Are there any unique operative or preparation steps required for this type of transplant regarding the donor, recipient, or both? Walk us through any differences from standard transplant procedures.

Dr. Lok: There’s nothing special about the surgical operation itself other than the surgeon’s need to remember that the organs came from an HCV+ donor, so they should be a little bit more careful. This procedure should only be done within a protocol where the possibility of putting in an organ from an HCV+ to HCV- recipient is being discussed ahead of time and agreed to by both the transplant team within the institute, and with the potential recipients.

Currently, all donors in the U.S. are tested for hepatitis C antibody and also for hepatitis C RNA using what we call nucleic acid (NAT or PCR) test. It is important to differentiate between a donor who is anti-HCV+ but NAT negative, versus someone who is anti-HCV+ and NAT positive. Someone who is anti-HCV+ and NAT or PCR positive is capable of transmitting the infection, whereas someone who is anti-HCV+ but NAT or PCR negative, had a prior infection, is no longer infected, and is not going to transmit the infection.

It is important to have a discussion with the recipient ahead of time. The recipients will most likely be HCV-, so we are going to be giving them an infection, because we are transplanting an organ from an HCV-infected donor. It is best to have the discussion at the time of listing, with written consent, and rediscuss as the patients get closer to the top of the list.  It can be several years before they move to the top and receive a transplant. What was discussed and agreed on with the patient 2 or 3 years ago might be forgotten, and it is important to bring it up again as the patients get closer to their transplant date. In addition, we need to reverify the consent when it is time for the actual transplant. The surgery itself is similar, whether the donor is HCV+ or HCV-, but the transplant center needs to have a protocol ahead of time. There are several ways to minimize the impact on the recipient. How do we monitor for infection in the recipient? When do we start HCV direct-acting antiviral (DAA) therapy? Who is going to pay for it? What about insurance coverage? The answers to all these questions need to be in place.

During the early post-transplant period, doctors place patients on many different medications, which can cause interference with the DAAs, so we need to be cautious about potential drug-drug interactions. Some programs start in the first few days post-transplant, others start the day before transplant and continue through the transplant period, yet others start only after the patient is stable post-transplant, which can vary from a few days to a few weeks. Some patients are not ready to take oral medications right after the transplant because they just had a major operation. Debate continues over whether we can crush these pills and put them down a feeding tube. The manufacturers of these medications have not provided the data to show how well these drugs are absorbed when crushed. Still, limited data appear to suggest that some DAAs can be crushed and are effective when put down the feeding tube. 

Q: In addition to increasing the donor pool, what are other benefits of this manner of transplantation?

Dr. Lok: Some patients may be sick, going in and out of the hospital because of the underlying end-organ damage, and it is getting worse. The willingness to accept an HCV+ organ might mean that they can get transplanted sooner. There are also some data to suggest that HCV+ donors tend to be younger, with fewer comorbidities, and potentially the organ quality could be better.

Q: Do the risks and possible side effects outweigh the potential benefits of this type of transplantation?

Dr. Lok: Overall, the benefits outweigh the risk, in my opinion. There are several reasons: 1) it allows the recipient to have an earlier transplant. So, they do not have to continue to suffer from the end-organ damage; and 2) the success rate of HCV cure with the DAA drugs is very high. And we certainly know that even when we administer it post-transplant, most of the regimens have been 95% to 100% successful.

A wide range of regimens are currently in practice. Many transplant centers use the classical regimen of 8 to 12 weeks of treatment. We know that some transplant programs have shortened the duration of treatment to 4 weeks or even shorter. But some of the ultra-short regimens may be associated with a lower rate of success. And that is why it is important for people to really think through what protocols would be most cost-effective.

The key thing here is to really ensure success. We are introducing a new infection; many of us would consider even a drop from a success rate of 98% to 90% to be unacceptable. There are times when a success rate is lower because patients encounter complications after the transplant operation that results in interruption of treatment. This is one reason why, I think, that if the patients cannot take the pills by mouth, we should consider administering the medications through the feeding tube rather than stopping the treatment.

We certainly know that when we start, DAAs can affect the success rate. If we wait until the patient is truly stable post-transplant, and if the patient did have postoperative complications lasting more than a couple of weeks, the delay would be too long. There have been occasional reports of these patients suffering adverse consequences, including kidney injury related to HCV glomerulonephritis, or Fibrosing cholestatic hepatitis (FCH)—a severe and rapidly progressive form of liver damage.

Thus, it is very important to make sure that we start the treatment as soon as possible and that is why some of the programs have moved to starting one day before a patient has transplant surgery.

Another aspect that should be considered is that some of the HCV+ donors might have underlying liver disease. When HCV+ livers are being used, a liver biopsy should be performed to ensure there is no significant liver damage. This is, generally speaking, not a problem because many of the HCV+ donors are young and likely have been infected for a short period of time. The use ofHCV+ organs in HCV- recipients is relatively new. We know that the risk is short-term, but we do not know what the long-term risk is. The data we have so far extends to one-year post-transplant and shows no negative impact, but a longer follow-up is needed.

Q: How reluctant have insurance companies been to lower treatment barriers, such as cost and coverage approvals?

Dr. Lok: There were many concerns early on, but now this procedure has become more common. This is an accepted practice within the transplant community and has been endorsed by professional societies. We also know that the cost of the DAAs has been greatly reduced. And it is certainly shown to be cost-effective and cost-saving. If it allows us to get these patients transplanted sooner, if we can save one hospital admission because of cirrhosis complications prior to transplant, it is a win for the patient, who will save money as a result.

Q: This transplantation method started with kidneys. How have other organs fared such as liver, heart, and lungs?

Dr. Lok: Yes, this procedure started with the kidneys, but is now widely accepted for liver, lung, heart, pancreas, and even some of the combined transplants such as kidney and pancreas. The good news is that the success rate of the DAA is similar whether you had a kidney or heart transplant. The willingness to accept HCV+ organs in 2018 had increased by about 30% to 40% for all organs compared to 2015, except for intestines, but intestinal transplant is rare. So, the increase has occurred for all organs.

“From a public health standpoint, I think we have an evolving situation,” said Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, in a moderated session with Lee Beers, MD, president of the American Academy of Pediatrics, at the virtual Pediatric Hospital Medicine annual conference.

“From a public health standpoint, I think we have an evolving situation,” said Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, in a moderated session with Lee Beers, MD, president of the American Academy of Pediatrics, at the virtual Pediatric Hospital Medicine annual conference.

“From a public health standpoint, I think we have an evolving situation,” said Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, in a moderated session with Lee Beers, MD, president of the American Academy of Pediatrics, at the virtual Pediatric Hospital Medicine annual conference.

Tumor necrosis factor inhibitors have long been the go-to treatment of choice for patients with psoriasis and psoriatic arthritis (PsA). They’ve served patients well since etanercept was first approved for PsA in 2002, but today, with the availability of more attractive interleukin-17 and IL-23 inhibitors, dermatologists and rheumatologists are asking whether it’s time to reconsider the use of TNF inhibitors as first-line therapy in psoriasis and PsA.

“TNF inhibitors have served psoriasis patients well for many years. The question is, ‘Is it time to move on from them as first-line agents for psoriasis?’ ” said April W. Armstrong, MD, MPH, a dermatologist and associate dean for clinical research at the University of Southern California, Los Angeles. Dr. Armstrong participated in a point/counterpoint debate about the merits of IL-17 and IL-23 inhibitors over TNF inhibitors at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. “For the majority of our patients, IL-17 and IL-23 inhibitors are probably rationally better than TNF inhibitors as first-line agents for moderate to severe plaque psoriasis,” she said.

In this debate, dermatologists and rheumatologists cited studies showing the safety and efficacy of IL-17 and IL-23 inhibitors over TNF inhibitors. TNF inhibitors include etanercept (Enbrel and biosimilars), infliximab (Remicade and biosimilars), adalimumab (Humira and biosimilars), certolizumab pegol (Cimzia), and golimumab (Simponi). IL-12/23 inhibitors are limited to ustekinumab (Stelara). IL-17 inhibitors include secukinumab (Cosentyx), ixekizumab (Taltz), and brodalumab (Siliq). IL-23 inhibitors include guselkumab (Tremfya), tildrakizumab (Ilumya), and risankizumab (Skyrizi).

TNF inhibitors are recommended by the American College of Rheumatology as first-line therapy for treatment-naive patients with active PsA, and they, along with IL-12/23, IL-17, and IL-23 inhibitors are all recommended by the American Academy of Dermatology as monotherapy treatment options in adult patients with moderate to severe plaque psoriasis. However, some studies have shown that non–TNF-inhibitor biologics have a higher efficacy than TNF inhibitors in some cases for some patients, such as those with moderate to severe psoriasis alone or for musculoskeletal efficacy in patients with PsA who have peripheral arthritis, enthesitis, dactylitis, or axial manifestations.

Favorable characteristics of non–TNF-inhibitor biologics

Dr. Armstrong cited a number of head-to-head trials to support her view that IL-17 and IL-23 inhibitors are better than TNF inhibitors as first-line agents for patients with moderate to severe plaque psoriasis. In the first head-to-head study of its kind in patients with moderate to severe psoriasis, ustekinumab proved superior to etanercept. Guselkumab was shown to be superior to adalimumab for patients with moderate to severe psoriasis. Tildrakizumab also proved superior to etanercept for patients with psoriasis. Risankizumab bested adalimumab in patients with moderate to severe psoriasis. Ixekizumab proved superior to etanercept in two pivotal studies of patients with widespread moderate-to-severe psoriasis.

