The Diagnosis: Kaposi Sarcoma

A punch biopsy of a lesion on the right side of the back revealed a diffuse, poorly circumscribed, spindle cell neoplasm of the papillary and reticular dermis with associated vascular and pseudovascular spaces distended by erythrocytes (Figure 1). Immunostaining was positive for human herpesvirus 8 (HHV-8)(Figure 2), ETS-related gene, CD31, and CD34 and negative for pan cytokeratin, confirming the diagnosis of Kaposi sarcoma (KS). Bacterial, fungal, and mycobacterial tissue cultures were negative. The patient was tested for HIV and referred to infectious disease and oncology. He subsequently was found to have HIV with a viral load greater than 1 million copies. He was started on antiretroviral therapy and Pneumocystis jirovecii pneumonia prophylaxis. Computed tomography of the chest, abdomen, and pelvis showed bilateral, multifocal, perihilar, flame-shaped consolidations suggestive of KS. The patient later disclosed having an intermittent dry cough of more than a year’s duration with occasional bright red blood per rectum after bowel movements. After workup, the patient was found to have cytomegalovirus esophagitis/gastritis and candidal esophagitis that were treated with valganciclovir and fluconazole, respectively.

Kaposi sarcoma is an angioproliferative, AIDSdefining disease associated with HHV-8. There are 4 types of KS as defined by the populations they affect. AIDS-associated KS occurs in individuals with HIV, as seen in our patient. It often is accompanied by extensive mucocutaneous and visceral lesions, as well as systemic symptoms such as fever, weight loss, and diarrhea.¹ Classic KS is a variant that presents in older men of Mediterranean, Eastern European, and South American descent. Cutaneous lesions typically are distributed on the lower extremities.^2,3 Endemic (African) KS is seen in HIV-negative children and young adults in equatorial Africa. It most commonly affects the lower extremities or lymph nodes and usually follows a more aggressive course.² Lastly, iatrogenic KS is associated with immunosuppressive medications or conditions, such as organ transplantation, chemotherapy, and rheumatologic disorders.^3,4

Kaposi sarcoma commonly presents as violaceous or dark red macules, patches, papules, plaques, and nodules on various parts of the body (Figure 3). Lesions typically begin as macules and progress into plaques or nodules. Our patient presented as a deceptively healthy young man with lesions at various stages of development. In addition to the skin and oral mucosa, the lungs, lymph nodes, and gastrointestinal tract commonly are involved in AIDS-associated KS.⁵ Patients may experience symptoms of internal involvement, including bleeding, hematochezia, odynophagia, or dyspnea.

The differential diagnosis includes conditions that can mimic KS, including bacillary angiomatosis, angioinvasive fungal disease, sarcoid, and other malignancies. A skin biopsy is the gold standard for definitive diagnosis of KS. Histopathology shows a vascular proliferation in the dermis and spindle cell proliferation.⁶ Kaposi sarcoma stains positively for factor VIII–related antigen, CD31, and CD34.² Additionally, staining for HHV-8 gene products, such as latency-associated nuclear antigen 1, is helpful in differentiating KS from other conditions.⁷

In HIV-associated KS, the mainstay of treatment is initiation of highly active antiretroviral therapy. Typically, as the CD4 count rises with treatment, the tumor burden classic KS, effective treatment options include recurrent cryotherapy or intralesional chemotherapeutics, such as vincristine, for localized lesions; for widespread disease, pegylated liposomal doxorubicin or radiation have been found to be effective options. Lastly, for patients with iatrogenic KS, reducing immunosuppressive medications is a reasonable first step in management. If this does not yield adequate improvement, transitioning from calcineurin inhibitors (eg, cyclosporine) to proliferation signal inhibitors (eg, sirolimus) may lead to resolution.⁷

The Diagnosis: Kaposi Sarcoma

A punch biopsy of a lesion on the right side of the back revealed a diffuse, poorly circumscribed, spindle cell neoplasm of the papillary and reticular dermis with associated vascular and pseudovascular spaces distended by erythrocytes (Figure 1). Immunostaining was positive for human herpesvirus 8 (HHV-8)(Figure 2), ETS-related gene, CD31, and CD34 and negative for pan cytokeratin, confirming the diagnosis of Kaposi sarcoma (KS). Bacterial, fungal, and mycobacterial tissue cultures were negative. The patient was tested for HIV and referred to infectious disease and oncology. He subsequently was found to have HIV with a viral load greater than 1 million copies. He was started on antiretroviral therapy and Pneumocystis jirovecii pneumonia prophylaxis. Computed tomography of the chest, abdomen, and pelvis showed bilateral, multifocal, perihilar, flame-shaped consolidations suggestive of KS. The patient later disclosed having an intermittent dry cough of more than a year’s duration with occasional bright red blood per rectum after bowel movements. After workup, the patient was found to have cytomegalovirus esophagitis/gastritis and candidal esophagitis that were treated with valganciclovir and fluconazole, respectively.

Kaposi sarcoma is an angioproliferative, AIDSdefining disease associated with HHV-8. There are 4 types of KS as defined by the populations they affect. AIDS-associated KS occurs in individuals with HIV, as seen in our patient. It often is accompanied by extensive mucocutaneous and visceral lesions, as well as systemic symptoms such as fever, weight loss, and diarrhea.¹ Classic KS is a variant that presents in older men of Mediterranean, Eastern European, and South American descent. Cutaneous lesions typically are distributed on the lower extremities.^2,3 Endemic (African) KS is seen in HIV-negative children and young adults in equatorial Africa. It most commonly affects the lower extremities or lymph nodes and usually follows a more aggressive course.² Lastly, iatrogenic KS is associated with immunosuppressive medications or conditions, such as organ transplantation, chemotherapy, and rheumatologic disorders.^3,4

Kaposi sarcoma commonly presents as violaceous or dark red macules, patches, papules, plaques, and nodules on various parts of the body (Figure 3). Lesions typically begin as macules and progress into plaques or nodules. Our patient presented as a deceptively healthy young man with lesions at various stages of development. In addition to the skin and oral mucosa, the lungs, lymph nodes, and gastrointestinal tract commonly are involved in AIDS-associated KS.⁵ Patients may experience symptoms of internal involvement, including bleeding, hematochezia, odynophagia, or dyspnea.

The differential diagnosis includes conditions that can mimic KS, including bacillary angiomatosis, angioinvasive fungal disease, sarcoid, and other malignancies. A skin biopsy is the gold standard for definitive diagnosis of KS. Histopathology shows a vascular proliferation in the dermis and spindle cell proliferation.⁶ Kaposi sarcoma stains positively for factor VIII–related antigen, CD31, and CD34.² Additionally, staining for HHV-8 gene products, such as latency-associated nuclear antigen 1, is helpful in differentiating KS from other conditions.⁷

In HIV-associated KS, the mainstay of treatment is initiation of highly active antiretroviral therapy. Typically, as the CD4 count rises with treatment, the tumor burden classic KS, effective treatment options include recurrent cryotherapy or intralesional chemotherapeutics, such as vincristine, for localized lesions; for widespread disease, pegylated liposomal doxorubicin or radiation have been found to be effective options. Lastly, for patients with iatrogenic KS, reducing immunosuppressive medications is a reasonable first step in management. If this does not yield adequate improvement, transitioning from calcineurin inhibitors (eg, cyclosporine) to proliferation signal inhibitors (eg, sirolimus) may lead to resolution.⁷

The Diagnosis: Kaposi Sarcoma

A punch biopsy of a lesion on the right side of the back revealed a diffuse, poorly circumscribed, spindle cell neoplasm of the papillary and reticular dermis with associated vascular and pseudovascular spaces distended by erythrocytes (Figure 1). Immunostaining was positive for human herpesvirus 8 (HHV-8)(Figure 2), ETS-related gene, CD31, and CD34 and negative for pan cytokeratin, confirming the diagnosis of Kaposi sarcoma (KS). Bacterial, fungal, and mycobacterial tissue cultures were negative. The patient was tested for HIV and referred to infectious disease and oncology. He subsequently was found to have HIV with a viral load greater than 1 million copies. He was started on antiretroviral therapy and Pneumocystis jirovecii pneumonia prophylaxis. Computed tomography of the chest, abdomen, and pelvis showed bilateral, multifocal, perihilar, flame-shaped consolidations suggestive of KS. The patient later disclosed having an intermittent dry cough of more than a year’s duration with occasional bright red blood per rectum after bowel movements. After workup, the patient was found to have cytomegalovirus esophagitis/gastritis and candidal esophagitis that were treated with valganciclovir and fluconazole, respectively.

Kaposi sarcoma is an angioproliferative, AIDSdefining disease associated with HHV-8. There are 4 types of KS as defined by the populations they affect. AIDS-associated KS occurs in individuals with HIV, as seen in our patient. It often is accompanied by extensive mucocutaneous and visceral lesions, as well as systemic symptoms such as fever, weight loss, and diarrhea.¹ Classic KS is a variant that presents in older men of Mediterranean, Eastern European, and South American descent. Cutaneous lesions typically are distributed on the lower extremities.^2,3 Endemic (African) KS is seen in HIV-negative children and young adults in equatorial Africa. It most commonly affects the lower extremities or lymph nodes and usually follows a more aggressive course.² Lastly, iatrogenic KS is associated with immunosuppressive medications or conditions, such as organ transplantation, chemotherapy, and rheumatologic disorders.^3,4

Kaposi sarcoma commonly presents as violaceous or dark red macules, patches, papules, plaques, and nodules on various parts of the body (Figure 3). Lesions typically begin as macules and progress into plaques or nodules. Our patient presented as a deceptively healthy young man with lesions at various stages of development. In addition to the skin and oral mucosa, the lungs, lymph nodes, and gastrointestinal tract commonly are involved in AIDS-associated KS.⁵ Patients may experience symptoms of internal involvement, including bleeding, hematochezia, odynophagia, or dyspnea.

The differential diagnosis includes conditions that can mimic KS, including bacillary angiomatosis, angioinvasive fungal disease, sarcoid, and other malignancies. A skin biopsy is the gold standard for definitive diagnosis of KS. Histopathology shows a vascular proliferation in the dermis and spindle cell proliferation.⁶ Kaposi sarcoma stains positively for factor VIII–related antigen, CD31, and CD34.² Additionally, staining for HHV-8 gene products, such as latency-associated nuclear antigen 1, is helpful in differentiating KS from other conditions.⁷

In HIV-associated KS, the mainstay of treatment is initiation of highly active antiretroviral therapy. Typically, as the CD4 count rises with treatment, the tumor burden classic KS, effective treatment options include recurrent cryotherapy or intralesional chemotherapeutics, such as vincristine, for localized lesions; for widespread disease, pegylated liposomal doxorubicin or radiation have been found to be effective options. Lastly, for patients with iatrogenic KS, reducing immunosuppressive medications is a reasonable first step in management. If this does not yield adequate improvement, transitioning from calcineurin inhibitors (eg, cyclosporine) to proliferation signal inhibitors (eg, sirolimus) may lead to resolution.⁷

It seems obvious that increased use of mosquito bed nets in sub-Saharan Africa would decrease the incidence of malaria, but a lingering question remained: Would controlling malaria in children under 5 years of age shift deaths to older children by delaying functional immunity?  A new report in the New England Journal of Medicine seems to have laid that concern to rest.

Malaria from Plasmodium falciparum infection exacts a significant toll in sub-Saharan Africa. According to the World Health Organization, there were about 228 million cases and 602,000 deaths from malaria in 2020 alone. About 80% of those deaths were in children less than 5 years old. In some areas, as many as 5% of children die from malaria by age 5.

Efforts to reduce the burden of malaria have been ongoing for decades. In the 1990s, insecticide-treated nets were shown to reduce illness and deaths from malaria in children.

As a result, the use of bed nets has grown significantly. In 2000, only 5% of households in sub-Saharan Africa had a net in the house. By 2020, that number had risen to 65%. From 2004 to 2019 about 1.9 billion nets were distributed in this region. The nets are estimated to have prevented more than 663 million malaria cases between 2000 and 2015.

As described in the NEJM report, public health researchers conducted a 22-year prospective longitudinal cohort study in rural southern Tanzania following 6,706 children born between 1998 and 2000. Initially, home visits were made every 4 months from May 1998 to April 2003. Remarkably, in 2019, they were able to verify the status of fully 89% of those people by reaching out to families and community/village leaders.

Günther Fink, PhD, associate professor of epidemiology and household economics, University of Basel (Switzerland), explained the approach and primary findings to this news organization. The analysis looked at three main groups – children whose parents said they always slept under treated nets, those who slept protected most of the time, and those who spent less than half the time under bed nets. The hazard ratio for death was 0.57 (95% confidence interval, 0.45-0.72) for the first two groups, compared with the least protected. The corresponding hazard ratio between age 5 and adulthood was 0.93 (95% CI, 0.58-1.49).

The findings confirmed what they had suspected. Dr. Fink summarized simply, “If you always slept under a net, you did much better than if you never slept under the net. If you slept [under a net] more than half of the time, it was much better than if you slept [under a net] less than half the time.” So the more time children slept under bed nets, the less likely they were to acquire malaria. Dr. Fink stressed that the findings showing protective efficacy persisted into adulthood. “It seems just having a healthier early life actually makes you more resilient against other future infections.”

One of the theoretical concerns was that using nets would delay developing functional immunity and that there might be an increase in mortality seen later. This study showed that did not happen.

An accompanying commentary noted that there was some potential that families receiving nets were better off than those that didn’t but concluded that such confounding had been accounted for in other analyses.

Mark Wilson, ScD, professor emeritus of epidemiology, University of Michigan, Ann Arbor, concurred. He told this news organization that the study was “very well designed,” and the researchers “did a fantastic job” in tracking patients 20 years later.

“This is astounding!” he added. “It’s very rare to find this amount of follow-up.”

Dr. Fink’s conclusion? “Bed nets protect you in the short run, and being protected in the short run is also beneficial in the long run. There is no evidence that protecting kids in early childhood is weakening them in any way. So we should keep doing this.”

Dr. Fink and Dr. Wilson report no relevant financial relationships.

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

It seems obvious that increased use of mosquito bed nets in sub-Saharan Africa would decrease the incidence of malaria, but a lingering question remained: Would controlling malaria in children under 5 years of age shift deaths to older children by delaying functional immunity?  A new report in the New England Journal of Medicine seems to have laid that concern to rest.

Malaria from Plasmodium falciparum infection exacts a significant toll in sub-Saharan Africa. According to the World Health Organization, there were about 228 million cases and 602,000 deaths from malaria in 2020 alone. About 80% of those deaths were in children less than 5 years old. In some areas, as many as 5% of children die from malaria by age 5.

Efforts to reduce the burden of malaria have been ongoing for decades. In the 1990s, insecticide-treated nets were shown to reduce illness and deaths from malaria in children.

As a result, the use of bed nets has grown significantly. In 2000, only 5% of households in sub-Saharan Africa had a net in the house. By 2020, that number had risen to 65%. From 2004 to 2019 about 1.9 billion nets were distributed in this region. The nets are estimated to have prevented more than 663 million malaria cases between 2000 and 2015.