IL-23 and IL-17 inhibitors tend to have less frequent maintenance dosing, with IL-17 inhibitors being once every 2 or 4 weeks and IL-23 inhibitors once every 8 or 12 weeks, compared with frequencies ranging from every week to every 8 weeks with TNF inhibitors, Dr. Armstrong said.

IL-17 and IL-23 inhibitors also appear to have fewer safety concerns than TNF inhibitors, although there is less long-term data for them overall and there are some notable exceptions in certain patient populations. TNF inhibitors should be avoided in patients with a history of demyelinating disease or hepatitis B virus infection, and they are not preferred in patients who have a history of latent tuberculosis or advanced heart failure. IL-17 inhibitors should not be used in patients with a history of inflammatory bowel disease, and their use is associated with a higher rate of oral candidiasis. IL-23 inhibitors have a good safety profile overall, she said.

“The IL-17/23 axis is very important to psoriatic arthritis and should be the focus of our treatments” for PsA, said Deepak Jadon, MBBCh, MRCP, PhD, a rheumatologist and director of the rheumatology research unit at Addenbrooke’s Hospital, Cambridge (England) University Hospitals NHS Foundation Trust. In his presentation, he proposed that IL-17 inhibitors and IL-23 inhibitors be used as first-line therapies in PsA ahead of TNF inhibitors.

One reason to go with IL-17 and IL-23 inhibitors may be to ”get it right immunologically the first time,” Dr. Jadon said. He cited evidence showing substantially better response to guselkumab when given to biologic-naive patients with PsA versus those who had a inadequate response to TNF inhibitors, as well as data indicating better response with secukinumab regardless of previous TNF inhibitor use.

IL-17 inhibitors target more domains of psoriatic disease than do TNF inhibitors, he said, noting that “they have excellent musculoskeletal efficacy in patients with moderate skin psoriasis, not just those with severe psoriasis.” Ixekizumab proved superior to adalimumab in biologic-naive patients with PsA. The results of this study also indicated that IL-17 inhibitors should not be reserved only for patients with severe psoriasis since a higher percentage of patients with moderate psoriasis who were taking ixekizumab achieved very low PsA activity. Secukinumab also beat adalimumab in a head-to-head comparison and showed a greater impact on some measures of health-related quality of life.

IL-17 inhibitors also do not require concomitant methotrexate, he said, “which is a major bonus for our patients. All of my patients wish to stop methotrexate even if tolerated. Not having to cope with prescribed methotrexate improves risk of adverse events and frequency of blood test monitoring.”

IL-17 and IL-23 inhibitors appear to have good efficacy against axial disease in patients with PsA. Randomized trial results for secukinumab versus placebo show high percentages of patients improving either 20% or 40% in Assessment in Spondyloarthritis International Society response criteria and reduced inflammatory MRI lesions in the spine and sacroiliac joints. Analyses of trial results in guselkumab-treated patients with axial manifestations of PsA have shown the IL-23 inhibitor’s efficacy versus placebo across different measures of disease activity.

Dr. Jadon also cited real-world data showing that patients stay longer on IL-17 and IL-12/23 inhibitors versus TNF inhibitors. A 2016 study of patients with psoriasis in the PSOLAR registry showed that patients persisted on treatment longer with ustekinumab than with adalimumab, etanercept, or infliximab. Similarly, a 2020 study of patients with psoriasis from the British Association of Dermatologists Biologics and Immunomodulators Register found that both ustekinumab and secukinumab had better sustained drug survival than did adalimumab.


Accessibility weighs heavily in using TNF inhibitor first

Clinical trials data show that IL-17 inhibitors outperform TNF inhibitors for psoriasis, but in clinical practice, TNF inhibitors still perform very well in individual patients and are well tolerated, said Amit Garg, MD, founding chair of the department of dermatology at Hofstra University, Hempstead, N.Y.

He argued in favor of TNF inhibitors as first-line therapy over IL-17 inhibitors for psoriasis. In this case, treatment decisions often come down to accessibility, Dr. Garg said. Not all insurance companies cover the cost of the newer IL-23 inhibitors. Plus, access to TNF inhibitors is widespread and costs are generally lower.

“As a physician, I don’t have complete autonomy in prescribing what I want. The reality is whether it be because of cross indication or discount pricing, [TNF inhibitors] – in particular adalimumab – is widely available on all plans and is usually the preferred treatment plan, at least in our area,” he said. “I’m not a big fan of plans that allow drugs at low or no cost for a year or 2, and then abandon the patients at that point thereafter. I like to use something that insurance will cover sustainably, and, quite frankly, TNFs have served well in that regard.”

However, TNF inhibitors are associated with more safety signals, plus they carry a greater risk of infection, leading to tolerability and persistence issues with patients.

“Psoriasis is a lifelong disease. I wish I could tell you that every drug is going to work well forever for individual patients, but I don’t think we know that yet. From my perspective, for efficacy, general well tolerance, convenience, and access, TNFs are still an important part of our ability to treat psoriasis effectively. I have no problem starting there and transitioning as needed for individual patients.

“In my experience, I think patients on TNFs generally do well. We don’t always get the patients clear and certainly there’s drop off of efficacy over time, but I’m not sure that’s a rationale for [changing treatment],” Dr. Garg said.

Ying Ying (Katy) Leung, MD, a rheumatologist with Singapore General Hospital, and a member of the GRAPPA peripheral arthritis working group, argued against the use of IL-17 and IL-23 inhibitors as first-line treatment for PsA over TNF inhibitors. She reasoned that TNF blockers are more accessible, have more long-term safety data (including data indicating safety during pregnancy), and have better cardiovascular protection. She also noted that GRAPPA treatment recommendations strongly advise using TNF blockers (or IL-17 inhibitors) for treatment-naive patients with PsA.

“Accessibility is very important as I learned along the way of leading the peripheral arthritis [GRAPPA] working group. Accessibility [issues] can be coming from a lot of sources, but if you don’t take good care of accessibility, you might be developing a guideline that is way out of reality and nobody is going to use it,” she said.

In her native Singapore, Dr. Leung said that patients pay for biologics out of pocket, so cost is a key factor for her patients. She stated that adalimumab is available as a biosimilar at about $200 monthly for patients with PsA in Singapore, while the average monthly costs are $1,400 for originator infliximab and $1,500 for originator etanercept. By comparison, secukinumab sells for about $750 monthly, ixekizumab $540 monthly, and guselkumab $2,000 monthly.

Treatment choices should be aligned with the disease manifestations of PsA, Dr. Leung said, keeping in mind that accessibility and individual patient needs and preferences should be considered as well. She conducted an informal comparison that found TNF inhibitors are most effective for patients with uveitis or inflammatory bowel disease. Evidence from head-to-head studies indicates that TNF inhibitors and IL-17 inhibitors have similar efficacy for peripheral arthritis, enthesitis, and dactylitis. But caution is warranted, she suggested, for determining the best biologics for axial disease because no head-to-head comparison trials have been conducted for IL-17 or IL-23 inhibitors versus TNF inhibitors.

Dr. Armstrong has been a consultant to AbbVie, Bristol-Myers Squibb, Dermira, Genzyme, Incyte, Janssen, Leo Pharma, Eli Lilly, Novartis, Pfizer, and UCB. Dr. Jadon has been a consultant to, has been on speakers bureaus for, and has received grant/research support from AbbVie, Amgen, Celgene, Celltrion, Gilead, Janssen, Eli Lilly, MSD, Novartis, Pfizer, Roche, Sandoz, and UCB. Dr. Garg has consulted for AbbVie, Boehringer Ingelheim, Janssen, and UCB. Dr. Leung has been a consultant to AbbVie, Boehringer Ingelheim, Janssen, Eli Lilly, Novartis, and Pfizer. She has been on speakers bureaus for AbbVie, Janssen Eli Lilly, and Novartis. She has received grant/research support from Pfizer and conference support from AbbVie,

Tumor necrosis factor inhibitors have long been the go-to treatment of choice for patients with psoriasis and psoriatic arthritis (PsA). They’ve served patients well since etanercept was first approved for PsA in 2002, but today, with the availability of more attractive interleukin-17 and IL-23 inhibitors, dermatologists and rheumatologists are asking whether it’s time to reconsider the use of TNF inhibitors as first-line therapy in psoriasis and PsA.

“TNF inhibitors have served psoriasis patients well for many years. The question is, ‘Is it time to move on from them as first-line agents for psoriasis?’ ” said April W. Armstrong, MD, MPH, a dermatologist and associate dean for clinical research at the University of Southern California, Los Angeles. Dr. Armstrong participated in a point/counterpoint debate about the merits of IL-17 and IL-23 inhibitors over TNF inhibitors at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. “For the majority of our patients, IL-17 and IL-23 inhibitors are probably rationally better than TNF inhibitors as first-line agents for moderate to severe plaque psoriasis,” she said.

In this debate, dermatologists and rheumatologists cited studies showing the safety and efficacy of IL-17 and IL-23 inhibitors over TNF inhibitors. TNF inhibitors include etanercept (Enbrel and biosimilars), infliximab (Remicade and biosimilars), adalimumab (Humira and biosimilars), certolizumab pegol (Cimzia), and golimumab (Simponi). IL-12/23 inhibitors are limited to ustekinumab (Stelara). IL-17 inhibitors include secukinumab (Cosentyx), ixekizumab (Taltz), and brodalumab (Siliq). IL-23 inhibitors include guselkumab (Tremfya), tildrakizumab (Ilumya), and risankizumab (Skyrizi).

TNF inhibitors are recommended by the American College of Rheumatology as first-line therapy for treatment-naive patients with active PsA, and they, along with IL-12/23, IL-17, and IL-23 inhibitors are all recommended by the American Academy of Dermatology as monotherapy treatment options in adult patients with moderate to severe plaque psoriasis. However, some studies have shown that non–TNF-inhibitor biologics have a higher efficacy than TNF inhibitors in some cases for some patients, such as those with moderate to severe psoriasis alone or for musculoskeletal efficacy in patients with PsA who have peripheral arthritis, enthesitis, dactylitis, or axial manifestations.

Favorable characteristics of non–TNF-inhibitor biologics

Dr. Armstrong cited a number of head-to-head trials to support her view that IL-17 and IL-23 inhibitors are better than TNF inhibitors as first-line agents for patients with moderate to severe plaque psoriasis. In the first head-to-head study of its kind in patients with moderate to severe psoriasis, ustekinumab proved superior to etanercept. Guselkumab was shown to be superior to adalimumab for patients with moderate to severe psoriasis. Tildrakizumab also proved superior to etanercept for patients with psoriasis. Risankizumab bested adalimumab in patients with moderate to severe psoriasis. Ixekizumab proved superior to etanercept in two pivotal studies of patients with widespread moderate-to-severe psoriasis.

IL-23 and IL-17 inhibitors tend to have less frequent maintenance dosing, with IL-17 inhibitors being once every 2 or 4 weeks and IL-23 inhibitors once every 8 or 12 weeks, compared with frequencies ranging from every week to every 8 weeks with TNF inhibitors, Dr. Armstrong said.

IL-17 and IL-23 inhibitors also appear to have fewer safety concerns than TNF inhibitors, although there is less long-term data for them overall and there are some notable exceptions in certain patient populations. TNF inhibitors should be avoided in patients with a history of demyelinating disease or hepatitis B virus infection, and they are not preferred in patients who have a history of latent tuberculosis or advanced heart failure. IL-17 inhibitors should not be used in patients with a history of inflammatory bowel disease, and their use is associated with a higher rate of oral candidiasis. IL-23 inhibitors have a good safety profile overall, she said.

“The IL-17/23 axis is very important to psoriatic arthritis and should be the focus of our treatments” for PsA, said Deepak Jadon, MBBCh, MRCP, PhD, a rheumatologist and director of the rheumatology research unit at Addenbrooke’s Hospital, Cambridge (England) University Hospitals NHS Foundation Trust. In his presentation, he proposed that IL-17 inhibitors and IL-23 inhibitors be used as first-line therapies in PsA ahead of TNF inhibitors.

One reason to go with IL-17 and IL-23 inhibitors may be to ”get it right immunologically the first time,” Dr. Jadon said. He cited evidence showing substantially better response to guselkumab when given to biologic-naive patients with PsA versus those who had a inadequate response to TNF inhibitors, as well as data indicating better response with secukinumab regardless of previous TNF inhibitor use.

IL-17 inhibitors target more domains of psoriatic disease than do TNF inhibitors, he said, noting that “they have excellent musculoskeletal efficacy in patients with moderate skin psoriasis, not just those with severe psoriasis.” Ixekizumab proved superior to adalimumab in biologic-naive patients with PsA. The results of this study also indicated that IL-17 inhibitors should not be reserved only for patients with severe psoriasis since a higher percentage of patients with moderate psoriasis who were taking ixekizumab achieved very low PsA activity. Secukinumab also beat adalimumab in a head-to-head comparison and showed a greater impact on some measures of health-related quality of life.

IL-17 inhibitors also do not require concomitant methotrexate, he said, “which is a major bonus for our patients. All of my patients wish to stop methotrexate even if tolerated. Not having to cope with prescribed methotrexate improves risk of adverse events and frequency of blood test monitoring.”

IL-17 and IL-23 inhibitors appear to have good efficacy against axial disease in patients with PsA. Randomized trial results for secukinumab versus placebo show high percentages of patients improving either 20% or 40% in Assessment in Spondyloarthritis International Society response criteria and reduced inflammatory MRI lesions in the spine and sacroiliac joints. Analyses of trial results in guselkumab-treated patients with axial manifestations of PsA have shown the IL-23 inhibitor’s efficacy versus placebo across different measures of disease activity.

Dr. Jadon also cited real-world data showing that patients stay longer on IL-17 and IL-12/23 inhibitors versus TNF inhibitors. A 2016 study of patients with psoriasis in the PSOLAR registry showed that patients persisted on treatment longer with ustekinumab than with adalimumab, etanercept, or infliximab. Similarly, a 2020 study of patients with psoriasis from the British Association of Dermatologists Biologics and Immunomodulators Register found that both ustekinumab and secukinumab had better sustained drug survival than did adalimumab.


Accessibility weighs heavily in using TNF inhibitor first

Clinical trials data show that IL-17 inhibitors outperform TNF inhibitors for psoriasis, but in clinical practice, TNF inhibitors still perform very well in individual patients and are well tolerated, said Amit Garg, MD, founding chair of the department of dermatology at Hofstra University, Hempstead, N.Y.

He argued in favor of TNF inhibitors as first-line therapy over IL-17 inhibitors for psoriasis. In this case, treatment decisions often come down to accessibility, Dr. Garg said. Not all insurance companies cover the cost of the newer IL-23 inhibitors. Plus, access to TNF inhibitors is widespread and costs are generally lower.

“As a physician, I don’t have complete autonomy in prescribing what I want. The reality is whether it be because of cross indication or discount pricing, [TNF inhibitors] – in particular adalimumab – is widely available on all plans and is usually the preferred treatment plan, at least in our area,” he said. “I’m not a big fan of plans that allow drugs at low or no cost for a year or 2, and then abandon the patients at that point thereafter. I like to use something that insurance will cover sustainably, and, quite frankly, TNFs have served well in that regard.”

However, TNF inhibitors are associated with more safety signals, plus they carry a greater risk of infection, leading to tolerability and persistence issues with patients.

“Psoriasis is a lifelong disease. I wish I could tell you that every drug is going to work well forever for individual patients, but I don’t think we know that yet. From my perspective, for efficacy, general well tolerance, convenience, and access, TNFs are still an important part of our ability to treat psoriasis effectively. I have no problem starting there and transitioning as needed for individual patients.

“In my experience, I think patients on TNFs generally do well. We don’t always get the patients clear and certainly there’s drop off of efficacy over time, but I’m not sure that’s a rationale for [changing treatment],” Dr. Garg said.

Ying Ying (Katy) Leung, MD, a rheumatologist with Singapore General Hospital, and a member of the GRAPPA peripheral arthritis working group, argued against the use of IL-17 and IL-23 inhibitors as first-line treatment for PsA over TNF inhibitors. She reasoned that TNF blockers are more accessible, have more long-term safety data (including data indicating safety during pregnancy), and have better cardiovascular protection. She also noted that GRAPPA treatment recommendations strongly advise using TNF blockers (or IL-17 inhibitors) for treatment-naive patients with PsA.

“Accessibility is very important as I learned along the way of leading the peripheral arthritis [GRAPPA] working group. Accessibility [issues] can be coming from a lot of sources, but if you don’t take good care of accessibility, you might be developing a guideline that is way out of reality and nobody is going to use it,” she said.

In her native Singapore, Dr. Leung said that patients pay for biologics out of pocket, so cost is a key factor for her patients. She stated that adalimumab is available as a biosimilar at about $200 monthly for patients with PsA in Singapore, while the average monthly costs are $1,400 for originator infliximab and $1,500 for originator etanercept. By comparison, secukinumab sells for about $750 monthly, ixekizumab $540 monthly, and guselkumab $2,000 monthly.

Treatment choices should be aligned with the disease manifestations of PsA, Dr. Leung said, keeping in mind that accessibility and individual patient needs and preferences should be considered as well. She conducted an informal comparison that found TNF inhibitors are most effective for patients with uveitis or inflammatory bowel disease. Evidence from head-to-head studies indicates that TNF inhibitors and IL-17 inhibitors have similar efficacy for peripheral arthritis, enthesitis, and dactylitis. But caution is warranted, she suggested, for determining the best biologics for axial disease because no head-to-head comparison trials have been conducted for IL-17 or IL-23 inhibitors versus TNF inhibitors.

Dr. Armstrong has been a consultant to AbbVie, Bristol-Myers Squibb, Dermira, Genzyme, Incyte, Janssen, Leo Pharma, Eli Lilly, Novartis, Pfizer, and UCB. Dr. Jadon has been a consultant to, has been on speakers bureaus for, and has received grant/research support from AbbVie, Amgen, Celgene, Celltrion, Gilead, Janssen, Eli Lilly, MSD, Novartis, Pfizer, Roche, Sandoz, and UCB. Dr. Garg has consulted for AbbVie, Boehringer Ingelheim, Janssen, and UCB. Dr. Leung has been a consultant to AbbVie, Boehringer Ingelheim, Janssen, Eli Lilly, Novartis, and Pfizer. She has been on speakers bureaus for AbbVie, Janssen Eli Lilly, and Novartis. She has received grant/research support from Pfizer and conference support from AbbVie,

Tumor necrosis factor inhibitors have long been the go-to treatment of choice for patients with psoriasis and psoriatic arthritis (PsA). They’ve served patients well since etanercept was first approved for PsA in 2002, but today, with the availability of more attractive interleukin-17 and IL-23 inhibitors, dermatologists and rheumatologists are asking whether it’s time to reconsider the use of TNF inhibitors as first-line therapy in psoriasis and PsA.