As described in the NEJM report, public health researchers conducted a 22-year prospective longitudinal cohort study in rural southern Tanzania following 6,706 children born between 1998 and 2000. Initially, home visits were made every 4 months from May 1998 to April 2003. Remarkably, in 2019, they were able to verify the status of fully 89% of those people by reaching out to families and community/village leaders.

Günther Fink, PhD, associate professor of epidemiology and household economics, University of Basel (Switzerland), explained the approach and primary findings to this news organization. The analysis looked at three main groups – children whose parents said they always slept under treated nets, those who slept protected most of the time, and those who spent less than half the time under bed nets. The hazard ratio for death was 0.57 (95% confidence interval, 0.45-0.72) for the first two groups, compared with the least protected. The corresponding hazard ratio between age 5 and adulthood was 0.93 (95% CI, 0.58-1.49).

The findings confirmed what they had suspected. Dr. Fink summarized simply, “If you always slept under a net, you did much better than if you never slept under the net. If you slept [under a net] more than half of the time, it was much better than if you slept [under a net] less than half the time.” So the more time children slept under bed nets, the less likely they were to acquire malaria. Dr. Fink stressed that the findings showing protective efficacy persisted into adulthood. “It seems just having a healthier early life actually makes you more resilient against other future infections.”

One of the theoretical concerns was that using nets would delay developing functional immunity and that there might be an increase in mortality seen later. This study showed that did not happen.

An accompanying commentary noted that there was some potential that families receiving nets were better off than those that didn’t but concluded that such confounding had been accounted for in other analyses.

Mark Wilson, ScD, professor emeritus of epidemiology, University of Michigan, Ann Arbor, concurred. He told this news organization that the study was “very well designed,” and the researchers “did a fantastic job” in tracking patients 20 years later.

“This is astounding!” he added. “It’s very rare to find this amount of follow-up.”

Dr. Fink’s conclusion? “Bed nets protect you in the short run, and being protected in the short run is also beneficial in the long run. There is no evidence that protecting kids in early childhood is weakening them in any way. So we should keep doing this.”

Dr. Fink and Dr. Wilson report no relevant financial relationships.

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

It seems obvious that increased use of mosquito bed nets in sub-Saharan Africa would decrease the incidence of malaria, but a lingering question remained: Would controlling malaria in children under 5 years of age shift deaths to older children by delaying functional immunity?  A new report in the New England Journal of Medicine seems to have laid that concern to rest.

Malaria from Plasmodium falciparum infection exacts a significant toll in sub-Saharan Africa. According to the World Health Organization, there were about 228 million cases and 602,000 deaths from malaria in 2020 alone. About 80% of those deaths were in children less than 5 years old. In some areas, as many as 5% of children die from malaria by age 5.

Efforts to reduce the burden of malaria have been ongoing for decades. In the 1990s, insecticide-treated nets were shown to reduce illness and deaths from malaria in children.

As a result, the use of bed nets has grown significantly. In 2000, only 5% of households in sub-Saharan Africa had a net in the house. By 2020, that number had risen to 65%. From 2004 to 2019 about 1.9 billion nets were distributed in this region. The nets are estimated to have prevented more than 663 million malaria cases between 2000 and 2015.

As described in the NEJM report, public health researchers conducted a 22-year prospective longitudinal cohort study in rural southern Tanzania following 6,706 children born between 1998 and 2000. Initially, home visits were made every 4 months from May 1998 to April 2003. Remarkably, in 2019, they were able to verify the status of fully 89% of those people by reaching out to families and community/village leaders.

Günther Fink, PhD, associate professor of epidemiology and household economics, University of Basel (Switzerland), explained the approach and primary findings to this news organization. The analysis looked at three main groups – children whose parents said they always slept under treated nets, those who slept protected most of the time, and those who spent less than half the time under bed nets. The hazard ratio for death was 0.57 (95% confidence interval, 0.45-0.72) for the first two groups, compared with the least protected. The corresponding hazard ratio between age 5 and adulthood was 0.93 (95% CI, 0.58-1.49).

The findings confirmed what they had suspected. Dr. Fink summarized simply, “If you always slept under a net, you did much better than if you never slept under the net. If you slept [under a net] more than half of the time, it was much better than if you slept [under a net] less than half the time.” So the more time children slept under bed nets, the less likely they were to acquire malaria. Dr. Fink stressed that the findings showing protective efficacy persisted into adulthood. “It seems just having a healthier early life actually makes you more resilient against other future infections.”

One of the theoretical concerns was that using nets would delay developing functional immunity and that there might be an increase in mortality seen later. This study showed that did not happen.

An accompanying commentary noted that there was some potential that families receiving nets were better off than those that didn’t but concluded that such confounding had been accounted for in other analyses.

Mark Wilson, ScD, professor emeritus of epidemiology, University of Michigan, Ann Arbor, concurred. He told this news organization that the study was “very well designed,” and the researchers “did a fantastic job” in tracking patients 20 years later.

“This is astounding!” he added. “It’s very rare to find this amount of follow-up.”

Dr. Fink’s conclusion? “Bed nets protect you in the short run, and being protected in the short run is also beneficial in the long run. There is no evidence that protecting kids in early childhood is weakening them in any way. So we should keep doing this.”

Dr. Fink and Dr. Wilson report no relevant financial relationships.

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

The current clinical classification tools for inflammatory bowel disease (IBD) are suboptimal, and revision beyond the broad categories of Crohn’s disease (CD) and ulcerative colitis (UC) could improve trial design, research, and ultimately patient outcomes, according to the authors of a recent review.

“Despite clear improvements in our understanding of disease biology and increasing treatment options, we still face an important therapeutic ceiling [in IBD],” wrote Bram Verstockt, MD, of University Hospitals Leuven, Belgium, and colleagues.

ChrisGorgio/Thinkstock

“In part, our limited therapeutic successes can be attributed to the disease heterogeneity of IBD: There is not one CD, nor a single UC phenotype,” therefore, a revision of the current systems based on better understanding of IBD is needed, the researchers said.

In a review article published in Gastroenterology, the researchers identified clinical features important to IBD heterogeneity, examined limitations of the current classifications, and proposed improvements.
 

Characterizing a complex condition

IBD diagnosis is challenging not only because of the overlapping phenotypes, but because other pathologies, including infections, can mimic IBD, the authors noted.

Age of onset should be considered in characterizing IBD, they wrote. Notably, patients with late-onset CD should be distinguished from elderly patients who have had CD for years. The authors cited research showing that “the development of IBD at extremes of age are specific sub-groups that require a different clinical recognition and clinical management,” and that large sample sizes and unbiased statistical methods are needed to define subgroups of IBD patients.

Current CD classification (the Montreal Classification) involves disease location, disease behavior, and age at diagnosis, and considers four phenotypes within disease location: involvement of the ileum, involvement of the colon, involvement of both the ileum and the colon, or isolated upper disease.* “Recently, there has been notable interest in the differential response rates among ileal predominant CD compared to colonic CD,” the authors wrote. Consequently, they proposed a revision of CD classification based on location. Genetic data appear to support this revision. In an IBD genotype-phenotype study including nearly 30,000 patients, three loci (NOD2, MHC, MST1 3p21) were strongly associated with disease location, they said. Other emerging evidence suggests that gut microbiota may vary according to disease location. The authors identified clinical aspects of CD classification based on disease location that distinguish small bowel predominant CD versus colonic predominant CD. Ileal disease patients have shown an increased risk for undergoing surgery, while those with colonic involvement have an increased risk for developing extraintestinal manifestations.

They also emphasized the value of considering rectal inflammation, which significantly impacts surgical procedures in CD.

Standard UC classification is based on macroscopic disease in the colon at the time of inflammation, the authors said. Although this approach allows for quick assessment of a patient’s risk of colectomy, the authors proposed improvements, including the use of serum biomarkers (C-reactive protein or erythrocyte sedimentation rate) to identify patients at highest risk for colectomy and colon cancer based on inflammation. The authors also suggested that patients with refractory proctitis be enrolled in UC clinical trials or in studies focusing on refractory proctitis in particular.

The pelvic pouch has become the most often performed surgical procedure for patients undergoing colectomy, but there is no agreement on classification of inflammatory pelvic pouch disorders, and studies of etiology and treatment are lacking, the authors noted. They advised a clinical assessment based on symptoms, including stool frequency, urgency, and incontinence. They also suggested that afferent limb ulcers of erosions should be classified separately from pouch inflammation.

The authors ended by noting that extraintestinal manifestations (EIMs) that occur in up to half of IBD patients may or may not be directly related to intestinal disease, and may represent a different phenotype, and the presence and type of EIM should be included in a revised IBD classification system, they said.

The authors emphasized that continuing to refer to IBD as only CD and UC “does a great disservice to our attempts to better understand IBD pathogenesis and to improve clinical patient management.”

They concluded: “Although revised clinical classification tools alone will not be sufficient and should be complemented by deeper and more detailed study into molecular subclassification of disease, the considerations here could be used as a springboard toward improved trial design, future translational research approaches and better treatment outcomes for patients.”
 

Review reflects complexity of IBD and challenges of change

The review is important at this time because of the growing recognition that IBD, while traditionally categorized as either UC or CD, is most likely composed of a range of heterogeneous conditions involving inflammation of the gastrointestinal tract, Jatin Roper, MD, of Duke University in Durham, N.C., said in an interview.

“Evidence that our current classification of IBD is suboptimal comes from both the wide range of clinical phenotypes as well as complexity in genetic markers that are associated with IBD,” he said.  “It is well accepted in the gastroenterology community that IBD is a complex condition; so it is surprising to me that the dichotomy of UC vs. Crohn’s disease has rarely been challenged,” said Dr. Roper. “The authors of this review should be commended for raising the question of whether IBD deserves a more nuanced classification system that reflects the growing recognition of the wide heterogeneity of patient presentations and genetics,” he said.   

“Challenging medical definitions is inherently difficult because patient diagnoses, treatment plans, as well as decades of clinical research have been based on well-accepted disease categories. Another major challenge in reclassification is that the course of IBD can vary greatly over time in the same patient in severity, range, and complexity, and potentially includes many disease subtypes noted by the authors of this review,” he added. “Therefore, I believe that the current system of dividing IBD in UC and CD is here to stay until subtypes based on mechanisms of disease pathogenesis are discovered.

“Additional research is needed to understand the molecular basis of IBD,” Dr. Roper emphasized. “Recent advances in RNA expression and proteomics at the single cell level may reveal distinct cell types or cell functions in tissues from IBD patients that may help us understand clinical phenotype or response to therapy.”

The study received no outside funding. The authors disclosed financial relationships with AbbVie, Biogen, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, and Truvion. Dr. Roper had no financial conflicts to disclose.

Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD.

*Correction, 4/11/22: An earlier version of this article misstated the Montreal Classification. 

The current clinical classification tools for inflammatory bowel disease (IBD) are suboptimal, and revision beyond the broad categories of Crohn’s disease (CD) and ulcerative colitis (UC) could improve trial design, research, and ultimately patient outcomes, according to the authors of a recent review.

“Despite clear improvements in our understanding of disease biology and increasing treatment options, we still face an important therapeutic ceiling [in IBD],” wrote Bram Verstockt, MD, of University Hospitals Leuven, Belgium, and colleagues.

ChrisGorgio/Thinkstock

“In part, our limited therapeutic successes can be attributed to the disease heterogeneity of IBD: There is not one CD, nor a single UC phenotype,” therefore, a revision of the current systems based on better understanding of IBD is needed, the researchers said.

In a review article published in Gastroenterology, the researchers identified clinical features important to IBD heterogeneity, examined limitations of the current classifications, and proposed improvements.
 

Characterizing a complex condition

IBD diagnosis is challenging not only because of the overlapping phenotypes, but because other pathologies, including infections, can mimic IBD, the authors noted.

Age of onset should be considered in characterizing IBD, they wrote. Notably, patients with late-onset CD should be distinguished from elderly patients who have had CD for years. The authors cited research showing that “the development of IBD at extremes of age are specific sub-groups that require a different clinical recognition and clinical management,” and that large sample sizes and unbiased statistical methods are needed to define subgroups of IBD patients.

Current CD classification (the Montreal Classification) involves disease location, disease behavior, and age at diagnosis, and considers four phenotypes within disease location: involvement of the ileum, involvement of the colon, involvement of both the ileum and the colon, or isolated upper disease.* “Recently, there has been notable interest in the differential response rates among ileal predominant CD compared to colonic CD,” the authors wrote. Consequently, they proposed a revision of CD classification based on location. Genetic data appear to support this revision. In an IBD genotype-phenotype study including nearly 30,000 patients, three loci (NOD2, MHC, MST1 3p21) were strongly associated with disease location, they said. Other emerging evidence suggests that gut microbiota may vary according to disease location. The authors identified clinical aspects of CD classification based on disease location that distinguish small bowel predominant CD versus colonic predominant CD. Ileal disease patients have shown an increased risk for undergoing surgery, while those with colonic involvement have an increased risk for developing extraintestinal manifestations.

They also emphasized the value of considering rectal inflammation, which significantly impacts surgical procedures in CD.

Standard UC classification is based on macroscopic disease in the colon at the time of inflammation, the authors said. Although this approach allows for quick assessment of a patient’s risk of colectomy, the authors proposed improvements, including the use of serum biomarkers (C-reactive protein or erythrocyte sedimentation rate) to identify patients at highest risk for colectomy and colon cancer based on inflammation. The authors also suggested that patients with refractory proctitis be enrolled in UC clinical trials or in studies focusing on refractory proctitis in particular.

The pelvic pouch has become the most often performed surgical procedure for patients undergoing colectomy, but there is no agreement on classification of inflammatory pelvic pouch disorders, and studies of etiology and treatment are lacking, the authors noted. They advised a clinical assessment based on symptoms, including stool frequency, urgency, and incontinence. They also suggested that afferent limb ulcers of erosions should be classified separately from pouch inflammation.

The authors ended by noting that extraintestinal manifestations (EIMs) that occur in up to half of IBD patients may or may not be directly related to intestinal disease, and may represent a different phenotype, and the presence and type of EIM should be included in a revised IBD classification system, they said.

The authors emphasized that continuing to refer to IBD as only CD and UC “does a great disservice to our attempts to better understand IBD pathogenesis and to improve clinical patient management.”

They concluded: “Although revised clinical classification tools alone will not be sufficient and should be complemented by deeper and more detailed study into molecular subclassification of disease, the considerations here could be used as a springboard toward improved trial design, future translational research approaches and better treatment outcomes for patients.”
 

Review reflects complexity of IBD and challenges of change

The review is important at this time because of the growing recognition that IBD, while traditionally categorized as either UC or CD, is most likely composed of a range of heterogeneous conditions involving inflammation of the gastrointestinal tract, Jatin Roper, MD, of Duke University in Durham, N.C., said in an interview.