“TNF inhibitors have served psoriasis patients well for many years. The question is, ‘Is it time to move on from them as first-line agents for psoriasis?’ ” said April W. Armstrong, MD, MPH, a dermatologist and associate dean for clinical research at the University of Southern California, Los Angeles. Dr. Armstrong participated in a point/counterpoint debate about the merits of IL-17 and IL-23 inhibitors over TNF inhibitors at the annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis. “For the majority of our patients, IL-17 and IL-23 inhibitors are probably rationally better than TNF inhibitors as first-line agents for moderate to severe plaque psoriasis,” she said.

In this debate, dermatologists and rheumatologists cited studies showing the safety and efficacy of IL-17 and IL-23 inhibitors over TNF inhibitors. TNF inhibitors include etanercept (Enbrel and biosimilars), infliximab (Remicade and biosimilars), adalimumab (Humira and biosimilars), certolizumab pegol (Cimzia), and golimumab (Simponi). IL-12/23 inhibitors are limited to ustekinumab (Stelara). IL-17 inhibitors include secukinumab (Cosentyx), ixekizumab (Taltz), and brodalumab (Siliq). IL-23 inhibitors include guselkumab (Tremfya), tildrakizumab (Ilumya), and risankizumab (Skyrizi).

TNF inhibitors are recommended by the American College of Rheumatology as first-line therapy for treatment-naive patients with active PsA, and they, along with IL-12/23, IL-17, and IL-23 inhibitors are all recommended by the American Academy of Dermatology as monotherapy treatment options in adult patients with moderate to severe plaque psoriasis. However, some studies have shown that non–TNF-inhibitor biologics have a higher efficacy than TNF inhibitors in some cases for some patients, such as those with moderate to severe psoriasis alone or for musculoskeletal efficacy in patients with PsA who have peripheral arthritis, enthesitis, dactylitis, or axial manifestations.

Favorable characteristics of non–TNF-inhibitor biologics

Dr. Armstrong cited a number of head-to-head trials to support her view that IL-17 and IL-23 inhibitors are better than TNF inhibitors as first-line agents for patients with moderate to severe plaque psoriasis. In the first head-to-head study of its kind in patients with moderate to severe psoriasis, ustekinumab proved superior to etanercept. Guselkumab was shown to be superior to adalimumab for patients with moderate to severe psoriasis. Tildrakizumab also proved superior to etanercept for patients with psoriasis. Risankizumab bested adalimumab in patients with moderate to severe psoriasis. Ixekizumab proved superior to etanercept in two pivotal studies of patients with widespread moderate-to-severe psoriasis.

IL-23 and IL-17 inhibitors tend to have less frequent maintenance dosing, with IL-17 inhibitors being once every 2 or 4 weeks and IL-23 inhibitors once every 8 or 12 weeks, compared with frequencies ranging from every week to every 8 weeks with TNF inhibitors, Dr. Armstrong said.

IL-17 and IL-23 inhibitors also appear to have fewer safety concerns than TNF inhibitors, although there is less long-term data for them overall and there are some notable exceptions in certain patient populations. TNF inhibitors should be avoided in patients with a history of demyelinating disease or hepatitis B virus infection, and they are not preferred in patients who have a history of latent tuberculosis or advanced heart failure. IL-17 inhibitors should not be used in patients with a history of inflammatory bowel disease, and their use is associated with a higher rate of oral candidiasis. IL-23 inhibitors have a good safety profile overall, she said.

“The IL-17/23 axis is very important to psoriatic arthritis and should be the focus of our treatments” for PsA, said Deepak Jadon, MBBCh, MRCP, PhD, a rheumatologist and director of the rheumatology research unit at Addenbrooke’s Hospital, Cambridge (England) University Hospitals NHS Foundation Trust. In his presentation, he proposed that IL-17 inhibitors and IL-23 inhibitors be used as first-line therapies in PsA ahead of TNF inhibitors.

One reason to go with IL-17 and IL-23 inhibitors may be to ”get it right immunologically the first time,” Dr. Jadon said. He cited evidence showing substantially better response to guselkumab when given to biologic-naive patients with PsA versus those who had a inadequate response to TNF inhibitors, as well as data indicating better response with secukinumab regardless of previous TNF inhibitor use.

IL-17 inhibitors target more domains of psoriatic disease than do TNF inhibitors, he said, noting that “they have excellent musculoskeletal efficacy in patients with moderate skin psoriasis, not just those with severe psoriasis.” Ixekizumab proved superior to adalimumab in biologic-naive patients with PsA. The results of this study also indicated that IL-17 inhibitors should not be reserved only for patients with severe psoriasis since a higher percentage of patients with moderate psoriasis who were taking ixekizumab achieved very low PsA activity. Secukinumab also beat adalimumab in a head-to-head comparison and showed a greater impact on some measures of health-related quality of life.

IL-17 inhibitors also do not require concomitant methotrexate, he said, “which is a major bonus for our patients. All of my patients wish to stop methotrexate even if tolerated. Not having to cope with prescribed methotrexate improves risk of adverse events and frequency of blood test monitoring.”

IL-17 and IL-23 inhibitors appear to have good efficacy against axial disease in patients with PsA. Randomized trial results for secukinumab versus placebo show high percentages of patients improving either 20% or 40% in Assessment in Spondyloarthritis International Society response criteria and reduced inflammatory MRI lesions in the spine and sacroiliac joints. Analyses of trial results in guselkumab-treated patients with axial manifestations of PsA have shown the IL-23 inhibitor’s efficacy versus placebo across different measures of disease activity.

Dr. Jadon also cited real-world data showing that patients stay longer on IL-17 and IL-12/23 inhibitors versus TNF inhibitors. A 2016 study of patients with psoriasis in the PSOLAR registry showed that patients persisted on treatment longer with ustekinumab than with adalimumab, etanercept, or infliximab. Similarly, a 2020 study of patients with psoriasis from the British Association of Dermatologists Biologics and Immunomodulators Register found that both ustekinumab and secukinumab had better sustained drug survival than did adalimumab.


Accessibility weighs heavily in using TNF inhibitor first

Clinical trials data show that IL-17 inhibitors outperform TNF inhibitors for psoriasis, but in clinical practice, TNF inhibitors still perform very well in individual patients and are well tolerated, said Amit Garg, MD, founding chair of the department of dermatology at Hofstra University, Hempstead, N.Y.

He argued in favor of TNF inhibitors as first-line therapy over IL-17 inhibitors for psoriasis. In this case, treatment decisions often come down to accessibility, Dr. Garg said. Not all insurance companies cover the cost of the newer IL-23 inhibitors. Plus, access to TNF inhibitors is widespread and costs are generally lower.

“As a physician, I don’t have complete autonomy in prescribing what I want. The reality is whether it be because of cross indication or discount pricing, [TNF inhibitors] – in particular adalimumab – is widely available on all plans and is usually the preferred treatment plan, at least in our area,” he said. “I’m not a big fan of plans that allow drugs at low or no cost for a year or 2, and then abandon the patients at that point thereafter. I like to use something that insurance will cover sustainably, and, quite frankly, TNFs have served well in that regard.”

However, TNF inhibitors are associated with more safety signals, plus they carry a greater risk of infection, leading to tolerability and persistence issues with patients.

“Psoriasis is a lifelong disease. I wish I could tell you that every drug is going to work well forever for individual patients, but I don’t think we know that yet. From my perspective, for efficacy, general well tolerance, convenience, and access, TNFs are still an important part of our ability to treat psoriasis effectively. I have no problem starting there and transitioning as needed for individual patients.

“In my experience, I think patients on TNFs generally do well. We don’t always get the patients clear and certainly there’s drop off of efficacy over time, but I’m not sure that’s a rationale for [changing treatment],” Dr. Garg said.

Ying Ying (Katy) Leung, MD, a rheumatologist with Singapore General Hospital, and a member of the GRAPPA peripheral arthritis working group, argued against the use of IL-17 and IL-23 inhibitors as first-line treatment for PsA over TNF inhibitors. She reasoned that TNF blockers are more accessible, have more long-term safety data (including data indicating safety during pregnancy), and have better cardiovascular protection. She also noted that GRAPPA treatment recommendations strongly advise using TNF blockers (or IL-17 inhibitors) for treatment-naive patients with PsA.

“Accessibility is very important as I learned along the way of leading the peripheral arthritis [GRAPPA] working group. Accessibility [issues] can be coming from a lot of sources, but if you don’t take good care of accessibility, you might be developing a guideline that is way out of reality and nobody is going to use it,” she said.

In her native Singapore, Dr. Leung said that patients pay for biologics out of pocket, so cost is a key factor for her patients. She stated that adalimumab is available as a biosimilar at about $200 monthly for patients with PsA in Singapore, while the average monthly costs are $1,400 for originator infliximab and $1,500 for originator etanercept. By comparison, secukinumab sells for about $750 monthly, ixekizumab $540 monthly, and guselkumab $2,000 monthly.