“Evidence that our current classification of IBD is suboptimal comes from both the wide range of clinical phenotypes as well as complexity in genetic markers that are associated with IBD,” he said.  “It is well accepted in the gastroenterology community that IBD is a complex condition; so it is surprising to me that the dichotomy of UC vs. Crohn’s disease has rarely been challenged,” said Dr. Roper. “The authors of this review should be commended for raising the question of whether IBD deserves a more nuanced classification system that reflects the growing recognition of the wide heterogeneity of patient presentations and genetics,” he said.   

“Challenging medical definitions is inherently difficult because patient diagnoses, treatment plans, as well as decades of clinical research have been based on well-accepted disease categories. Another major challenge in reclassification is that the course of IBD can vary greatly over time in the same patient in severity, range, and complexity, and potentially includes many disease subtypes noted by the authors of this review,” he added. “Therefore, I believe that the current system of dividing IBD in UC and CD is here to stay until subtypes based on mechanisms of disease pathogenesis are discovered.

“Additional research is needed to understand the molecular basis of IBD,” Dr. Roper emphasized. “Recent advances in RNA expression and proteomics at the single cell level may reveal distinct cell types or cell functions in tissues from IBD patients that may help us understand clinical phenotype or response to therapy.”

The study received no outside funding. The authors disclosed financial relationships with AbbVie, Biogen, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, and Truvion. Dr. Roper had no financial conflicts to disclose.

Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD.

*Correction, 4/11/22: An earlier version of this article misstated the Montreal Classification. 

The current clinical classification tools for inflammatory bowel disease (IBD) are suboptimal, and revision beyond the broad categories of Crohn’s disease (CD) and ulcerative colitis (UC) could improve trial design, research, and ultimately patient outcomes, according to the authors of a recent review.

“Despite clear improvements in our understanding of disease biology and increasing treatment options, we still face an important therapeutic ceiling [in IBD],” wrote Bram Verstockt, MD, of University Hospitals Leuven, Belgium, and colleagues.

ChrisGorgio/Thinkstock

“In part, our limited therapeutic successes can be attributed to the disease heterogeneity of IBD: There is not one CD, nor a single UC phenotype,” therefore, a revision of the current systems based on better understanding of IBD is needed, the researchers said.

In a review article published in Gastroenterology, the researchers identified clinical features important to IBD heterogeneity, examined limitations of the current classifications, and proposed improvements.
 

Characterizing a complex condition

IBD diagnosis is challenging not only because of the overlapping phenotypes, but because other pathologies, including infections, can mimic IBD, the authors noted.

Age of onset should be considered in characterizing IBD, they wrote. Notably, patients with late-onset CD should be distinguished from elderly patients who have had CD for years. The authors cited research showing that “the development of IBD at extremes of age are specific sub-groups that require a different clinical recognition and clinical management,” and that large sample sizes and unbiased statistical methods are needed to define subgroups of IBD patients.

Current CD classification (the Montreal Classification) involves disease location, disease behavior, and age at diagnosis, and considers four phenotypes within disease location: involvement of the ileum, involvement of the colon, involvement of both the ileum and the colon, or isolated upper disease.* “Recently, there has been notable interest in the differential response rates among ileal predominant CD compared to colonic CD,” the authors wrote. Consequently, they proposed a revision of CD classification based on location. Genetic data appear to support this revision. In an IBD genotype-phenotype study including nearly 30,000 patients, three loci (NOD2, MHC, MST1 3p21) were strongly associated with disease location, they said. Other emerging evidence suggests that gut microbiota may vary according to disease location. The authors identified clinical aspects of CD classification based on disease location that distinguish small bowel predominant CD versus colonic predominant CD. Ileal disease patients have shown an increased risk for undergoing surgery, while those with colonic involvement have an increased risk for developing extraintestinal manifestations.

They also emphasized the value of considering rectal inflammation, which significantly impacts surgical procedures in CD.

Standard UC classification is based on macroscopic disease in the colon at the time of inflammation, the authors said. Although this approach allows for quick assessment of a patient’s risk of colectomy, the authors proposed improvements, including the use of serum biomarkers (C-reactive protein or erythrocyte sedimentation rate) to identify patients at highest risk for colectomy and colon cancer based on inflammation. The authors also suggested that patients with refractory proctitis be enrolled in UC clinical trials or in studies focusing on refractory proctitis in particular.

The pelvic pouch has become the most often performed surgical procedure for patients undergoing colectomy, but there is no agreement on classification of inflammatory pelvic pouch disorders, and studies of etiology and treatment are lacking, the authors noted. They advised a clinical assessment based on symptoms, including stool frequency, urgency, and incontinence. They also suggested that afferent limb ulcers of erosions should be classified separately from pouch inflammation.

The authors ended by noting that extraintestinal manifestations (EIMs) that occur in up to half of IBD patients may or may not be directly related to intestinal disease, and may represent a different phenotype, and the presence and type of EIM should be included in a revised IBD classification system, they said.

The authors emphasized that continuing to refer to IBD as only CD and UC “does a great disservice to our attempts to better understand IBD pathogenesis and to improve clinical patient management.”

They concluded: “Although revised clinical classification tools alone will not be sufficient and should be complemented by deeper and more detailed study into molecular subclassification of disease, the considerations here could be used as a springboard toward improved trial design, future translational research approaches and better treatment outcomes for patients.”
 

Review reflects complexity of IBD and challenges of change

The review is important at this time because of the growing recognition that IBD, while traditionally categorized as either UC or CD, is most likely composed of a range of heterogeneous conditions involving inflammation of the gastrointestinal tract, Jatin Roper, MD, of Duke University in Durham, N.C., said in an interview.

“Evidence that our current classification of IBD is suboptimal comes from both the wide range of clinical phenotypes as well as complexity in genetic markers that are associated with IBD,” he said.  “It is well accepted in the gastroenterology community that IBD is a complex condition; so it is surprising to me that the dichotomy of UC vs. Crohn’s disease has rarely been challenged,” said Dr. Roper. “The authors of this review should be commended for raising the question of whether IBD deserves a more nuanced classification system that reflects the growing recognition of the wide heterogeneity of patient presentations and genetics,” he said.   

“Challenging medical definitions is inherently difficult because patient diagnoses, treatment plans, as well as decades of clinical research have been based on well-accepted disease categories. Another major challenge in reclassification is that the course of IBD can vary greatly over time in the same patient in severity, range, and complexity, and potentially includes many disease subtypes noted by the authors of this review,” he added. “Therefore, I believe that the current system of dividing IBD in UC and CD is here to stay until subtypes based on mechanisms of disease pathogenesis are discovered.

“Additional research is needed to understand the molecular basis of IBD,” Dr. Roper emphasized. “Recent advances in RNA expression and proteomics at the single cell level may reveal distinct cell types or cell functions in tissues from IBD patients that may help us understand clinical phenotype or response to therapy.”

The study received no outside funding. The authors disclosed financial relationships with AbbVie, Biogen, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, and Truvion. Dr. Roper had no financial conflicts to disclose.

Help your patients better understand their IBD treatment options by sharing AGA’s patient education, “Living with IBD,” in the AGA GI Patient Center at www.gastro.org/IBD.

*Correction, 4/11/22: An earlier version of this article misstated the Montreal Classification. 

The current clinical classification tools for inflammatory bowel disease (IBD) are suboptimal, and revision beyond the broad categories of Crohn’s disease (CD) and ulcerative colitis (UC) could improve trial design, research, and ultimately patient outcomes, according to the authors of a recent review.

“Despite clear improvements in our understanding of disease biology and increasing treatment options, we still face an important therapeutic ceiling [in IBD],” wrote Bram Verstockt, MD, of University Hospitals Leuven, Belgium, and colleagues.

ChrisGorgio/Thinkstock

“In part, our limited therapeutic successes can be attributed to the disease heterogeneity of IBD: There is not one CD, nor a single UC phenotype,” therefore, a revision of the current systems based on better understanding of IBD is needed, the researchers said.

In a review article published in Gastroenterology, the researchers identified clinical features important to IBD heterogeneity, examined limitations of the current classifications, and proposed improvements.
 

Characterizing a complex condition

IBD diagnosis is challenging not only because of the overlapping phenotypes, but because other pathologies, including infections, can mimic IBD, the authors noted.

Age of onset should be considered in characterizing IBD, they wrote. Notably, patients with late-onset CD should be distinguished from elderly patients who have had CD for years. The authors cited research showing that “the development of IBD at extremes of age are specific sub-groups that require a different clinical recognition and clinical management,” and that large sample sizes and unbiased statistical methods are needed to define subgroups of IBD patients.

Current CD classification (the Montreal Classification) involves disease location, disease behavior, and age at diagnosis, and considers four phenotypes within disease location: involvement of the ileum, involvement of the colon, involvement of both the ileum and the colon, or isolated upper disease.* “Recently, there has been notable interest in the differential response rates among ileal predominant CD compared to colonic CD,” the authors wrote. Consequently, they proposed a revision of CD classification based on location. Genetic data appear to support this revision. In an IBD genotype-phenotype study including nearly 30,000 patients, three loci (NOD2, MHC, MST1 3p21) were strongly associated with disease location, they said. Other emerging evidence suggests that gut microbiota may vary according to disease location. The authors identified clinical aspects of CD classification based on disease location that distinguish small bowel predominant CD versus colonic predominant CD. Ileal disease patients have shown an increased risk for undergoing surgery, while those with colonic involvement have an increased risk for developing extraintestinal manifestations.

They also emphasized the value of considering rectal inflammation, which significantly impacts surgical procedures in CD.

Standard UC classification is based on macroscopic disease in the colon at the time of inflammation, the authors said. Although this approach allows for quick assessment of a patient’s risk of colectomy, the authors proposed improvements, including the use of serum biomarkers (C-reactive protein or erythrocyte sedimentation rate) to identify patients at highest risk for colectomy and colon cancer based on inflammation. The authors also suggested that patients with refractory proctitis be enrolled in UC clinical trials or in studies focusing on refractory proctitis in particular.

The pelvic pouch has become the most often performed surgical procedure for patients undergoing colectomy, but there is no agreement on classification of inflammatory pelvic pouch disorders, and studies of etiology and treatment are lacking, the authors noted. They advised a clinical assessment based on symptoms, including stool frequency, urgency, and incontinence. They also suggested that afferent limb ulcers of erosions should be classified separately from pouch inflammation.

The authors ended by noting that extraintestinal manifestations (EIMs) that occur in up to half of IBD patients may or may not be directly related to intestinal disease, and may represent a different phenotype, and the presence and type of EIM should be included in a revised IBD classification system, they said.

The authors emphasized that continuing to refer to IBD as only CD and UC “does a great disservice to our attempts to better understand IBD pathogenesis and to improve clinical patient management.”

They concluded: “Although revised clinical classification tools alone will not be sufficient and should be complemented by deeper and more detailed study into molecular subclassification of disease, the considerations here could be used as a springboard toward improved trial design, future translational research approaches and better treatment outcomes for patients.”

Review reflects complexity of IBD and challenges of change

The review is important at this time because of the growing recognition that IBD, while traditionally categorized as either UC or CD, is most likely composed of a range of heterogeneous conditions involving inflammation of the gastrointestinal tract, Jatin Roper, MD, of Duke University in Durham, N.C., said in an interview.

“Evidence that our current classification of IBD is suboptimal comes from both the wide range of clinical phenotypes as well as complexity in genetic markers that are associated with IBD,” he said.  “It is well accepted in the gastroenterology community that IBD is a complex condition; so it is surprising to me that the dichotomy of UC vs. Crohn’s disease has rarely been challenged,” said Dr. Roper. “The authors of this review should be commended for raising the question of whether IBD deserves a more nuanced classification system that reflects the growing recognition of the wide heterogeneity of patient presentations and genetics,” he said.   

“Challenging medical definitions is inherently difficult because patient diagnoses, treatment plans, as well as decades of clinical research have been based on well-accepted disease categories. Another major challenge in reclassification is that the course of IBD can vary greatly over time in the same patient in severity, range, and complexity, and potentially includes many disease subtypes noted by the authors of this review,” he added. “Therefore, I believe that the current system of dividing IBD in UC and CD is here to stay until subtypes based on mechanisms of disease pathogenesis are discovered.

“Additional research is needed to understand the molecular basis of IBD,” Dr. Roper emphasized. “Recent advances in RNA expression and proteomics at the single cell level may reveal distinct cell types or cell functions in tissues from IBD patients that may help us understand clinical phenotype or response to therapy.”

The study received no outside funding. The authors disclosed financial relationships with AbbVie, Biogen, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, and Truvion. Dr. Roper had no financial conflicts to disclose.

Correction, 4/13/22: An earlier version of this article misstated the Montreal Classification.

The current clinical classification tools for inflammatory bowel disease (IBD) are suboptimal, and revision beyond the broad categories of Crohn’s disease (CD) and ulcerative colitis (UC) could improve trial design, research, and ultimately patient outcomes, according to the authors of a recent review.

“Despite clear improvements in our understanding of disease biology and increasing treatment options, we still face an important therapeutic ceiling [in IBD],” wrote Bram Verstockt, MD, of University Hospitals Leuven, Belgium, and colleagues.

ChrisGorgio/Thinkstock

“In part, our limited therapeutic successes can be attributed to the disease heterogeneity of IBD: There is not one CD, nor a single UC phenotype,” therefore, a revision of the current systems based on better understanding of IBD is needed, the researchers said.

In a review article published in Gastroenterology, the researchers identified clinical features important to IBD heterogeneity, examined limitations of the current classifications, and proposed improvements.
 

Characterizing a complex condition

IBD diagnosis is challenging not only because of the overlapping phenotypes, but because other pathologies, including infections, can mimic IBD, the authors noted.

Age of onset should be considered in characterizing IBD, they wrote. Notably, patients with late-onset CD should be distinguished from elderly patients who have had CD for years. The authors cited research showing that “the development of IBD at extremes of age are specific sub-groups that require a different clinical recognition and clinical management,” and that large sample sizes and unbiased statistical methods are needed to define subgroups of IBD patients.

Current CD classification (the Montreal Classification) involves disease location, disease behavior, and age at diagnosis, and considers four phenotypes within disease location: involvement of the ileum, involvement of the colon, involvement of both the ileum and the colon, or isolated upper disease.* “Recently, there has been notable interest in the differential response rates among ileal predominant CD compared to colonic CD,” the authors wrote. Consequently, they proposed a revision of CD classification based on location. Genetic data appear to support this revision. In an IBD genotype-phenotype study including nearly 30,000 patients, three loci (NOD2, MHC, MST1 3p21) were strongly associated with disease location, they said. Other emerging evidence suggests that gut microbiota may vary according to disease location. The authors identified clinical aspects of CD classification based on disease location that distinguish small bowel predominant CD versus colonic predominant CD. Ileal disease patients have shown an increased risk for undergoing surgery, while those with colonic involvement have an increased risk for developing extraintestinal manifestations.

They also emphasized the value of considering rectal inflammation, which significantly impacts surgical procedures in CD.

Standard UC classification is based on macroscopic disease in the colon at the time of inflammation, the authors said. Although this approach allows for quick assessment of a patient’s risk of colectomy, the authors proposed improvements, including the use of serum biomarkers (C-reactive protein or erythrocyte sedimentation rate) to identify patients at highest risk for colectomy and colon cancer based on inflammation. The authors also suggested that patients with refractory proctitis be enrolled in UC clinical trials or in studies focusing on refractory proctitis in particular.

The pelvic pouch has become the most often performed surgical procedure for patients undergoing colectomy, but there is no agreement on classification of inflammatory pelvic pouch disorders, and studies of etiology and treatment are lacking, the authors noted. They advised a clinical assessment based on symptoms, including stool frequency, urgency, and incontinence. They also suggested that afferent limb ulcers of erosions should be classified separately from pouch inflammation.

The authors ended by noting that extraintestinal manifestations (EIMs) that occur in up to half of IBD patients may or may not be directly related to intestinal disease, and may represent a different phenotype, and the presence and type of EIM should be included in a revised IBD classification system, they said.

The authors emphasized that continuing to refer to IBD as only CD and UC “does a great disservice to our attempts to better understand IBD pathogenesis and to improve clinical patient management.”

They concluded: “Although revised clinical classification tools alone will not be sufficient and should be complemented by deeper and more detailed study into molecular subclassification of disease, the considerations here could be used as a springboard toward improved trial design, future translational research approaches and better treatment outcomes for patients.”

Review reflects complexity of IBD and challenges of change

The review is important at this time because of the growing recognition that IBD, while traditionally categorized as either UC or CD, is most likely composed of a range of heterogeneous conditions involving inflammation of the gastrointestinal tract, Jatin Roper, MD, of Duke University in Durham, N.C., said in an interview.

“Evidence that our current classification of IBD is suboptimal comes from both the wide range of clinical phenotypes as well as complexity in genetic markers that are associated with IBD,” he said.  “It is well accepted in the gastroenterology community that IBD is a complex condition; so it is surprising to me that the dichotomy of UC vs. Crohn’s disease has rarely been challenged,” said Dr. Roper. “The authors of this review should be commended for raising the question of whether IBD deserves a more nuanced classification system that reflects the growing recognition of the wide heterogeneity of patient presentations and genetics,” he said.   

“Challenging medical definitions is inherently difficult because patient diagnoses, treatment plans, as well as decades of clinical research have been based on well-accepted disease categories. Another major challenge in reclassification is that the course of IBD can vary greatly over time in the same patient in severity, range, and complexity, and potentially includes many disease subtypes noted by the authors of this review,” he added. “Therefore, I believe that the current system of dividing IBD in UC and CD is here to stay until subtypes based on mechanisms of disease pathogenesis are discovered.

“Additional research is needed to understand the molecular basis of IBD,” Dr. Roper emphasized. “Recent advances in RNA expression and proteomics at the single cell level may reveal distinct cell types or cell functions in tissues from IBD patients that may help us understand clinical phenotype or response to therapy.”

The study received no outside funding. The authors disclosed financial relationships with AbbVie, Biogen, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, and Truvion. Dr. Roper had no financial conflicts to disclose.

Correction, 4/13/22: An earlier version of this article misstated the Montreal Classification.

The current clinical classification tools for inflammatory bowel disease (IBD) are suboptimal, and revision beyond the broad categories of Crohn’s disease (CD) and ulcerative colitis (UC) could improve trial design, research, and ultimately patient outcomes, according to the authors of a recent review.

“Despite clear improvements in our understanding of disease biology and increasing treatment options, we still face an important therapeutic ceiling [in IBD],” wrote Bram Verstockt, MD, of University Hospitals Leuven, Belgium, and colleagues.

ChrisGorgio/Thinkstock

“In part, our limited therapeutic successes can be attributed to the disease heterogeneity of IBD: There is not one CD, nor a single UC phenotype,” therefore, a revision of the current systems based on better understanding of IBD is needed, the researchers said.

In a review article published in Gastroenterology, the researchers identified clinical features important to IBD heterogeneity, examined limitations of the current classifications, and proposed improvements.
 

Characterizing a complex condition

IBD diagnosis is challenging not only because of the overlapping phenotypes, but because other pathologies, including infections, can mimic IBD, the authors noted.

Age of onset should be considered in characterizing IBD, they wrote. Notably, patients with late-onset CD should be distinguished from elderly patients who have had CD for years. The authors cited research showing that “the development of IBD at extremes of age are specific sub-groups that require a different clinical recognition and clinical management,” and that large sample sizes and unbiased statistical methods are needed to define subgroups of IBD patients.

Current CD classification (the Montreal Classification) involves disease location, disease behavior, and age at diagnosis, and considers four phenotypes within disease location: involvement of the ileum, involvement of the colon, involvement of both the ileum and the colon, or isolated upper disease.* “Recently, there has been notable interest in the differential response rates among ileal predominant CD compared to colonic CD,” the authors wrote. Consequently, they proposed a revision of CD classification based on location. Genetic data appear to support this revision. In an IBD genotype-phenotype study including nearly 30,000 patients, three loci (NOD2, MHC, MST1 3p21) were strongly associated with disease location, they said. Other emerging evidence suggests that gut microbiota may vary according to disease location. The authors identified clinical aspects of CD classification based on disease location that distinguish small bowel predominant CD versus colonic predominant CD. Ileal disease patients have shown an increased risk for undergoing surgery, while those with colonic involvement have an increased risk for developing extraintestinal manifestations.

They also emphasized the value of considering rectal inflammation, which significantly impacts surgical procedures in CD.

Standard UC classification is based on macroscopic disease in the colon at the time of inflammation, the authors said. Although this approach allows for quick assessment of a patient’s risk of colectomy, the authors proposed improvements, including the use of serum biomarkers (C-reactive protein or erythrocyte sedimentation rate) to identify patients at highest risk for colectomy and colon cancer based on inflammation. The authors also suggested that patients with refractory proctitis be enrolled in UC clinical trials or in studies focusing on refractory proctitis in particular.

The pelvic pouch has become the most often performed surgical procedure for patients undergoing colectomy, but there is no agreement on classification of inflammatory pelvic pouch disorders, and studies of etiology and treatment are lacking, the authors noted. They advised a clinical assessment based on symptoms, including stool frequency, urgency, and incontinence. They also suggested that afferent limb ulcers of erosions should be classified separately from pouch inflammation.

The authors ended by noting that extraintestinal manifestations (EIMs) that occur in up to half of IBD patients may or may not be directly related to intestinal disease, and may represent a different phenotype, and the presence and type of EIM should be included in a revised IBD classification system, they said.

The authors emphasized that continuing to refer to IBD as only CD and UC “does a great disservice to our attempts to better understand IBD pathogenesis and to improve clinical patient management.”

They concluded: “Although revised clinical classification tools alone will not be sufficient and should be complemented by deeper and more detailed study into molecular subclassification of disease, the considerations here could be used as a springboard toward improved trial design, future translational research approaches and better treatment outcomes for patients.”

Review reflects complexity of IBD and challenges of change

The review is important at this time because of the growing recognition that IBD, while traditionally categorized as either UC or CD, is most likely composed of a range of heterogeneous conditions involving inflammation of the gastrointestinal tract, Jatin Roper, MD, of Duke University in Durham, N.C., said in an interview.

“Evidence that our current classification of IBD is suboptimal comes from both the wide range of clinical phenotypes as well as complexity in genetic markers that are associated with IBD,” he said.  “It is well accepted in the gastroenterology community that IBD is a complex condition; so it is surprising to me that the dichotomy of UC vs. Crohn’s disease has rarely been challenged,” said Dr. Roper. “The authors of this review should be commended for raising the question of whether IBD deserves a more nuanced classification system that reflects the growing recognition of the wide heterogeneity of patient presentations and genetics,” he said.   

“Challenging medical definitions is inherently difficult because patient diagnoses, treatment plans, as well as decades of clinical research have been based on well-accepted disease categories. Another major challenge in reclassification is that the course of IBD can vary greatly over time in the same patient in severity, range, and complexity, and potentially includes many disease subtypes noted by the authors of this review,” he added. “Therefore, I believe that the current system of dividing IBD in UC and CD is here to stay until subtypes based on mechanisms of disease pathogenesis are discovered.

“Additional research is needed to understand the molecular basis of IBD,” Dr. Roper emphasized. “Recent advances in RNA expression and proteomics at the single cell level may reveal distinct cell types or cell functions in tissues from IBD patients that may help us understand clinical phenotype or response to therapy.”

The study received no outside funding. The authors disclosed financial relationships with AbbVie, Biogen, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, and Truvion. Dr. Roper had no financial conflicts to disclose.

Correction, 4/13/22: An earlier version of this article misstated the Montreal Classification.

The U.S. Food and Drug Administration has approved rilpivirine and cabotegravir (Cabenuva) to 2-month dosing for adults living with HIV-1 infection.

Cabenuva was first approved by the FDA in January 2021 to be administered once monthly to treat HIV-1 infection in virologically suppressed adults. The medication was the first injectable complete antiretroviral regimen approved by the FDA.

Cabenuva can replace a current treatment in virologically suppressed adults on a stable antiretroviral regimen with no history of treatment failure and no known or suspected resistance to rilpivirine and cabotegravir, the Janssen Pharmaceutical Companies of Johnson & Johnson said in a press release. Janssen and ViiV Healthcare codeveloped the injectable antiretroviral medication Cabenuva.

The expanded label approval “marks an important step forward in advancing the treatment landscape for people living with HIV,” said Candice Long, the president of infectious diseases and vaccines at Janssen Therapeutics, in a Feb. 1 press release. “With this milestone, adults living with HIV have a treatment option that further reduces the frequency of medication.”

This expanded approval was based on global clinical trial of 1,045 adults with HIV-1, which found Cabenuva administered every 8 weeks (3 mL dose of both cabotegravir and rilpivirine) to be noninferior to the 4-week regimen (2 mL dose of both medicines). At week 48 of the trial, the proportion of participants with viral loads above 50 copies per milliliter was 1.7% in the 2-month arm and 1.0% in the 1-month arm. The study found that rates of virological suppression were similar for both the 1-month and 2-month regimens (93.5% and 94.3%, respectively).

The most common side effects were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash. Adverse reactions reported in individuals receiving the regimen every 2 months or once monthly were similar. Cabenuva is contraindicated for patients with a hypersensitivity reaction to cabotegravir or rilpivirine or for those receiving carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John’s wort, and more than one dose of systemic dexamethasone.

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

The U.S. Food and Drug Administration has approved rilpivirine and cabotegravir (Cabenuva) to 2-month dosing for adults living with HIV-1 infection.

Cabenuva was first approved by the FDA in January 2021 to be administered once monthly to treat HIV-1 infection in virologically suppressed adults. The medication was the first injectable complete antiretroviral regimen approved by the FDA.

Cabenuva can replace a current treatment in virologically suppressed adults on a stable antiretroviral regimen with no history of treatment failure and no known or suspected resistance to rilpivirine and cabotegravir, the Janssen Pharmaceutical Companies of Johnson & Johnson said in a press release. Janssen and ViiV Healthcare codeveloped the injectable antiretroviral medication Cabenuva.

The expanded label approval “marks an important step forward in advancing the treatment landscape for people living with HIV,” said Candice Long, the president of infectious diseases and vaccines at Janssen Therapeutics, in a Feb. 1 press release. “With this milestone, adults living with HIV have a treatment option that further reduces the frequency of medication.”

This expanded approval was based on global clinical trial of 1,045 adults with HIV-1, which found Cabenuva administered every 8 weeks (3 mL dose of both cabotegravir and rilpivirine) to be noninferior to the 4-week regimen (2 mL dose of both medicines). At week 48 of the trial, the proportion of participants with viral loads above 50 copies per milliliter was 1.7% in the 2-month arm and 1.0% in the 1-month arm. The study found that rates of virological suppression were similar for both the 1-month and 2-month regimens (93.5% and 94.3%, respectively).

The most common side effects were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash. Adverse reactions reported in individuals receiving the regimen every 2 months or once monthly were similar. Cabenuva is contraindicated for patients with a hypersensitivity reaction to cabotegravir or rilpivirine or for those receiving carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John’s wort, and more than one dose of systemic dexamethasone.

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

The U.S. Food and Drug Administration has approved rilpivirine and cabotegravir (Cabenuva) to 2-month dosing for adults living with HIV-1 infection.

Cabenuva was first approved by the FDA in January 2021 to be administered once monthly to treat HIV-1 infection in virologically suppressed adults. The medication was the first injectable complete antiretroviral regimen approved by the FDA.

Cabenuva can replace a current treatment in virologically suppressed adults on a stable antiretroviral regimen with no history of treatment failure and no known or suspected resistance to rilpivirine and cabotegravir, the Janssen Pharmaceutical Companies of Johnson & Johnson said in a press release. Janssen and ViiV Healthcare codeveloped the injectable antiretroviral medication Cabenuva.

The expanded label approval “marks an important step forward in advancing the treatment landscape for people living with HIV,” said Candice Long, the president of infectious diseases and vaccines at Janssen Therapeutics, in a Feb. 1 press release. “With this milestone, adults living with HIV have a treatment option that further reduces the frequency of medication.”

This expanded approval was based on global clinical trial of 1,045 adults with HIV-1, which found Cabenuva administered every 8 weeks (3 mL dose of both cabotegravir and rilpivirine) to be noninferior to the 4-week regimen (2 mL dose of both medicines). At week 48 of the trial, the proportion of participants with viral loads above 50 copies per milliliter was 1.7% in the 2-month arm and 1.0% in the 1-month arm. The study found that rates of virological suppression were similar for both the 1-month and 2-month regimens (93.5% and 94.3%, respectively).

The most common side effects were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash. Adverse reactions reported in individuals receiving the regimen every 2 months or once monthly were similar. Cabenuva is contraindicated for patients with a hypersensitivity reaction to cabotegravir or rilpivirine or for those receiving carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St. John’s wort, and more than one dose of systemic dexamethasone.

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

Psoriasis vulgaris is a chronic inflammatory skin condition associated with notable elevation in helper T cell (T_H) production of T_H1/T_H17-mediated inflammatory cytokines, including IL-17A.¹ Upon binding of IL-17A to IL-17 receptors in the skin, an inflammatory cascade is triggered, resulting in the classic clinical appearance of psoriasis. Moderate to severe psoriasis often is managed by suppressing T_H1/T_H17-mediated inflammation using targeted immune therapy such as secukinumab, an IL-17A inhibitor.² Atopic dermatitis (AD), another chronic inflammatory dermatosis, is associated with substantial elevation in T_H2-mediated inflammatory cytokines, such as IL-4.³ Dupilumab, which interacts with IL-4R, disrupts the IL-4 and IL-13 signaling pathways and demonstrates considerable efficacy in the treatment of moderate to severe AD.⁴

A case series has shown that suppression of the T_H1/T_H17-mediated inflammation of psoriasis may paradoxically result in the development of T_H2-mediated AD.⁵ Similarly, a recent case report described a patient who developed psoriasis following treatment of AD with dupilumab.⁶ Herein, we describe a patient with a history of psoriasis that was well controlled with secukinumab who developed severe refractory erythrodermic AD that resolved with dupilumab treatment. Following clearance of AD with dupilumab, he exhibited psoriasis recurrence.