Treatment choices should be aligned with the disease manifestations of PsA, Dr. Leung said, keeping in mind that accessibility and individual patient needs and preferences should be considered as well. She conducted an informal comparison that found TNF inhibitors are most effective for patients with uveitis or inflammatory bowel disease. Evidence from head-to-head studies indicates that TNF inhibitors and IL-17 inhibitors have similar efficacy for peripheral arthritis, enthesitis, and dactylitis. But caution is warranted, she suggested, for determining the best biologics for axial disease because no head-to-head comparison trials have been conducted for IL-17 or IL-23 inhibitors versus TNF inhibitors.

Dr. Armstrong has been a consultant to AbbVie, Bristol-Myers Squibb, Dermira, Genzyme, Incyte, Janssen, Leo Pharma, Eli Lilly, Novartis, Pfizer, and UCB. Dr. Jadon has been a consultant to, has been on speakers bureaus for, and has received grant/research support from AbbVie, Amgen, Celgene, Celltrion, Gilead, Janssen, Eli Lilly, MSD, Novartis, Pfizer, Roche, Sandoz, and UCB. Dr. Garg has consulted for AbbVie, Boehringer Ingelheim, Janssen, and UCB. Dr. Leung has been a consultant to AbbVie, Boehringer Ingelheim, Janssen, Eli Lilly, Novartis, and Pfizer. She has been on speakers bureaus for AbbVie, Janssen Eli Lilly, and Novartis. She has received grant/research support from Pfizer and conference support from AbbVie,

Over the 10 years we’ve been writing this column, we have often found inspiration for topics while traveling – especially while flying. This is not just because of the idle time spent in the air, but instead because of the many ways that air travel and health care experiences are similar. Both industries focus heavily on safety, are tightly regulated, and employ highly trained individuals.

Consumers may recognize the similarities as well – health care and air travel are both well-known for long waits, uncertainty, and implicit risk. Both sectors are also notorious drivers of innovation, constantly leveraging new technologies in pursuit of better outcomes and experiences. Occasionally, however, advancements in technology can present unforeseen challenges and even compromise safety, with the potential to produce unexpected consequences.

A familiar reminder of this potential was provided to us at the commencement of a recent flight, when we were instructed to turn off our personal electronic devices or flip them into “airplane mode.” This same admonishment is often given to patients and visitors in health care settings – everywhere from clinic waiting rooms to intensive care units – though the reason for this is typically left vague. This got us thinking. We wondered, what is the real risk of smart phones in medicine , or aviation, for that matter. More importantly, what other emerging technologies have the potential to create issues we may not have anticipated?

Mayo Clinic findings on radio communication used by mobile phones

Once our flight landed, we did some research to answer our initial question about personal communication technology and its ability to interfere with sensitive electronic devices. Specifically, we wanted to know whether radio communication used by mobile phones could affect the operation of medical equipment, potentially leading to dire consequences for patients. Spoiler alert: There is very little evidence that this can occur. In fact, a well-documented study performed by the Mayo Clinic in 2007 found interference in 0 out of 300 tests performed. To quote the authors, “the incidence of clinically important interference was 0%.”

We could find no other studies since 2007 that strongly contradict Mayo’s findings, except for several anecdotal reports and articles that postulate the theoretical possibility.

This is confirmed by the American Heart Association, who maintains a list of devices that may interfere with ICDs and pacemakers on their website. According to the AHA, “wireless transmissions from the antennae of phones available in the United States are a very small risk to ICDs and even less of a risk for pacemakers.” And in case you’re wondering, the story is quite similar for airplanes as well.

The latest publication from NASA’s Aviation Safety Reporting System (ASRS) documents incidents related to personal electronic devices during air travel. Most involve smoke production – or even small fires – caused by malfunctioning phone batteries during charging. Only a few entries reference wireless interference, and these were all minor and unconfirmed events. As with health care environments, airplanes don’t appear to face significant risks from radio interference. But that doesn’t mean personal electronics are completely harmless to patients.

Smartphones’ risks to patient with cardiac devices

On May 13 of 2021, the FDA issued a warning to cardiac patients about their smart phones and smart watches. Many current personal electronic devices and accessories are equipped with strong magnets, such as those contained in the “MagSafe” connector on the iPhone 12, that can deactivate pacemakers and implanted cardiac defibrillators. These medical devices are designed to be manipulated by magnets for diagnostic and therapeutic purposes, but strong magnetic fields can disable them unintentionally, leading to catastrophic results.

Apple and other manufacturers have acknowledged this risk and recommend that smartphones and other devices be kept at least 6 inches from cardiac devices. Given the ubiquity of offending products, it is also imperative that we warn our patients about this risk to their physical wellbeing.

Dr. Notte is a family physician and chief medical officer of Abington (Pa.) Hospital–Jefferson Health. Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece.

Over the 10 years we’ve been writing this column, we have often found inspiration for topics while traveling – especially while flying. This is not just because of the idle time spent in the air, but instead because of the many ways that air travel and health care experiences are similar. Both industries focus heavily on safety, are tightly regulated, and employ highly trained individuals.

Consumers may recognize the similarities as well – health care and air travel are both well-known for long waits, uncertainty, and implicit risk. Both sectors are also notorious drivers of innovation, constantly leveraging new technologies in pursuit of better outcomes and experiences. Occasionally, however, advancements in technology can present unforeseen challenges and even compromise safety, with the potential to produce unexpected consequences.

A familiar reminder of this potential was provided to us at the commencement of a recent flight, when we were instructed to turn off our personal electronic devices or flip them into “airplane mode.” This same admonishment is often given to patients and visitors in health care settings – everywhere from clinic waiting rooms to intensive care units – though the reason for this is typically left vague. This got us thinking. We wondered, what is the real risk of smart phones in medicine , or aviation, for that matter. More importantly, what other emerging technologies have the potential to create issues we may not have anticipated?

Mayo Clinic findings on radio communication used by mobile phones

Once our flight landed, we did some research to answer our initial question about personal communication technology and its ability to interfere with sensitive electronic devices. Specifically, we wanted to know whether radio communication used by mobile phones could affect the operation of medical equipment, potentially leading to dire consequences for patients. Spoiler alert: There is very little evidence that this can occur. In fact, a well-documented study performed by the Mayo Clinic in 2007 found interference in 0 out of 300 tests performed. To quote the authors, “the incidence of clinically important interference was 0%.”

We could find no other studies since 2007 that strongly contradict Mayo’s findings, except for several anecdotal reports and articles that postulate the theoretical possibility.

This is confirmed by the American Heart Association, who maintains a list of devices that may interfere with ICDs and pacemakers on their website. According to the AHA, “wireless transmissions from the antennae of phones available in the United States are a very small risk to ICDs and even less of a risk for pacemakers.” And in case you’re wondering, the story is quite similar for airplanes as well.

The latest publication from NASA’s Aviation Safety Reporting System (ASRS) documents incidents related to personal electronic devices during air travel. Most involve smoke production – or even small fires – caused by malfunctioning phone batteries during charging. Only a few entries reference wireless interference, and these were all minor and unconfirmed events. As with health care environments, airplanes don’t appear to face significant risks from radio interference. But that doesn’t mean personal electronics are completely harmless to patients.

Smartphones’ risks to patient with cardiac devices

On May 13 of 2021, the FDA issued a warning to cardiac patients about their smart phones and smart watches. Many current personal electronic devices and accessories are equipped with strong magnets, such as those contained in the “MagSafe” connector on the iPhone 12, that can deactivate pacemakers and implanted cardiac defibrillators. These medical devices are designed to be manipulated by magnets for diagnostic and therapeutic purposes, but strong magnetic fields can disable them unintentionally, leading to catastrophic results.

Apple and other manufacturers have acknowledged this risk and recommend that smartphones and other devices be kept at least 6 inches from cardiac devices. Given the ubiquity of offending products, it is also imperative that we warn our patients about this risk to their physical wellbeing.

Dr. Notte is a family physician and chief medical officer of Abington (Pa.) Hospital–Jefferson Health. Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece.

Over the 10 years we’ve been writing this column, we have often found inspiration for topics while traveling – especially while flying. This is not just because of the idle time spent in the air, but instead because of the many ways that air travel and health care experiences are similar. Both industries focus heavily on safety, are tightly regulated, and employ highly trained individuals.

Consumers may recognize the similarities as well – health care and air travel are both well-known for long waits, uncertainty, and implicit risk. Both sectors are also notorious drivers of innovation, constantly leveraging new technologies in pursuit of better outcomes and experiences. Occasionally, however, advancements in technology can present unforeseen challenges and even compromise safety, with the potential to produce unexpected consequences.

A familiar reminder of this potential was provided to us at the commencement of a recent flight, when we were instructed to turn off our personal electronic devices or flip them into “airplane mode.” This same admonishment is often given to patients and visitors in health care settings – everywhere from clinic waiting rooms to intensive care units – though the reason for this is typically left vague. This got us thinking. We wondered, what is the real risk of smart phones in medicine , or aviation, for that matter. More importantly, what other emerging technologies have the potential to create issues we may not have anticipated?

Mayo Clinic findings on radio communication used by mobile phones

Once our flight landed, we did some research to answer our initial question about personal communication technology and its ability to interfere with sensitive electronic devices. Specifically, we wanted to know whether radio communication used by mobile phones could affect the operation of medical equipment, potentially leading to dire consequences for patients. Spoiler alert: There is very little evidence that this can occur. In fact, a well-documented study performed by the Mayo Clinic in 2007 found interference in 0 out of 300 tests performed. To quote the authors, “the incidence of clinically important interference was 0%.”