Case Report

A 39-year-old man with a lifelong history of psoriasis was admitted to the hospital for management of severe erythroderma. Four years prior, secukinumab was initiated for treatment of psoriasis, resulting in excellent clinical response. He discontinued secukinumab after 2 years of treatment because of insurance coverage issues and managed his condition with only topical corticosteroids. He restarted secukinumab 10 months before admission because of a psoriasis flare. Shortly after resuming secukinumab, he developed a severe exfoliative erythroderma that was not responsive to corticosteroids, etanercept, methotrexate, or ustekinumab.

On initial presentation, physical examination revealed diffuse erythema and scaling with associated edema of the face, trunk, and extremities (Figure 1). A biopsy from the patient’s right arm demonstrated a superficial perivascular inflammatory infiltrate composed of lymphocytes, histiocytes, and scattered eosinophils consistent with spongiotic dermatitis (Figure 2). Cyclosporine 225 mg twice daily and topical corticosteroids were started.

Over the next several months, the patient had several admissions secondary to recurrent skin abscesses in the setting of refractory erythroderma. He underwent trials of infliximab, corticosteroids, intravenous immunoglobulin, guselkumab, and acitretin with minimal improvement. He underwent an extensive laboratory and radiologic workup, which was notable for cyclical peripheral eosinophilia and elevated IgE levels correlating with the erythroderma flares. A second biopsy was obtained and continued to demonstrate changes consistent with AD.

Four months after the initial hospitalization, all psoriasis medications were stopped, and the patient was started on dupilumab 300 mg/2 mL every 2 weeks and an 8-week oral prednisone taper. This combination led to notable clinical improvement and resolution of peripheral eosinophilia. Several months after disease remission, he began to develop worsening erythema and pruritus on the trunk and extremities, followed by the development of new psoriatic lesions (Figure 3) with a biopsy consistent with psoriasis (Figure 4). The patient was continued on dupilumab, but cyclosporine was added. The patient self-discontinued dupilumab owing to injection-site discomfort and has been slowly weaning off oral cyclosporine with 1 to 2 remaining eczematous plaques and 1 to 2 psoriatic plaques managed by topical corticosteroids.

Comment

We present a patient with psoriasis that was well controlled on secukinumab who developed severe AD following treatment with secukinumab. The AD resolved following treatment with dupilumab and a tapering dose of prednisone. However, after several months of treatment with dupilumab alone, he began to develop psoriatic lesions again. This case supports findings in a case series describing the development of AD in patients with psoriasis treated with IL-17 inhibitors⁵ and a recent case report describing a patient with AD who developed psoriasis following treatment with an IL-4/IL-13 inhibitor.⁶

Recognized adverse effects demonstrate biologic medications’ contributions to both normal as well as aberrant immunologic responses. For example, IL-17 plays an essential role in innate and adaptive immune responses against infections at mucosal and cutaneous interfaces, as demonstrated by chronic mucocutaneous candidiasis in patients with genetic defects in IL-17–related pathways.⁷ Similarly, in patients taking IL-17 antagonists, an increase in the incidence of Candida infections has been observed.⁸ In patients with concurrent psoriasis and inflammatory bowel disease (IBD), treatment with IL-17 inhibitors is contraindicated due to the risk of exacerbating the IBD. This observation is somewhat paradoxical, as increased IL-17 release by T_H17 cells is implicated in the pathogenesis of IBD.⁹ Interestingly, it is now thought that IL-17 may play a protective role in T-cell–driven intestinal inflammation through induction of protective intestinal epithelial gene expression and increased mucosal defense against gut microbes, explaining the worsening of IBD in patients on IL-17 inhibitors.¹⁰ These adverse effects illustrate the complicated and varied roles biologic medications play in immunologic response.

Given that T_H1 and T_H2 exert opposing immune mechanisms, it is uncommon for psoriasis and AD to coexist in a single patient. However, patients who exhibit concurrent findings may represent a unique population in which psoriasis and AD coexist, perhaps because of an underlying genetic predisposition. Moreover, targeted treatment of pathways unique to these disease processes may result in paradoxical flaring of the nontargeted pathway. It also is possible that inhibition of a specific T-cell pathway in a subset of patients will result in an immunologic imbalance, favoring increased activity of the opposing pathway in the absence of coexisting disease. In the case presented here, the findings may be explained by secukinumab’s inhibition of T_H1/T_H17-mediated inflammation, which resulted in a shift to a T_H2-mediated inflammatory response manifesting as AD, as well as dupilumab’s inhibition of T_H2-mediated inflammation, which caused a shift back to T_H1-mediated inflammatory pathways. Additionally, for patients with changing morphologies exacerbated by biologic medications, alternative diagnoses, such as cutaneous T-cell lymphoma, may be considered.

Conclusion

We report an unusual case of secukinumab-induced AD in a patient with psoriasis that resolved following several months of treatment with dupilumab and a tapering dose of prednisone. Subsequently, this same patient developed re-emergence of psoriatic lesions with continued use of dupilumab, which was eventually discontinued by the patient despite appropriate disease control. In addition to illustrating the underlying pathophysiologic mechanisms of 2 common inflammatory dermatologic conditions, this case highlights how pharmacologic interventions targeted at specific immunologic pathways may have unintended consequences. Further investigation into the effects of targeted biologics on the T_H1/T_H2 immune axis is warranted to better understand the mechanism and possible implications of the phenotypic switching presented in this case.

Psoriasis vulgaris is a chronic inflammatory skin condition associated with notable elevation in helper T cell (T_H) production of T_H1/T_H17-mediated inflammatory cytokines, including IL-17A.¹ Upon binding of IL-17A to IL-17 receptors in the skin, an inflammatory cascade is triggered, resulting in the classic clinical appearance of psoriasis. Moderate to severe psoriasis often is managed by suppressing T_H1/T_H17-mediated inflammation using targeted immune therapy such as secukinumab, an IL-17A inhibitor.² Atopic dermatitis (AD), another chronic inflammatory dermatosis, is associated with substantial elevation in T_H2-mediated inflammatory cytokines, such as IL-4.³ Dupilumab, which interacts with IL-4R, disrupts the IL-4 and IL-13 signaling pathways and demonstrates considerable efficacy in the treatment of moderate to severe AD.⁴

A case series has shown that suppression of the T_H1/T_H17-mediated inflammation of psoriasis may paradoxically result in the development of T_H2-mediated AD.⁵ Similarly, a recent case report described a patient who developed psoriasis following treatment of AD with dupilumab.⁶ Herein, we describe a patient with a history of psoriasis that was well controlled with secukinumab who developed severe refractory erythrodermic AD that resolved with dupilumab treatment. Following clearance of AD with dupilumab, he exhibited psoriasis recurrence.

Case Report

A 39-year-old man with a lifelong history of psoriasis was admitted to the hospital for management of severe erythroderma. Four years prior, secukinumab was initiated for treatment of psoriasis, resulting in excellent clinical response. He discontinued secukinumab after 2 years of treatment because of insurance coverage issues and managed his condition with only topical corticosteroids. He restarted secukinumab 10 months before admission because of a psoriasis flare. Shortly after resuming secukinumab, he developed a severe exfoliative erythroderma that was not responsive to corticosteroids, etanercept, methotrexate, or ustekinumab.

On initial presentation, physical examination revealed diffuse erythema and scaling with associated edema of the face, trunk, and extremities (Figure 1). A biopsy from the patient’s right arm demonstrated a superficial perivascular inflammatory infiltrate composed of lymphocytes, histiocytes, and scattered eosinophils consistent with spongiotic dermatitis (Figure 2). Cyclosporine 225 mg twice daily and topical corticosteroids were started.

Over the next several months, the patient had several admissions secondary to recurrent skin abscesses in the setting of refractory erythroderma. He underwent trials of infliximab, corticosteroids, intravenous immunoglobulin, guselkumab, and acitretin with minimal improvement. He underwent an extensive laboratory and radiologic workup, which was notable for cyclical peripheral eosinophilia and elevated IgE levels correlating with the erythroderma flares. A second biopsy was obtained and continued to demonstrate changes consistent with AD.

Four months after the initial hospitalization, all psoriasis medications were stopped, and the patient was started on dupilumab 300 mg/2 mL every 2 weeks and an 8-week oral prednisone taper. This combination led to notable clinical improvement and resolution of peripheral eosinophilia. Several months after disease remission, he began to develop worsening erythema and pruritus on the trunk and extremities, followed by the development of new psoriatic lesions (Figure 3) with a biopsy consistent with psoriasis (Figure 4). The patient was continued on dupilumab, but cyclosporine was added. The patient self-discontinued dupilumab owing to injection-site discomfort and has been slowly weaning off oral cyclosporine with 1 to 2 remaining eczematous plaques and 1 to 2 psoriatic plaques managed by topical corticosteroids.

Comment

We present a patient with psoriasis that was well controlled on secukinumab who developed severe AD following treatment with secukinumab. The AD resolved following treatment with dupilumab and a tapering dose of prednisone. However, after several months of treatment with dupilumab alone, he began to develop psoriatic lesions again. This case supports findings in a case series describing the development of AD in patients with psoriasis treated with IL-17 inhibitors⁵ and a recent case report describing a patient with AD who developed psoriasis following treatment with an IL-4/IL-13 inhibitor.⁶

Recognized adverse effects demonstrate biologic medications’ contributions to both normal as well as aberrant immunologic responses. For example, IL-17 plays an essential role in innate and adaptive immune responses against infections at mucosal and cutaneous interfaces, as demonstrated by chronic mucocutaneous candidiasis in patients with genetic defects in IL-17–related pathways.⁷ Similarly, in patients taking IL-17 antagonists, an increase in the incidence of Candida infections has been observed.⁸ In patients with concurrent psoriasis and inflammatory bowel disease (IBD), treatment with IL-17 inhibitors is contraindicated due to the risk of exacerbating the IBD. This observation is somewhat paradoxical, as increased IL-17 release by T_H17 cells is implicated in the pathogenesis of IBD.⁹ Interestingly, it is now thought that IL-17 may play a protective role in T-cell–driven intestinal inflammation through induction of protective intestinal epithelial gene expression and increased mucosal defense against gut microbes, explaining the worsening of IBD in patients on IL-17 inhibitors.¹⁰ These adverse effects illustrate the complicated and varied roles biologic medications play in immunologic response.

Given that T_H1 and T_H2 exert opposing immune mechanisms, it is uncommon for psoriasis and AD to coexist in a single patient. However, patients who exhibit concurrent findings may represent a unique population in which psoriasis and AD coexist, perhaps because of an underlying genetic predisposition. Moreover, targeted treatment of pathways unique to these disease processes may result in paradoxical flaring of the nontargeted pathway. It also is possible that inhibition of a specific T-cell pathway in a subset of patients will result in an immunologic imbalance, favoring increased activity of the opposing pathway in the absence of coexisting disease. In the case presented here, the findings may be explained by secukinumab’s inhibition of T_H1/T_H17-mediated inflammation, which resulted in a shift to a T_H2-mediated inflammatory response manifesting as AD, as well as dupilumab’s inhibition of T_H2-mediated inflammation, which caused a shift back to T_H1-mediated inflammatory pathways. Additionally, for patients with changing morphologies exacerbated by biologic medications, alternative diagnoses, such as cutaneous T-cell lymphoma, may be considered.

Conclusion

We report an unusual case of secukinumab-induced AD in a patient with psoriasis that resolved following several months of treatment with dupilumab and a tapering dose of prednisone. Subsequently, this same patient developed re-emergence of psoriatic lesions with continued use of dupilumab, which was eventually discontinued by the patient despite appropriate disease control. In addition to illustrating the underlying pathophysiologic mechanisms of 2 common inflammatory dermatologic conditions, this case highlights how pharmacologic interventions targeted at specific immunologic pathways may have unintended consequences. Further investigation into the effects of targeted biologics on the T_H1/T_H2 immune axis is warranted to better understand the mechanism and possible implications of the phenotypic switching presented in this case.

Psoriasis vulgaris is a chronic inflammatory skin condition associated with notable elevation in helper T cell (T_H) production of T_H1/T_H17-mediated inflammatory cytokines, including IL-17A.¹ Upon binding of IL-17A to IL-17 receptors in the skin, an inflammatory cascade is triggered, resulting in the classic clinical appearance of psoriasis. Moderate to severe psoriasis often is managed by suppressing T_H1/T_H17-mediated inflammation using targeted immune therapy such as secukinumab, an IL-17A inhibitor.² Atopic dermatitis (AD), another chronic inflammatory dermatosis, is associated with substantial elevation in T_H2-mediated inflammatory cytokines, such as IL-4.³ Dupilumab, which interacts with IL-4R, disrupts the IL-4 and IL-13 signaling pathways and demonstrates considerable efficacy in the treatment of moderate to severe AD.⁴

A case series has shown that suppression of the T_H1/T_H17-mediated inflammation of psoriasis may paradoxically result in the development of T_H2-mediated AD.⁵ Similarly, a recent case report described a patient who developed psoriasis following treatment of AD with dupilumab.⁶ Herein, we describe a patient with a history of psoriasis that was well controlled with secukinumab who developed severe refractory erythrodermic AD that resolved with dupilumab treatment. Following clearance of AD with dupilumab, he exhibited psoriasis recurrence.

Case Report

A 39-year-old man with a lifelong history of psoriasis was admitted to the hospital for management of severe erythroderma. Four years prior, secukinumab was initiated for treatment of psoriasis, resulting in excellent clinical response. He discontinued secukinumab after 2 years of treatment because of insurance coverage issues and managed his condition with only topical corticosteroids. He restarted secukinumab 10 months before admission because of a psoriasis flare. Shortly after resuming secukinumab, he developed a severe exfoliative erythroderma that was not responsive to corticosteroids, etanercept, methotrexate, or ustekinumab.

On initial presentation, physical examination revealed diffuse erythema and scaling with associated edema of the face, trunk, and extremities (Figure 1). A biopsy from the patient’s right arm demonstrated a superficial perivascular inflammatory infiltrate composed of lymphocytes, histiocytes, and scattered eosinophils consistent with spongiotic dermatitis (Figure 2). Cyclosporine 225 mg twice daily and topical corticosteroids were started.

Over the next several months, the patient had several admissions secondary to recurrent skin abscesses in the setting of refractory erythroderma. He underwent trials of infliximab, corticosteroids, intravenous immunoglobulin, guselkumab, and acitretin with minimal improvement. He underwent an extensive laboratory and radiologic workup, which was notable for cyclical peripheral eosinophilia and elevated IgE levels correlating with the erythroderma flares. A second biopsy was obtained and continued to demonstrate changes consistent with AD.

Four months after the initial hospitalization, all psoriasis medications were stopped, and the patient was started on dupilumab 300 mg/2 mL every 2 weeks and an 8-week oral prednisone taper. This combination led to notable clinical improvement and resolution of peripheral eosinophilia. Several months after disease remission, he began to develop worsening erythema and pruritus on the trunk and extremities, followed by the development of new psoriatic lesions (Figure 3) with a biopsy consistent with psoriasis (Figure 4). The patient was continued on dupilumab, but cyclosporine was added. The patient self-discontinued dupilumab owing to injection-site discomfort and has been slowly weaning off oral cyclosporine with 1 to 2 remaining eczematous plaques and 1 to 2 psoriatic plaques managed by topical corticosteroids.

Comment

We present a patient with psoriasis that was well controlled on secukinumab who developed severe AD following treatment with secukinumab. The AD resolved following treatment with dupilumab and a tapering dose of prednisone. However, after several months of treatment with dupilumab alone, he began to develop psoriatic lesions again. This case supports findings in a case series describing the development of AD in patients with psoriasis treated with IL-17 inhibitors⁵ and a recent case report describing a patient with AD who developed psoriasis following treatment with an IL-4/IL-13 inhibitor.⁶

Recognized adverse effects demonstrate biologic medications’ contributions to both normal as well as aberrant immunologic responses. For example, IL-17 plays an essential role in innate and adaptive immune responses against infections at mucosal and cutaneous interfaces, as demonstrated by chronic mucocutaneous candidiasis in patients with genetic defects in IL-17–related pathways.⁷ Similarly, in patients taking IL-17 antagonists, an increase in the incidence of Candida infections has been observed.⁸ In patients with concurrent psoriasis and inflammatory bowel disease (IBD), treatment with IL-17 inhibitors is contraindicated due to the risk of exacerbating the IBD. This observation is somewhat paradoxical, as increased IL-17 release by T_H17 cells is implicated in the pathogenesis of IBD.⁹ Interestingly, it is now thought that IL-17 may play a protective role in T-cell–driven intestinal inflammation through induction of protective intestinal epithelial gene expression and increased mucosal defense against gut microbes, explaining the worsening of IBD in patients on IL-17 inhibitors.¹⁰ These adverse effects illustrate the complicated and varied roles biologic medications play in immunologic response.

Given that T_H1 and T_H2 exert opposing immune mechanisms, it is uncommon for psoriasis and AD to coexist in a single patient. However, patients who exhibit concurrent findings may represent a unique population in which psoriasis and AD coexist, perhaps because of an underlying genetic predisposition. Moreover, targeted treatment of pathways unique to these disease processes may result in paradoxical flaring of the nontargeted pathway. It also is possible that inhibition of a specific T-cell pathway in a subset of patients will result in an immunologic imbalance, favoring increased activity of the opposing pathway in the absence of coexisting disease. In the case presented here, the findings may be explained by secukinumab’s inhibition of T_H1/T_H17-mediated inflammation, which resulted in a shift to a T_H2-mediated inflammatory response manifesting as AD, as well as dupilumab’s inhibition of T_H2-mediated inflammation, which caused a shift back to T_H1-mediated inflammatory pathways. Additionally, for patients with changing morphologies exacerbated by biologic medications, alternative diagnoses, such as cutaneous T-cell lymphoma, may be considered.

Conclusion

We report an unusual case of secukinumab-induced AD in a patient with psoriasis that resolved following several months of treatment with dupilumab and a tapering dose of prednisone. Subsequently, this same patient developed re-emergence of psoriatic lesions with continued use of dupilumab, which was eventually discontinued by the patient despite appropriate disease control. In addition to illustrating the underlying pathophysiologic mechanisms of 2 common inflammatory dermatologic conditions, this case highlights how pharmacologic interventions targeted at specific immunologic pathways may have unintended consequences. Further investigation into the effects of targeted biologics on the T_H1/T_H2 immune axis is warranted to better understand the mechanism and possible implications of the phenotypic switching presented in this case.

Total knee replacement (TKR) is one of the most common surgeries worldwide, with > 1 million performed last year. Many patients have seen tremendous benefit from TKR; however, studies have shown that up to 20% of patients are not satisfied with the results of this procedure.^1,2 This equates to about 200,000 patients worldwide every year who are dissatisfied. This is a huge concern to patients, surgeons, implant manufacturers, hospitals, and health care payers.

Many attempts to improve satisfaction in TKR have been tried, including computer navigation, minimally invasive surgery, rotating platform prostheses, gender-specific implants, different materials, changes in pain management, and revised postoperative rehabilitation.^3-7 However, these efforts show no significant improvement in satisfaction.

The most common method of TKR today involves using a long rod placed through a drill hole in the femur. Standardized cuts on the femur and tibia are made through metal cutting blocks. Only metal mechanical instruments are used to perform the surgery, and all patients are aligned the same. However, anatomic studies have shown that patient anatomy in 3 dimensions (3D) varies widely from patient to patient.⁸ Our current technique seems far removed from modern engineering, where we now see extensive use of artificial intelligence (AI) to improve outcomes.

Machine learning (ML) is considered a subset of AI that involves the use of various computer algorithms. ML allows the computer to learn and continually improve analysis of data. Large sets of inputs and outputs are used to train the machine to make autonomous recommendations or decisions.^9,10

Seven years ago, our team at the Phoenix Veteran Affairs Medical Center in Arizona published a randomized controlled trial evaluating a new, individualized alignment technique for TKR.¹¹ This method used 3D-printed guides made from an MRI of an individual patient’s knee. Instead of aligning all knee replacements the same, each patient was aligned according to their unique anatomy. Compared with the conventional alignment technique, the newer technique showed significant improvement in all outcome scores and range of motion at 2 years postsurgery. There has been a great deal of interest in individualizing TKR, and many articles and techniques have followed.¹²

Our surgical technique has evolved since publishing our trial. Currently, knee X-rays are digitally templated for each patient. Understanding the patient’s preoperative alignment can then assist in planning a TKR in 3D. A plastic 3D-printed guide is manufactured in Belgium, shipped to the US, sterilized, and used in surgery. These guides fit accurately on the patient’s anatomy and allow precise angles and depth of resection for each surgical bone cut. Our research has shown that these guides are accurate to within 0.5° and 0.5 mm for the bone cuts performed in surgery. After surgery, we track patient-reported outcomes (PROs), which can then be used in ML or logistic regression analysis to determine alignment factors that contribute to the best outcome.¹³

Soon, use of a robot will take the place of the templating and preplanning, allowing the 3D plan to be immediately produced in surgery by the software installed in the robot.^14-16 Each patient’s preoperative alignment can then be immediately compared with the postoperative result, and smartphone technology can allow a patient to input their PRO after the surgery is healed.¹⁷

Collecting all this information in a large database can allow ML analyses of the outcomes and individual alignment.^14-17 As the factors contributing to the best clinical results are determined, the computer can be programmed to learn how to make the best recommendations for alignment of each patient, which can be incorporated into the robotic platform for each surgery. Also pre- and postoperative factors can be added to the ML platform so we can identify the best preoperative patient parameters, anticoagulation program postoperative rehabilitation program, etc, to help drive higher PROs and satisfaction.

Multiple surgical robots for TKR are now on the market. Orthopedic literature includes ML algorithms to improve outcomes after total hip arthroplasty.¹⁸ The EHR can be used to develop models to predict poor outcomes after TKR. Integrating these models into clinical decision support could improve patient selection, education, and satisfaction.¹⁹ AI for adult spinal surgery using predictive analytics can help surgeons better inform patients about outcomes after corrective surgery.^20,21

With worldwide TKRs expected to exceed 3 million over the next decade, ML using large databases, robotic surgery, and PROs could be key to improving our TKR outcomes.²² This form of AI may reduce the large number of patients currently not satisfied with their knee replacement.

Total knee replacement (TKR) is one of the most common surgeries worldwide, with > 1 million performed last year. Many patients have seen tremendous benefit from TKR; however, studies have shown that up to 20% of patients are not satisfied with the results of this procedure.^1,2 This equates to about 200,000 patients worldwide every year who are dissatisfied. This is a huge concern to patients, surgeons, implant manufacturers, hospitals, and health care payers.

Many attempts to improve satisfaction in TKR have been tried, including computer navigation, minimally invasive surgery, rotating platform prostheses, gender-specific implants, different materials, changes in pain management, and revised postoperative rehabilitation.^3-7 However, these efforts show no significant improvement in satisfaction.

The most common method of TKR today involves using a long rod placed through a drill hole in the femur. Standardized cuts on the femur and tibia are made through metal cutting blocks. Only metal mechanical instruments are used to perform the surgery, and all patients are aligned the same. However, anatomic studies have shown that patient anatomy in 3 dimensions (3D) varies widely from patient to patient.⁸ Our current technique seems far removed from modern engineering, where we now see extensive use of artificial intelligence (AI) to improve outcomes.

Machine learning (ML) is considered a subset of AI that involves the use of various computer algorithms. ML allows the computer to learn and continually improve analysis of data. Large sets of inputs and outputs are used to train the machine to make autonomous recommendations or decisions.^9,10

Seven years ago, our team at the Phoenix Veteran Affairs Medical Center in Arizona published a randomized controlled trial evaluating a new, individualized alignment technique for TKR.¹¹ This method used 3D-printed guides made from an MRI of an individual patient’s knee. Instead of aligning all knee replacements the same, each patient was aligned according to their unique anatomy. Compared with the conventional alignment technique, the newer technique showed significant improvement in all outcome scores and range of motion at 2 years postsurgery. There has been a great deal of interest in individualizing TKR, and many articles and techniques have followed.¹²

Our surgical technique has evolved since publishing our trial. Currently, knee X-rays are digitally templated for each patient. Understanding the patient’s preoperative alignment can then assist in planning a TKR in 3D. A plastic 3D-printed guide is manufactured in Belgium, shipped to the US, sterilized, and used in surgery. These guides fit accurately on the patient’s anatomy and allow precise angles and depth of resection for each surgical bone cut. Our research has shown that these guides are accurate to within 0.5° and 0.5 mm for the bone cuts performed in surgery. After surgery, we track patient-reported outcomes (PROs), which can then be used in ML or logistic regression analysis to determine alignment factors that contribute to the best outcome.¹³

Soon, use of a robot will take the place of the templating and preplanning, allowing the 3D plan to be immediately produced in surgery by the software installed in the robot.^14-16 Each patient’s preoperative alignment can then be immediately compared with the postoperative result, and smartphone technology can allow a patient to input their PRO after the surgery is healed.¹⁷

Collecting all this information in a large database can allow ML analyses of the outcomes and individual alignment.^14-17 As the factors contributing to the best clinical results are determined, the computer can be programmed to learn how to make the best recommendations for alignment of each patient, which can be incorporated into the robotic platform for each surgery. Also pre- and postoperative factors can be added to the ML platform so we can identify the best preoperative patient parameters, anticoagulation program postoperative rehabilitation program, etc, to help drive higher PROs and satisfaction.

Multiple surgical robots for TKR are now on the market. Orthopedic literature includes ML algorithms to improve outcomes after total hip arthroplasty.¹⁸ The EHR can be used to develop models to predict poor outcomes after TKR. Integrating these models into clinical decision support could improve patient selection, education, and satisfaction.¹⁹ AI for adult spinal surgery using predictive analytics can help surgeons better inform patients about outcomes after corrective surgery.^20,21

With worldwide TKRs expected to exceed 3 million over the next decade, ML using large databases, robotic surgery, and PROs could be key to improving our TKR outcomes.²² This form of AI may reduce the large number of patients currently not satisfied with their knee replacement.

Total knee replacement (TKR) is one of the most common surgeries worldwide, with > 1 million performed last year. Many patients have seen tremendous benefit from TKR; however, studies have shown that up to 20% of patients are not satisfied with the results of this procedure.^1,2 This equates to about 200,000 patients worldwide every year who are dissatisfied. This is a huge concern to patients, surgeons, implant manufacturers, hospitals, and health care payers.

Many attempts to improve satisfaction in TKR have been tried, including computer navigation, minimally invasive surgery, rotating platform prostheses, gender-specific implants, different materials, changes in pain management, and revised postoperative rehabilitation.^3-7 However, these efforts show no significant improvement in satisfaction.

The most common method of TKR today involves using a long rod placed through a drill hole in the femur. Standardized cuts on the femur and tibia are made through metal cutting blocks. Only metal mechanical instruments are used to perform the surgery, and all patients are aligned the same. However, anatomic studies have shown that patient anatomy in 3 dimensions (3D) varies widely from patient to patient.⁸ Our current technique seems far removed from modern engineering, where we now see extensive use of artificial intelligence (AI) to improve outcomes.

Machine learning (ML) is considered a subset of AI that involves the use of various computer algorithms. ML allows the computer to learn and continually improve analysis of data. Large sets of inputs and outputs are used to train the machine to make autonomous recommendations or decisions.^9,10

Seven years ago, our team at the Phoenix Veteran Affairs Medical Center in Arizona published a randomized controlled trial evaluating a new, individualized alignment technique for TKR.¹¹ This method used 3D-printed guides made from an MRI of an individual patient’s knee. Instead of aligning all knee replacements the same, each patient was aligned according to their unique anatomy. Compared with the conventional alignment technique, the newer technique showed significant improvement in all outcome scores and range of motion at 2 years postsurgery. There has been a great deal of interest in individualizing TKR, and many articles and techniques have followed.¹²

Our surgical technique has evolved since publishing our trial. Currently, knee X-rays are digitally templated for each patient. Understanding the patient’s preoperative alignment can then assist in planning a TKR in 3D. A plastic 3D-printed guide is manufactured in Belgium, shipped to the US, sterilized, and used in surgery. These guides fit accurately on the patient’s anatomy and allow precise angles and depth of resection for each surgical bone cut. Our research has shown that these guides are accurate to within 0.5° and 0.5 mm for the bone cuts performed in surgery. After surgery, we track patient-reported outcomes (PROs), which can then be used in ML or logistic regression analysis to determine alignment factors that contribute to the best outcome.¹³

Soon, use of a robot will take the place of the templating and preplanning, allowing the 3D plan to be immediately produced in surgery by the software installed in the robot.^14-16 Each patient’s preoperative alignment can then be immediately compared with the postoperative result, and smartphone technology can allow a patient to input their PRO after the surgery is healed.¹⁷

Collecting all this information in a large database can allow ML analyses of the outcomes and individual alignment.^14-17 As the factors contributing to the best clinical results are determined, the computer can be programmed to learn how to make the best recommendations for alignment of each patient, which can be incorporated into the robotic platform for each surgery. Also pre- and postoperative factors can be added to the ML platform so we can identify the best preoperative patient parameters, anticoagulation program postoperative rehabilitation program, etc, to help drive higher PROs and satisfaction.