We could find no other studies since 2007 that strongly contradict Mayo’s findings, except for several anecdotal reports and articles that postulate the theoretical possibility.

This is confirmed by the American Heart Association, who maintains a list of devices that may interfere with ICDs and pacemakers on their website. According to the AHA, “wireless transmissions from the antennae of phones available in the United States are a very small risk to ICDs and even less of a risk for pacemakers.” And in case you’re wondering, the story is quite similar for airplanes as well.

The latest publication from NASA’s Aviation Safety Reporting System (ASRS) documents incidents related to personal electronic devices during air travel. Most involve smoke production – or even small fires – caused by malfunctioning phone batteries during charging. Only a few entries reference wireless interference, and these were all minor and unconfirmed events. As with health care environments, airplanes don’t appear to face significant risks from radio interference. But that doesn’t mean personal electronics are completely harmless to patients.

Smartphones’ risks to patient with cardiac devices

On May 13 of 2021, the FDA issued a warning to cardiac patients about their smart phones and smart watches. Many current personal electronic devices and accessories are equipped with strong magnets, such as those contained in the “MagSafe” connector on the iPhone 12, that can deactivate pacemakers and implanted cardiac defibrillators. These medical devices are designed to be manipulated by magnets for diagnostic and therapeutic purposes, but strong magnetic fields can disable them unintentionally, leading to catastrophic results.

Apple and other manufacturers have acknowledged this risk and recommend that smartphones and other devices be kept at least 6 inches from cardiac devices. Given the ubiquity of offending products, it is also imperative that we warn our patients about this risk to their physical wellbeing.

Dr. Notte is a family physician and chief medical officer of Abington (Pa.) Hospital–Jefferson Health. Dr. Skolnik is professor of family and community medicine at Sidney Kimmel Medical College, Philadelphia, and associate director of the family medicine residency program at Abington Hospital–Jefferson Health. They have no conflicts related to the content of this piece.

Having a mobile interventional stroke team (MIST) travel to treat stroke patients soon after stroke onset may improve patient outcomes, according to a new study. A retrospective analysis of a pilot program in New York found that patients who were treated on the ground by the MIST team rather than transferred to a specialized stroke center received faster care and were almost twice as likely to be functionally independent 3 months later.

“The use of a Mobile Interventional Stroke Team (MIST) traveling to Thrombectomy Capable Stroke Centers to perform endovascular thrombectomy has been shown to be significantly faster with improved discharge outcomes,” wrote lead author Jacob Morey, a doctoral Candidate at Icahn School of Medicine at Mount Sinai in New York and coauthors in the paper. Prior to this study, “the effect of the MIST model stratified by time of presentation” had yet to be studied.

The findings were published online on Aug. 5 in Stroke.
 

MIST model versus drip-and-ship

The researchers analyzed 226 patients who underwent endovascular thrombectomy between January 2017 and February 2020 at four hospitals in the Mount Sinai health system using the NYC MIST Trial and a stroke database. At baseline, all patients were functionally independent as assessed by the modified Rankin Scale (mRS, score of 0-2). 106 patients were treated by a MIST team – staffed by a neurointerventionalist, a fellow or physician assistant, and radiologic technologist – that traveled to the patient’s location. A total of 120 patients were transferred to a comprehensive stroke center (CSC) or a hospital with endovascular thrombectomy expertise. The analysis was stratified based on whether the patient presented in the early time window (≤ 6 hours) or late time window (> 6 hours).

Patients treated in the early time window were significantly more likely to be mobile and able to perform daily tasks (mRS ≤ 2) 90 days after the procedure in the MIST group (54%), compared with the transferred group (28%, P < 0.01). Outcomes did not differ significantly between groups in the late time window (35% vs. 41%, P = 0.77).

Similarly, early-time-window patients in the MIST group were more likely to have higher functionality at discharge, compared with transferred patients, based on the on the National Institutes of Health Stroke Scale (median score of 5.0 vs. 12.0, P < 0.01). There was no significant difference between groups treated in the late time window (median score of 5.0 vs. 11.0, P = 0.11).

“Ischemic strokes often progress rapidly and can cause severe damage because brain tissue dies quickly without oxygen, resulting in serious long-term disabilities or death,“ said Johanna Fifi, MD, of Icahn School of Medicine, said in a statement to the American Heart Association. “Assessing and treating stroke patients in the early window means that a greater number of fast-progressing strokes are identified and treated.”

Time is brain

Endovascular thrombectomy is a time-sensitive surgical procedure to remove large blood clots in acute ischemic stroke that has “historically been limited to comprehensive stroke centers,” the authors wrote in their paper. It is considered the standard of care in ischemic strokes, which make up 90% of all strokes. “Less than 50% of Americans have direct access to endovascular thrombectomy, the others must be transferred to a thrombectomy-capable hospital for treatment, often losing over 2 hours of time to treatment,” said Dr. Fifi. “Every minute is precious in treating stroke, and getting to a center that offers thrombectomy is very important. The MIST model would address this by providing faster access to this potentially life-saving, disability-reducing procedure.”

Access to timely endovascular thrombectomy is gradually improving as “more institutions and cities have implemented the [MIST] model.” Dr. Fifi said.

“This study stresses the importance of ‘time is brain,’ especially for patients in the early time window. Although the study is limited by the observational, retrospective design and was performed at a single integrated center, the findings are provocative,” said Louise McCullough, MD, of the University of Texas Health Science Center at Houston said in a statement to the American Heart Association. “The use of a MIST model highlights the potential benefit of early and urgent treatment for patients with large-vessel stroke. Stroke systems of care need to take advantage of any opportunity to treat patients early, wherever they are.”

The study was partly funded by a Stryker Foundation grant.

Having a mobile interventional stroke team (MIST) travel to treat stroke patients soon after stroke onset may improve patient outcomes, according to a new study. A retrospective analysis of a pilot program in New York found that patients who were treated on the ground by the MIST team rather than transferred to a specialized stroke center received faster care and were almost twice as likely to be functionally independent 3 months later.

“The use of a Mobile Interventional Stroke Team (MIST) traveling to Thrombectomy Capable Stroke Centers to perform endovascular thrombectomy has been shown to be significantly faster with improved discharge outcomes,” wrote lead author Jacob Morey, a doctoral Candidate at Icahn School of Medicine at Mount Sinai in New York and coauthors in the paper. Prior to this study, “the effect of the MIST model stratified by time of presentation” had yet to be studied.

The findings were published online on Aug. 5 in Stroke.
 

MIST model versus drip-and-ship

The researchers analyzed 226 patients who underwent endovascular thrombectomy between January 2017 and February 2020 at four hospitals in the Mount Sinai health system using the NYC MIST Trial and a stroke database. At baseline, all patients were functionally independent as assessed by the modified Rankin Scale (mRS, score of 0-2). 106 patients were treated by a MIST team – staffed by a neurointerventionalist, a fellow or physician assistant, and radiologic technologist – that traveled to the patient’s location. A total of 120 patients were transferred to a comprehensive stroke center (CSC) or a hospital with endovascular thrombectomy expertise. The analysis was stratified based on whether the patient presented in the early time window (≤ 6 hours) or late time window (> 6 hours).

Patients treated in the early time window were significantly more likely to be mobile and able to perform daily tasks (mRS ≤ 2) 90 days after the procedure in the MIST group (54%), compared with the transferred group (28%, P < 0.01). Outcomes did not differ significantly between groups in the late time window (35% vs. 41%, P = 0.77).

Similarly, early-time-window patients in the MIST group were more likely to have higher functionality at discharge, compared with transferred patients, based on the on the National Institutes of Health Stroke Scale (median score of 5.0 vs. 12.0, P < 0.01). There was no significant difference between groups treated in the late time window (median score of 5.0 vs. 11.0, P = 0.11).

“Ischemic strokes often progress rapidly and can cause severe damage because brain tissue dies quickly without oxygen, resulting in serious long-term disabilities or death,“ said Johanna Fifi, MD, of Icahn School of Medicine, said in a statement to the American Heart Association. “Assessing and treating stroke patients in the early window means that a greater number of fast-progressing strokes are identified and treated.”

Time is brain

Endovascular thrombectomy is a time-sensitive surgical procedure to remove large blood clots in acute ischemic stroke that has “historically been limited to comprehensive stroke centers,” the authors wrote in their paper. It is considered the standard of care in ischemic strokes, which make up 90% of all strokes. “Less than 50% of Americans have direct access to endovascular thrombectomy, the others must be transferred to a thrombectomy-capable hospital for treatment, often losing over 2 hours of time to treatment,” said Dr. Fifi. “Every minute is precious in treating stroke, and getting to a center that offers thrombectomy is very important. The MIST model would address this by providing faster access to this potentially life-saving, disability-reducing procedure.”

Access to timely endovascular thrombectomy is gradually improving as “more institutions and cities have implemented the [MIST] model.” Dr. Fifi said.

“This study stresses the importance of ‘time is brain,’ especially for patients in the early time window. Although the study is limited by the observational, retrospective design and was performed at a single integrated center, the findings are provocative,” said Louise McCullough, MD, of the University of Texas Health Science Center at Houston said in a statement to the American Heart Association. “The use of a MIST model highlights the potential benefit of early and urgent treatment for patients with large-vessel stroke. Stroke systems of care need to take advantage of any opportunity to treat patients early, wherever they are.”