Multiple surgical robots for TKR are now on the market. Orthopedic literature includes ML algorithms to improve outcomes after total hip arthroplasty.¹⁸ The EHR can be used to develop models to predict poor outcomes after TKR. Integrating these models into clinical decision support could improve patient selection, education, and satisfaction.¹⁹ AI for adult spinal surgery using predictive analytics can help surgeons better inform patients about outcomes after corrective surgery.^20,21

With worldwide TKRs expected to exceed 3 million over the next decade, ML using large databases, robotic surgery, and PROs could be key to improving our TKR outcomes.²² This form of AI may reduce the large number of patients currently not satisfied with their knee replacement.

Cutis Reviewers, JANUARY TO DECEMBER 2021

Jennifer L. Adams, MD

Brandon Adler, MD

Iris Ahronowitz, MD

Abdullah Aleisa, MD

Justin Bandino, MD

Robert Baran, MD

Naiara S. Barbosa, MD

Kristina R. Burke, MD

Craig Burkhart, MD

Jeffrey P. Callen, MD

Charles Camisa, MD

Ashley B. Crew, MD

Zoe Diana Draelos, MD

Joseph S. Eastern, MD

Nada Elbuluk, MD, MSc

Joseph C. English III, MD

Tammie C. Ferringer, MD

Bahar F. Firoz, MD, MPH

John R. Griffin, MD

Kristi Hawley, DO

Thomas N. Helm, MD

Stephen Ellsworth Helms, MD

Brian P. Hibler, MD

Ranella J. Hirsch, MD

Jenny Hu, MD, MPH

Erick Jacobson-Dunlop, MD

William D. James, MD

Camilla K. Janniger, MD

Ronald Belle Johnston Jr, MD

Theodora Karagounis, MD

Michael Kasperkiewicz, MD

Brett H. Keeling, MD

Chesahna Kindred, MD, MBA

Christina Nicole Kraus, MD

Eun Ji Kwon, MD

Eden Lake, MD

Nicholas Logemann, DO

Michele S. Maroon, MD

Cathy Massoud, MD

Elizabeth I. McBurney, MD

Lynn J. McKinley-Grant, MD

Amy J. McMichael, MD

Darius R. Mehregan, MD

Jon Hamilton Meyerle, MD

Robert Micheletti, MD

Binh Ngo, MD

Anh Nguyen, MD

Josephine Nguyen, MD, MHCDS

Joe Niamtu III, DMD

Rajiv I. Nijhawan, MD

Michael A. Nowak, MD

Maria T. Ochoa, MD

Chika Ohata, MD

Lawrence C. Parish, MD

Marion Apter Quinn, MD

Phoebe Rich, MD

Maureen Riegert, MD

Bethany Rohr, MD

Lorraine L. Rosamilia, MD

Ted Rosen, MD

Robert I. Rudolph, MD

Elizabeth K. Satter, MD, MPH

Robert A. Schwartz, MD, MPH

Michael J. Scott III, DO, MD, MPH

Jane Scribner, MD

Bridget E. Shields, MD

Daniel Mark Siegel, MD, MS

Nanette B. Silverberg, MD

Steven Brett Sloan, MD

Leonard Sperling, MD

Stephen P. Stone, MD

Brian L. Swick, MD

Susan C. Taylor, MD

Manuel Valdebran, MD

Richard F. Wagner Jr, MD

Emily Wong, MD

Julie Woodward, MD

Scott Worswick, MD

Julia Wu, MD

If you are interested in serving as a reviewer, please email the Editorial Office at cutis@mdedge.com.

Cutis Reviewers, JANUARY TO DECEMBER 2021

Jennifer L. Adams, MD

Brandon Adler, MD

Iris Ahronowitz, MD

Abdullah Aleisa, MD

Justin Bandino, MD

Robert Baran, MD

Naiara S. Barbosa, MD

Kristina R. Burke, MD

Craig Burkhart, MD

Jeffrey P. Callen, MD

Charles Camisa, MD

Ashley B. Crew, MD

Zoe Diana Draelos, MD

Joseph S. Eastern, MD

Nada Elbuluk, MD, MSc

Joseph C. English III, MD

Tammie C. Ferringer, MD

Bahar F. Firoz, MD, MPH

John R. Griffin, MD

Kristi Hawley, DO

Thomas N. Helm, MD

Stephen Ellsworth Helms, MD

Brian P. Hibler, MD

Ranella J. Hirsch, MD

Jenny Hu, MD, MPH

Erick Jacobson-Dunlop, MD

William D. James, MD

Camilla K. Janniger, MD

Ronald Belle Johnston Jr, MD

Theodora Karagounis, MD

Michael Kasperkiewicz, MD

Brett H. Keeling, MD

Chesahna Kindred, MD, MBA

Christina Nicole Kraus, MD

Eun Ji Kwon, MD

Eden Lake, MD

Nicholas Logemann, DO

Michele S. Maroon, MD

Cathy Massoud, MD

Elizabeth I. McBurney, MD

Lynn J. McKinley-Grant, MD

Amy J. McMichael, MD

Darius R. Mehregan, MD

Jon Hamilton Meyerle, MD

Robert Micheletti, MD

Binh Ngo, MD

Anh Nguyen, MD

Josephine Nguyen, MD, MHCDS

Joe Niamtu III, DMD

Rajiv I. Nijhawan, MD

Michael A. Nowak, MD

Maria T. Ochoa, MD

Chika Ohata, MD

Lawrence C. Parish, MD

Marion Apter Quinn, MD

Phoebe Rich, MD

Maureen Riegert, MD

Bethany Rohr, MD

Lorraine L. Rosamilia, MD

Ted Rosen, MD

Robert I. Rudolph, MD

Elizabeth K. Satter, MD, MPH

Robert A. Schwartz, MD, MPH

Michael J. Scott III, DO, MD, MPH

Jane Scribner, MD

Bridget E. Shields, MD

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If you are interested in serving as a reviewer, please email the Editorial Office at cutis@mdedge.com.

Dietary intake of polyunsaturated fatty acids (PUFA), particularly omega 6, is associated with improved cognitive function in older adults, new research suggests.

The study provides important “pieces of the puzzle” of the diet and cognition connection, but the results aren’t “ready for prime time,” study investigator Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, said in an interview.

“I don’t think we’re there yet when it comes to recommending supplementation to the general public,” said Dr. McIntyre, adding a larger “more compelling study” is needed.

The study was published online Jan. 14 in The American Journal of Geriatric Psychiatry.
 

Clinically meaningful?

Research shows that 25%-50% of community-dwelling adults aged 65-85 years have some cognitive impairment. Other evidence indicates cognition is affected by dietary fat intake.

Many lines of research show that alterations in lipid homeostasis can cause brain dysfunction, said Dr. McIntyre. “This shouldn’t surprise us because our brain is made up of protein, water, and fat.”

This new analysis used combined data from the 2011-2012 and 2013-2014 cycles of the National Health and Nutrition Examination Survey (NHANES), a series of ongoing cross-sectional surveys conducted by the Centers for Disease Control and Prevention. The data are collected in two phases, an in-home face-to-face interview and a physical examination.

Researchers obtained dietary intake information through two 24-hour dietary recall interviews. Dietary information included total energy (kcal/d), intakes in grams per day (g/d) of total fat, saturated fatty acid (SFAT), monounsaturated fatty acid (MUFA), PUFA, total omega-3 and total omega-6 fatty acids, and milligrams per day (mg/d) of cholesterol.

For cognitive function, the researchers used total and delayed recall scores of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), the animal fluency test, and the digit symbol substitution test (DSST).

The study included 2,253 adults aged 60 years and older (mean age, 69.4 years) and 51% were non-Hispanic White individuals.

After adjustment for age, sex, race/ethnicity, educational attainment, smoking status, alcohol consumption, income, and total energy, dietary intake of PUFA and omega-6 fatty acid was positively associated with DSST.

The DSST score increased about 0.06 standard deviation (SD) (about 1 score) with each SD increase in these fatty acids (8.8 g/d for PUFA and 7.9 g/d for omega-6) (P values were .02 for PUFA and .01 for omega-6).

However, it’s unclear what an improvement of 1 DSST score means clinically, said Dr. McIntyre. “The P value is significant, but how does that translate? Does this mean a person can now think more clearly or function better?”
 

‘Million dollar question’ remains unanswered

The fact that omega-6, considered neuroinflammatory, was associated with improved DSST score illustrates the complexity of this field, said Dr. McIntyre.

“We’re learning that when it comes to inflammation, many of the molecules in our brain that are implicated as anti-inflammatory can also be pro-inflammatory, so bad guys can be good guys and good guys can be bad guys.”

It speaks to the notion of homeostasis, he added. “Just like a seesaw; when you push this part down, that part goes up.”

The analysis showed the animal fluency score increased about 0.05 SD (around 0.3 score) with each SD (1.1 g/d) increase in dietary intake of omega-3.

There were no significant associations between other dietary fat intake and cognitive performance.

The researchers investigated the role of oxidative stress and antioxidant biomarkers (gamma glutamyl transpeptidase [GGT], bilirubin, uric acid, and vitamin D).

Cells produce oxidative radicals that are normally “mopped up” by our “innate antioxidant capability,” said Dr. McIntyre. “But in states of cognitive impairment, these oxidative stress markers accumulate and they exceed what the normal innate response is able to manage.”

The study showed GGT levels decreased with increased PUFA and omega-6 fatty acid intakes; levels of bilirubin decreased with increase in most dietary fat intakes; uric acid levels decreased with MUFA intake and omega-6/omega-3 ratio; and vitamin D levels increased with omega-3 fatty acid intake but decreased with SFAT intake.

Causal mediation analysis showed the association between dietary intake of fatty acids and DSST performance was partially mediated by GGT levels. However, Dr. McIntyre emphasized that this does not prove causality.

“The million dollar question is, is this the sole explanation for the association? In other words, is it the oxidative stress that caused the cognitive impairment and therefore correcting it improved it, or is it the case that oxidative stress is a proxy of other activities that are also taking place?”
 

A ‘plausible’ link

In an editorial, Candida Rebello, PhD, of the department of integrated physiology and molecular medicine at Pennington Biomedical Research Center, Baton Rouge, La., said the finding that omega-3 and omega-6 fatty acids are positively associated with cognition in older adults makes some sense.

She noted that aging is associated with an overt inflammatory phenotype, and evidence shows these fatty acids are precursors for bioactive molecules that play a role in self-limiting the acute inflammatory response.

Dr. Rebello said the positive association of omega-6 fatty acid with cognition shown in this study contrasts with the “common belief” that increasing dietary intake of these fatty acids enhances inflammation, but agreed the association is “plausible.”

She said it’s “essential” to determine “the underlying mechanisms that regulate the diverse features of inflammation and sort out the processes that protect from neuronal damage and those that contribute towards it.”

She noted the ratio of omega-6 to omega-3 is about 15:1 in the present day Western diet, as opposed to a 1:1 ratio in diets of the past. Omega-3 fatty acids are found in fish oil supplements and fatty fish like mackerel and salmon, while cereal, grains, and vegetable oil are sources of omega-6.

Attaining a measure of balance of fatty acids in the diet may be a “prudent approach,” said Dr. Rebello. “Substituting some meat entrées with fatty fish and polyunsaturated vegetable oils with monounsaturated fats such as olive oil are small changes that are likely to garner adherence.”

Dr. Rebello noted that the study used NHANES food intake data, which rely on participant self-report and so may not be accurate.

The study received funding from the MOE (Ministry of Education in China) Project of Humanities and Social Sciences and the Research Startup Fund of Southwest University. Dr. McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, and AbbVie. He is a CEO of Braxia Scientific Corp.

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

Dietary intake of polyunsaturated fatty acids (PUFA), particularly omega 6, is associated with improved cognitive function in older adults, new research suggests.

The study provides important “pieces of the puzzle” of the diet and cognition connection, but the results aren’t “ready for prime time,” study investigator Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, said in an interview.

“I don’t think we’re there yet when it comes to recommending supplementation to the general public,” said Dr. McIntyre, adding a larger “more compelling study” is needed.

The study was published online Jan. 14 in The American Journal of Geriatric Psychiatry.
 

Clinically meaningful?

Research shows that 25%-50% of community-dwelling adults aged 65-85 years have some cognitive impairment. Other evidence indicates cognition is affected by dietary fat intake.

Many lines of research show that alterations in lipid homeostasis can cause brain dysfunction, said Dr. McIntyre. “This shouldn’t surprise us because our brain is made up of protein, water, and fat.”

This new analysis used combined data from the 2011-2012 and 2013-2014 cycles of the National Health and Nutrition Examination Survey (NHANES), a series of ongoing cross-sectional surveys conducted by the Centers for Disease Control and Prevention. The data are collected in two phases, an in-home face-to-face interview and a physical examination.

Researchers obtained dietary intake information through two 24-hour dietary recall interviews. Dietary information included total energy (kcal/d), intakes in grams per day (g/d) of total fat, saturated fatty acid (SFAT), monounsaturated fatty acid (MUFA), PUFA, total omega-3 and total omega-6 fatty acids, and milligrams per day (mg/d) of cholesterol.

For cognitive function, the researchers used total and delayed recall scores of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), the animal fluency test, and the digit symbol substitution test (DSST).

The study included 2,253 adults aged 60 years and older (mean age, 69.4 years) and 51% were non-Hispanic White individuals.

After adjustment for age, sex, race/ethnicity, educational attainment, smoking status, alcohol consumption, income, and total energy, dietary intake of PUFA and omega-6 fatty acid was positively associated with DSST.

The DSST score increased about 0.06 standard deviation (SD) (about 1 score) with each SD increase in these fatty acids (8.8 g/d for PUFA and 7.9 g/d for omega-6) (P values were .02 for PUFA and .01 for omega-6).

However, it’s unclear what an improvement of 1 DSST score means clinically, said Dr. McIntyre. “The P value is significant, but how does that translate? Does this mean a person can now think more clearly or function better?”
 

‘Million dollar question’ remains unanswered

The fact that omega-6, considered neuroinflammatory, was associated with improved DSST score illustrates the complexity of this field, said Dr. McIntyre.

“We’re learning that when it comes to inflammation, many of the molecules in our brain that are implicated as anti-inflammatory can also be pro-inflammatory, so bad guys can be good guys and good guys can be bad guys.”

It speaks to the notion of homeostasis, he added. “Just like a seesaw; when you push this part down, that part goes up.”

The analysis showed the animal fluency score increased about 0.05 SD (around 0.3 score) with each SD (1.1 g/d) increase in dietary intake of omega-3.

There were no significant associations between other dietary fat intake and cognitive performance.

The researchers investigated the role of oxidative stress and antioxidant biomarkers (gamma glutamyl transpeptidase [GGT], bilirubin, uric acid, and vitamin D).

Cells produce oxidative radicals that are normally “mopped up” by our “innate antioxidant capability,” said Dr. McIntyre. “But in states of cognitive impairment, these oxidative stress markers accumulate and they exceed what the normal innate response is able to manage.”

The study showed GGT levels decreased with increased PUFA and omega-6 fatty acid intakes; levels of bilirubin decreased with increase in most dietary fat intakes; uric acid levels decreased with MUFA intake and omega-6/omega-3 ratio; and vitamin D levels increased with omega-3 fatty acid intake but decreased with SFAT intake.