The study was partly funded by a Stryker Foundation grant.

Having a mobile interventional stroke team (MIST) travel to treat stroke patients soon after stroke onset may improve patient outcomes, according to a new study. A retrospective analysis of a pilot program in New York found that patients who were treated on the ground by the MIST team rather than transferred to a specialized stroke center received faster care and were almost twice as likely to be functionally independent 3 months later.

“The use of a Mobile Interventional Stroke Team (MIST) traveling to Thrombectomy Capable Stroke Centers to perform endovascular thrombectomy has been shown to be significantly faster with improved discharge outcomes,” wrote lead author Jacob Morey, a doctoral Candidate at Icahn School of Medicine at Mount Sinai in New York and coauthors in the paper. Prior to this study, “the effect of the MIST model stratified by time of presentation” had yet to be studied.

The findings were published online on Aug. 5 in Stroke.
 

MIST model versus drip-and-ship

The researchers analyzed 226 patients who underwent endovascular thrombectomy between January 2017 and February 2020 at four hospitals in the Mount Sinai health system using the NYC MIST Trial and a stroke database. At baseline, all patients were functionally independent as assessed by the modified Rankin Scale (mRS, score of 0-2). 106 patients were treated by a MIST team – staffed by a neurointerventionalist, a fellow or physician assistant, and radiologic technologist – that traveled to the patient’s location. A total of 120 patients were transferred to a comprehensive stroke center (CSC) or a hospital with endovascular thrombectomy expertise. The analysis was stratified based on whether the patient presented in the early time window (≤ 6 hours) or late time window (> 6 hours).

Patients treated in the early time window were significantly more likely to be mobile and able to perform daily tasks (mRS ≤ 2) 90 days after the procedure in the MIST group (54%), compared with the transferred group (28%, P < 0.01). Outcomes did not differ significantly between groups in the late time window (35% vs. 41%, P = 0.77).

Similarly, early-time-window patients in the MIST group were more likely to have higher functionality at discharge, compared with transferred patients, based on the on the National Institutes of Health Stroke Scale (median score of 5.0 vs. 12.0, P < 0.01). There was no significant difference between groups treated in the late time window (median score of 5.0 vs. 11.0, P = 0.11).

“Ischemic strokes often progress rapidly and can cause severe damage because brain tissue dies quickly without oxygen, resulting in serious long-term disabilities or death,“ said Johanna Fifi, MD, of Icahn School of Medicine, said in a statement to the American Heart Association. “Assessing and treating stroke patients in the early window means that a greater number of fast-progressing strokes are identified and treated.”

Time is brain

Endovascular thrombectomy is a time-sensitive surgical procedure to remove large blood clots in acute ischemic stroke that has “historically been limited to comprehensive stroke centers,” the authors wrote in their paper. It is considered the standard of care in ischemic strokes, which make up 90% of all strokes. “Less than 50% of Americans have direct access to endovascular thrombectomy, the others must be transferred to a thrombectomy-capable hospital for treatment, often losing over 2 hours of time to treatment,” said Dr. Fifi. “Every minute is precious in treating stroke, and getting to a center that offers thrombectomy is very important. The MIST model would address this by providing faster access to this potentially life-saving, disability-reducing procedure.”

Access to timely endovascular thrombectomy is gradually improving as “more institutions and cities have implemented the [MIST] model.” Dr. Fifi said.

“This study stresses the importance of ‘time is brain,’ especially for patients in the early time window. Although the study is limited by the observational, retrospective design and was performed at a single integrated center, the findings are provocative,” said Louise McCullough, MD, of the University of Texas Health Science Center at Houston said in a statement to the American Heart Association. “The use of a MIST model highlights the potential benefit of early and urgent treatment for patients with large-vessel stroke. Stroke systems of care need to take advantage of any opportunity to treat patients early, wherever they are.”

The study was partly funded by a Stryker Foundation grant.

A combination of two monoclonal antibodies given as a subcutaneous injection prevented COVID-19 in patients at a high risk of infection due to household exposure, according to results of a randomized, double-blind, placebo-controlled clinical trial published online August 4, 2021, in the New England Journal of Medicine.

The cocktail of the monoclonal antibodies casirivimab and imdevimab (REGEN-COV, Regeneron Pharmaceuticals) reduced participants’ relative risk of infection by 72%, compared with placebo within the first week. After the first week, risk reduction increased to 93%.

“Long after you would be exposed by your household, there is an enduring effect that prevents you from community spread,” said David Wohl, MD, professor of medicine in the division of infectious diseases at the University of North Carolina at Chapel Hill, who was a site investigator for the trial but not a study author.

Participants were enrolled within 96 hours after someone in their household tested positive for SARS-CoV-2. Participants were randomly assigned to receive 1,200 mg of REGEN-COV subcutaneously or a placebo. Based on serologic testing, study participants showed no evidence of current or previous SARS-CoV-2 infection. The median age of participants was 42.9, but 45% were male teenagers (ages 12-17).

In the group that received REGEN-COV, 11 out of 753 participants developed symptomatic COVID-19, compared with 59 out of 752 participants who received placebo. The relative risk reduction for the study’s 4-week period was 81.4% (P < .001). Of the participants that did develop a SARS-CoV-2 infection, those that received REGEN-COV were less likely to be symptomatic. Asymptomatic infections developed in 25 participants who received REGEN-COV versus 48 in the placebo group. The relative risk of developing any SARS-CoV-2 infection, symptomatic or asymptomatic, was reduced by 66.4% with REGEN-COV (P < .001).

Among the patients who were symptomatic, symptoms subsided within a median of 1.2 weeks for the group that received REGEN-COV, 2 weeks earlier than the placebo group. These patients also had a shorter duration of a high viral load (>104 copies/mL). Few adverse events were reported in the treatment or placebo groups. Monoclonal antibodies “seem to be incredibly safe,” Dr. Wohl said.

“These monoclonal antibodies have proven they can reduce the viral replication in the nose,” said study author Myron Cohen, MD, an infectious disease specialist and professor of epidemiology at the University of North Carolina.

The Food and Drug Administration first granted REGEN-COV emergency use authorization (EUA) in November 2020 for use in patients with mild or moderate COVID-19 who were also at high risk for progressing to severe COVID-19. At that time, the cocktail of monoclonal antibodies was delivered by a single intravenous infusion.

In January, Regeneron first announced the success of this trial of the subcutaneous injection for exposed household contacts based on early results, and in June of 2021, the FDA expanded the EUA to include a subcutaneous delivery when IV is not feasible. On July 30, the EUA was expanded again to include prophylactic use in exposed patients based on these trial results.

The U.S. government has purchased approximately 1.5 million doses of REGEN-COV from Regeneron and has agreed to make the treatments free of charge to patients.

But despite being free, available, and backed by promising data, monoclonal antibodies as a therapeutic answer to COVID-19 still hasn’t really taken off. “The problem is, it first requires knowledge and awareness,” Dr. Wohl said. “A lot [of people] don’t know this exists. To be honest, vaccination has taken up all the oxygen in the room.”

Dr. Cohen agreed. One reason for the slow uptake may be because the drug supply is owned by the government and not a pharmaceutical company. There hasn’t been a typical marketing push to make physicians and consumers aware. Additionally, “the logistics are daunting,” Dr. Cohen said. The office spaces where many physicians care for patients “often aren’t appropriate for patients who think they have SARS-CoV-2.”

“Right now, there’s not a mechanism” to administer the drug to people who could benefit from it, Dr. Wohl said. Eligible patients are either immunocompromised and unlikely to mount a sufficient immune response with vaccination, or not fully vaccinated. They should have been exposed to an infected individual or have a high likelihood of exposure due to where they live, such as in a prison or nursing home. Local doctors are unlikely to be the primary administrators of the drug, Dr. Wohl added. “How do we operationalize this for people who fit the criteria?”

There’s also an issue of timing. REGEN-COV is most effective when given early, Dr. Cohen said. “[Monoclonal antibodies] really only work well in the replication phase.” Many patients who would be eligible delay care until they’ve had symptoms for several days, when REGEN-COV would no longer have the desired effect.

Eventually, Dr. Wohl suspects demand will increase when people realize REGEN-COV can help those with COVID-19 and those who have been exposed. But before then, “we do have to think about how to integrate this into a workflow people can access without being confused.”

The trial was done before there was widespread vaccination, so it’s unclear what the results mean for people who have been vaccinated. Dr. Cohen and Dr. Wohl said there are ongoing conversations about whether monoclonal antibodies could be complementary to vaccination and if there’s potential for continued monthly use of these therapies.

Cohen and Wohl reported no relevant financial relationships. The trial was supported by Regeneron Pharmaceuticals, F. Hoffmann–La Roche, the National Institute of Allergy and Infectious Diseases, NIH, and the COVID-19 Prevention Network.

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

A combination of two monoclonal antibodies given as a subcutaneous injection prevented COVID-19 in patients at a high risk of infection due to household exposure, according to results of a randomized, double-blind, placebo-controlled clinical trial published online August 4, 2021, in the New England Journal of Medicine.

The cocktail of the monoclonal antibodies casirivimab and imdevimab (REGEN-COV, Regeneron Pharmaceuticals) reduced participants’ relative risk of infection by 72%, compared with placebo within the first week. After the first week, risk reduction increased to 93%.

“Long after you would be exposed by your household, there is an enduring effect that prevents you from community spread,” said David Wohl, MD, professor of medicine in the division of infectious diseases at the University of North Carolina at Chapel Hill, who was a site investigator for the trial but not a study author.

Participants were enrolled within 96 hours after someone in their household tested positive for SARS-CoV-2. Participants were randomly assigned to receive 1,200 mg of REGEN-COV subcutaneously or a placebo. Based on serologic testing, study participants showed no evidence of current or previous SARS-CoV-2 infection. The median age of participants was 42.9, but 45% were male teenagers (ages 12-17).

In the group that received REGEN-COV, 11 out of 753 participants developed symptomatic COVID-19, compared with 59 out of 752 participants who received placebo. The relative risk reduction for the study’s 4-week period was 81.4% (P < .001). Of the participants that did develop a SARS-CoV-2 infection, those that received REGEN-COV were less likely to be symptomatic. Asymptomatic infections developed in 25 participants who received REGEN-COV versus 48 in the placebo group. The relative risk of developing any SARS-CoV-2 infection, symptomatic or asymptomatic, was reduced by 66.4% with REGEN-COV (P < .001).

Among the patients who were symptomatic, symptoms subsided within a median of 1.2 weeks for the group that received REGEN-COV, 2 weeks earlier than the placebo group. These patients also had a shorter duration of a high viral load (>104 copies/mL). Few adverse events were reported in the treatment or placebo groups. Monoclonal antibodies “seem to be incredibly safe,” Dr. Wohl said.

“These monoclonal antibodies have proven they can reduce the viral replication in the nose,” said study author Myron Cohen, MD, an infectious disease specialist and professor of epidemiology at the University of North Carolina.

The Food and Drug Administration first granted REGEN-COV emergency use authorization (EUA) in November 2020 for use in patients with mild or moderate COVID-19 who were also at high risk for progressing to severe COVID-19. At that time, the cocktail of monoclonal antibodies was delivered by a single intravenous infusion.

In January, Regeneron first announced the success of this trial of the subcutaneous injection for exposed household contacts based on early results, and in June of 2021, the FDA expanded the EUA to include a subcutaneous delivery when IV is not feasible. On July 30, the EUA was expanded again to include prophylactic use in exposed patients based on these trial results.

The U.S. government has purchased approximately 1.5 million doses of REGEN-COV from Regeneron and has agreed to make the treatments free of charge to patients.

But despite being free, available, and backed by promising data, monoclonal antibodies as a therapeutic answer to COVID-19 still hasn’t really taken off. “The problem is, it first requires knowledge and awareness,” Dr. Wohl said. “A lot [of people] don’t know this exists. To be honest, vaccination has taken up all the oxygen in the room.”

Dr. Cohen agreed. One reason for the slow uptake may be because the drug supply is owned by the government and not a pharmaceutical company. There hasn’t been a typical marketing push to make physicians and consumers aware. Additionally, “the logistics are daunting,” Dr. Cohen said. The office spaces where many physicians care for patients “often aren’t appropriate for patients who think they have SARS-CoV-2.”

“Right now, there’s not a mechanism” to administer the drug to people who could benefit from it, Dr. Wohl said. Eligible patients are either immunocompromised and unlikely to mount a sufficient immune response with vaccination, or not fully vaccinated. They should have been exposed to an infected individual or have a high likelihood of exposure due to where they live, such as in a prison or nursing home. Local doctors are unlikely to be the primary administrators of the drug, Dr. Wohl added. “How do we operationalize this for people who fit the criteria?”

There’s also an issue of timing. REGEN-COV is most effective when given early, Dr. Cohen said. “[Monoclonal antibodies] really only work well in the replication phase.” Many patients who would be eligible delay care until they’ve had symptoms for several days, when REGEN-COV would no longer have the desired effect.

Eventually, Dr. Wohl suspects demand will increase when people realize REGEN-COV can help those with COVID-19 and those who have been exposed. But before then, “we do have to think about how to integrate this into a workflow people can access without being confused.”

The trial was done before there was widespread vaccination, so it’s unclear what the results mean for people who have been vaccinated. Dr. Cohen and Dr. Wohl said there are ongoing conversations about whether monoclonal antibodies could be complementary to vaccination and if there’s potential for continued monthly use of these therapies.

Cohen and Wohl reported no relevant financial relationships. The trial was supported by Regeneron Pharmaceuticals, F. Hoffmann–La Roche, the National Institute of Allergy and Infectious Diseases, NIH, and the COVID-19 Prevention Network.

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

A combination of two monoclonal antibodies given as a subcutaneous injection prevented COVID-19 in patients at a high risk of infection due to household exposure, according to results of a randomized, double-blind, placebo-controlled clinical trial published online August 4, 2021, in the New England Journal of Medicine.

The cocktail of the monoclonal antibodies casirivimab and imdevimab (REGEN-COV, Regeneron Pharmaceuticals) reduced participants’ relative risk of infection by 72%, compared with placebo within the first week. After the first week, risk reduction increased to 93%.

“Long after you would be exposed by your household, there is an enduring effect that prevents you from community spread,” said David Wohl, MD, professor of medicine in the division of infectious diseases at the University of North Carolina at Chapel Hill, who was a site investigator for the trial but not a study author.

Participants were enrolled within 96 hours after someone in their household tested positive for SARS-CoV-2. Participants were randomly assigned to receive 1,200 mg of REGEN-COV subcutaneously or a placebo. Based on serologic testing, study participants showed no evidence of current or previous SARS-CoV-2 infection. The median age of participants was 42.9, but 45% were male teenagers (ages 12-17).

In the group that received REGEN-COV, 11 out of 753 participants developed symptomatic COVID-19, compared with 59 out of 752 participants who received placebo. The relative risk reduction for the study’s 4-week period was 81.4% (P < .001). Of the participants that did develop a SARS-CoV-2 infection, those that received REGEN-COV were less likely to be symptomatic. Asymptomatic infections developed in 25 participants who received REGEN-COV versus 48 in the placebo group. The relative risk of developing any SARS-CoV-2 infection, symptomatic or asymptomatic, was reduced by 66.4% with REGEN-COV (P < .001).

Among the patients who were symptomatic, symptoms subsided within a median of 1.2 weeks for the group that received REGEN-COV, 2 weeks earlier than the placebo group. These patients also had a shorter duration of a high viral load (>104 copies/mL). Few adverse events were reported in the treatment or placebo groups. Monoclonal antibodies “seem to be incredibly safe,” Dr. Wohl said.

“These monoclonal antibodies have proven they can reduce the viral replication in the nose,” said study author Myron Cohen, MD, an infectious disease specialist and professor of epidemiology at the University of North Carolina.

The Food and Drug Administration first granted REGEN-COV emergency use authorization (EUA) in November 2020 for use in patients with mild or moderate COVID-19 who were also at high risk for progressing to severe COVID-19. At that time, the cocktail of monoclonal antibodies was delivered by a single intravenous infusion.

In January, Regeneron first announced the success of this trial of the subcutaneous injection for exposed household contacts based on early results, and in June of 2021, the FDA expanded the EUA to include a subcutaneous delivery when IV is not feasible. On July 30, the EUA was expanded again to include prophylactic use in exposed patients based on these trial results.

The U.S. government has purchased approximately 1.5 million doses of REGEN-COV from Regeneron and has agreed to make the treatments free of charge to patients.

But despite being free, available, and backed by promising data, monoclonal antibodies as a therapeutic answer to COVID-19 still hasn’t really taken off. “The problem is, it first requires knowledge and awareness,” Dr. Wohl said. “A lot [of people] don’t know this exists. To be honest, vaccination has taken up all the oxygen in the room.”

Dr. Cohen agreed. One reason for the slow uptake may be because the drug supply is owned by the government and not a pharmaceutical company. There hasn’t been a typical marketing push to make physicians and consumers aware. Additionally, “the logistics are daunting,” Dr. Cohen said. The office spaces where many physicians care for patients “often aren’t appropriate for patients who think they have SARS-CoV-2.”

“Right now, there’s not a mechanism” to administer the drug to people who could benefit from it, Dr. Wohl said. Eligible patients are either immunocompromised and unlikely to mount a sufficient immune response with vaccination, or not fully vaccinated. They should have been exposed to an infected individual or have a high likelihood of exposure due to where they live, such as in a prison or nursing home. Local doctors are unlikely to be the primary administrators of the drug, Dr. Wohl added. “How do we operationalize this for people who fit the criteria?”

There’s also an issue of timing. REGEN-COV is most effective when given early, Dr. Cohen said. “[Monoclonal antibodies] really only work well in the replication phase.” Many patients who would be eligible delay care until they’ve had symptoms for several days, when REGEN-COV would no longer have the desired effect.

Eventually, Dr. Wohl suspects demand will increase when people realize REGEN-COV can help those with COVID-19 and those who have been exposed. But before then, “we do have to think about how to integrate this into a workflow people can access without being confused.”

The trial was done before there was widespread vaccination, so it’s unclear what the results mean for people who have been vaccinated. Dr. Cohen and Dr. Wohl said there are ongoing conversations about whether monoclonal antibodies could be complementary to vaccination and if there’s potential for continued monthly use of these therapies.

Cohen and Wohl reported no relevant financial relationships. The trial was supported by Regeneron Pharmaceuticals, F. Hoffmann–La Roche, the National Institute of Allergy and Infectious Diseases, NIH, and the COVID-19 Prevention Network.

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