Causal mediation analysis showed the association between dietary intake of fatty acids and DSST performance was partially mediated by GGT levels. However, Dr. McIntyre emphasized that this does not prove causality.

“The million dollar question is, is this the sole explanation for the association? In other words, is it the oxidative stress that caused the cognitive impairment and therefore correcting it improved it, or is it the case that oxidative stress is a proxy of other activities that are also taking place?”
 

A ‘plausible’ link

In an editorial, Candida Rebello, PhD, of the department of integrated physiology and molecular medicine at Pennington Biomedical Research Center, Baton Rouge, La., said the finding that omega-3 and omega-6 fatty acids are positively associated with cognition in older adults makes some sense.

She noted that aging is associated with an overt inflammatory phenotype, and evidence shows these fatty acids are precursors for bioactive molecules that play a role in self-limiting the acute inflammatory response.

Dr. Rebello said the positive association of omega-6 fatty acid with cognition shown in this study contrasts with the “common belief” that increasing dietary intake of these fatty acids enhances inflammation, but agreed the association is “plausible.”

She said it’s “essential” to determine “the underlying mechanisms that regulate the diverse features of inflammation and sort out the processes that protect from neuronal damage and those that contribute towards it.”

She noted the ratio of omega-6 to omega-3 is about 15:1 in the present day Western diet, as opposed to a 1:1 ratio in diets of the past. Omega-3 fatty acids are found in fish oil supplements and fatty fish like mackerel and salmon, while cereal, grains, and vegetable oil are sources of omega-6.

Attaining a measure of balance of fatty acids in the diet may be a “prudent approach,” said Dr. Rebello. “Substituting some meat entrées with fatty fish and polyunsaturated vegetable oils with monounsaturated fats such as olive oil are small changes that are likely to garner adherence.”

Dr. Rebello noted that the study used NHANES food intake data, which rely on participant self-report and so may not be accurate.

The study received funding from the MOE (Ministry of Education in China) Project of Humanities and Social Sciences and the Research Startup Fund of Southwest University. Dr. McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, and AbbVie. He is a CEO of Braxia Scientific Corp.

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

Dietary intake of polyunsaturated fatty acids (PUFA), particularly omega 6, is associated with improved cognitive function in older adults, new research suggests.

The study provides important “pieces of the puzzle” of the diet and cognition connection, but the results aren’t “ready for prime time,” study investigator Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, said in an interview.

“I don’t think we’re there yet when it comes to recommending supplementation to the general public,” said Dr. McIntyre, adding a larger “more compelling study” is needed.

The study was published online Jan. 14 in The American Journal of Geriatric Psychiatry.
 

Clinically meaningful?

Research shows that 25%-50% of community-dwelling adults aged 65-85 years have some cognitive impairment. Other evidence indicates cognition is affected by dietary fat intake.

Many lines of research show that alterations in lipid homeostasis can cause brain dysfunction, said Dr. McIntyre. “This shouldn’t surprise us because our brain is made up of protein, water, and fat.”

This new analysis used combined data from the 2011-2012 and 2013-2014 cycles of the National Health and Nutrition Examination Survey (NHANES), a series of ongoing cross-sectional surveys conducted by the Centers for Disease Control and Prevention. The data are collected in two phases, an in-home face-to-face interview and a physical examination.

Researchers obtained dietary intake information through two 24-hour dietary recall interviews. Dietary information included total energy (kcal/d), intakes in grams per day (g/d) of total fat, saturated fatty acid (SFAT), monounsaturated fatty acid (MUFA), PUFA, total omega-3 and total omega-6 fatty acids, and milligrams per day (mg/d) of cholesterol.

For cognitive function, the researchers used total and delayed recall scores of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD), the animal fluency test, and the digit symbol substitution test (DSST).

The study included 2,253 adults aged 60 years and older (mean age, 69.4 years) and 51% were non-Hispanic White individuals.

After adjustment for age, sex, race/ethnicity, educational attainment, smoking status, alcohol consumption, income, and total energy, dietary intake of PUFA and omega-6 fatty acid was positively associated with DSST.

The DSST score increased about 0.06 standard deviation (SD) (about 1 score) with each SD increase in these fatty acids (8.8 g/d for PUFA and 7.9 g/d for omega-6) (P values were .02 for PUFA and .01 for omega-6).

However, it’s unclear what an improvement of 1 DSST score means clinically, said Dr. McIntyre. “The P value is significant, but how does that translate? Does this mean a person can now think more clearly or function better?”
 

‘Million dollar question’ remains unanswered

The fact that omega-6, considered neuroinflammatory, was associated with improved DSST score illustrates the complexity of this field, said Dr. McIntyre.

“We’re learning that when it comes to inflammation, many of the molecules in our brain that are implicated as anti-inflammatory can also be pro-inflammatory, so bad guys can be good guys and good guys can be bad guys.”

It speaks to the notion of homeostasis, he added. “Just like a seesaw; when you push this part down, that part goes up.”

The analysis showed the animal fluency score increased about 0.05 SD (around 0.3 score) with each SD (1.1 g/d) increase in dietary intake of omega-3.

There were no significant associations between other dietary fat intake and cognitive performance.

The researchers investigated the role of oxidative stress and antioxidant biomarkers (gamma glutamyl transpeptidase [GGT], bilirubin, uric acid, and vitamin D).

Cells produce oxidative radicals that are normally “mopped up” by our “innate antioxidant capability,” said Dr. McIntyre. “But in states of cognitive impairment, these oxidative stress markers accumulate and they exceed what the normal innate response is able to manage.”

The study showed GGT levels decreased with increased PUFA and omega-6 fatty acid intakes; levels of bilirubin decreased with increase in most dietary fat intakes; uric acid levels decreased with MUFA intake and omega-6/omega-3 ratio; and vitamin D levels increased with omega-3 fatty acid intake but decreased with SFAT intake.

Causal mediation analysis showed the association between dietary intake of fatty acids and DSST performance was partially mediated by GGT levels. However, Dr. McIntyre emphasized that this does not prove causality.

“The million dollar question is, is this the sole explanation for the association? In other words, is it the oxidative stress that caused the cognitive impairment and therefore correcting it improved it, or is it the case that oxidative stress is a proxy of other activities that are also taking place?”
 

A ‘plausible’ link

In an editorial, Candida Rebello, PhD, of the department of integrated physiology and molecular medicine at Pennington Biomedical Research Center, Baton Rouge, La., said the finding that omega-3 and omega-6 fatty acids are positively associated with cognition in older adults makes some sense.

She noted that aging is associated with an overt inflammatory phenotype, and evidence shows these fatty acids are precursors for bioactive molecules that play a role in self-limiting the acute inflammatory response.

Dr. Rebello said the positive association of omega-6 fatty acid with cognition shown in this study contrasts with the “common belief” that increasing dietary intake of these fatty acids enhances inflammation, but agreed the association is “plausible.”

She said it’s “essential” to determine “the underlying mechanisms that regulate the diverse features of inflammation and sort out the processes that protect from neuronal damage and those that contribute towards it.”

She noted the ratio of omega-6 to omega-3 is about 15:1 in the present day Western diet, as opposed to a 1:1 ratio in diets of the past. Omega-3 fatty acids are found in fish oil supplements and fatty fish like mackerel and salmon, while cereal, grains, and vegetable oil are sources of omega-6.

Attaining a measure of balance of fatty acids in the diet may be a “prudent approach,” said Dr. Rebello. “Substituting some meat entrées with fatty fish and polyunsaturated vegetable oils with monounsaturated fats such as olive oil are small changes that are likely to garner adherence.”

Dr. Rebello noted that the study used NHANES food intake data, which rely on participant self-report and so may not be accurate.

The study received funding from the MOE (Ministry of Education in China) Project of Humanities and Social Sciences and the Research Startup Fund of Southwest University. Dr. McIntyre has received research grant support from CIHR/GACD/Chinese National Natural Research Foundation and speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, and AbbVie. He is a CEO of Braxia Scientific Corp.

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

Heart disease. Cancer. Diabetes. Dementia.

Researchers spend billions of dollars every year trying to eradicate these medical scourges.

Yet even if we discover cures to these and all other chronic conditions, it won’t change our ultimate prognosis: death.

“That’s because you haven’t stopped aging,” says Jay Olshansky, PhD, a professor of epidemiology and biostatistics at the University of Illinois at Chicago School of Public Health.

But what if we could? What if we are trying to extend longevity in the wrong way? Instead of focusing on diseases, should we take aim at aging itself?

Some scientists think so. Fueled in part by a billion dollars of investor money, they are attempting to reverse-engineer your molecular biological clock. Their goal? To eliminate not merely diseases that kill people, but to prevent death itself. 
 

Hacking the code for immortality

Aubrey de Grey, PhD, a biomedical gerontologist, has drawn wide attention for his belief that the first person who will live to be 1,000 years old is already among us. 

He believes there’s no cap on how long we can live, depending on what medicines we develop in the future.

“The whole idea is that there would not be a limit on how long we can keep people healthy,” Dr. de Grey says. He’s the chief science officer and co-founder of the SENS Research Foundation, which funds research on how to put the brakes on aging.

Dr. De Grey’s view, in theory, isn’t so far-fetched.

Scientists have studied the immortal jellyfish, Turritopsis dohrnii. It’s the only animal that can cheat death by reverting from adulthood back to its polyp stage when threatened with danger or starvation.

Other clues to possible eternal life also may exist underwater. Certain marine clams can live more than 500 years. And lobsters stock a seemingly limitless supply of a youthful enzyme that has some scientists wondering if the crustacean, under the best conditions, just might live forever.

Among humans, researchers have been studying “super-agers” – people who not only live exceptionally long, but also do so without many of the chronic diseases that plague their peers. That’s even though they share some of the same bad habits as everyone else.

“They are making it past the age of 80 with their minds completely intact. That’s what’s so unusual,” Dr. Olshansky says. The rest of their bodies are doing better than those of average 80-year-olds, too.

People who reached ages 95 to 112 got cancer, heart disease, diabetes, osteoporosis, and stroke up to 24 years later than those with average lifespans, data show. Figuring out why might pave the way for targeted gene therapy to mimic the DNA of these nonagenarians and centenarians.

“There’s likely to be secrets contained within their genome that are eventually discovered that will help us develop therapeutic interventions to mimic the effects of decelerated aging,” Dr. Olshansky says.

Treating aging this way may offer a bigger payoff than targeting individual diseases. That’s because even if you manage to dodge any illnesses, there’s ultimately no escaping old age.

“Longevity is a side effect of health,” Dr. de Grey says. “If we can keep people healthy, then their likelihood of dying is reduced.”
 

Aging as a preventable condition

In 2015, Michael Cantor was prescribed metformin for prediabetes. Once that was under control, his doctor said Mr. Cantor could quit the drug. But Mr. Cantor had heard about studies testing it as an anti-aging drug. The 62-year-old Connecticut-based attorney asked if he could stay on it. A year ago Cantor’s wife, Shari, who is mayor of West Hartford, Conn., started to take metformin, too.

“I read the articles, they made a lot of sense to me, and with the number of people that have been taking this drug worldwide for decades, I felt like there was nothing to lose,” he says.

The couple can’t say if their daily doses have led to any changes in how they look or feel. After all, they’re taking the pills not to treat current ailments but to prevent ones in the future.

They may have answers soon. Nir Barzilai, MD, director of the National Institutes of Health’s Nathan Shock Centers of Excellence in the Basic Biology of Aging, is leading a study that hopes to prove aging is a preventable health condition. The TAME (Targeting Aging with Metformin) study is designed to do this by demonstrating that metformin, a cheap and widely prescribed pill for diabetes, may also be an anti-aging elixir.

The TAME trial is currently in phase III – typically the final step of research into any treatment before drugmakers can apply for FDA approval.

Earlier studies found that people with type 2 diabetes who take metformin have lower death rates from any cause, compared to peers who don’t take the drug. Metformin also seems to help curb the incidence of age-related diseases, including heart disease, dementia, and Alzheimer›s. It also may lower the risk of many types of cancer as well as raise the chances of survival. Observations made since the beginning of the COVID-19 pandemic suggest that people who get the virus while taking metformin are less likely to land in the hospital or die from it.

It’s not clear exactly how metformin works to do all that. The compound was originally derived from Galega officinalis, also known as goat’s rue, a perennial plant used as medicine since medieval times.

Dr. Barzilai says he hopes to prove that aging is a preventable condition.

“If the results are what they think they will be, the whole world could go on metformin and extend life for everybody – extend your good quality of life,” Dr. Barzilai says. “That’s what we all want. Every extra year that we could get where we’re still vigorous and vital would be amazing.”

Long life versus healthy life

Some researchers argue that only the “healthspan” – the period of life free of illness – is worth extending. Of course, a healthy lifestyle can add years to most people’s lives and actually improve cellular aging. Some of the biggest payoffs come from quitting or never smoking, logging more than 5½ hours of physical activity per week, and keeping a normal weight.

Drugs may be able to do that as well by interrupting common markers of aging, including telomere length, inflammation, oxidative stress, and slower cell metabolism.

“You don’t have to target all of these hallmarks to get improvement” in healthspans, says Dr. Barzilai, who also is director of the Institute for Aging Research at the Albert Einstein College of Medicine in the Bronx and scientific director of the American Federation for Aging Research.

“If you target one, you show benefit in the others.”

The medical term for growing old is senescence. Buffeted by DNA damage and stresses, your cells deteriorate and eventually stop multiplying, but don’t die.

That slowdown may have big consequences for your health. Your genes become more likely to get mutations, which can pave the way for cancer. Mitochondria, which produce energy in the cell, struggle to fuel your body. That can damage cells and cause chronic inflammation, which plays a part in diabetes, arthritis, ulcerative colitis, and many other diseases.

One major hallmark of aging is the growing stockpile of these senescent cells. Damaged cells become deactivated as a way to protect your body from harmful or uncontrolled cell division. But like the rotten apple that spoils the whole bunch, senescent cells encourage their neighbors to turn dysfunctional, too. They also emit proteins that trigger inflammation. Your body naturally removes these dormant cells. But older immune systems have a harder time cleaning up, so the senescent cells are more likely to hang around.

Flushing out this accumulated debris may be one way to avert aging, some experts say.

Dr. De Grey also believes that could be done with drugs.

“These therapies would actually repair [cellular] damage,” he says. “They’ll eliminate damage from the body by resetting or turning back the clock.”

James Kirkland, MD, PhD, of the Mayo Clinic, is one researcher exploring this theory. He gave a mixture of the cancer drug dasatinib and a plant pigment called quercetin to people with diabetic kidney disease. Quercetin is an antioxidant that gives grapes, tomatoes, and other fruits and vegetables their flavor.

A small phase I clinical trial showed that the dasatinib-quercetin combination got rid of senescent cells in the tissues of people with the disease.

The researchers don’t know yet if the results will translate into prolonged youth. They also don’t know how high a dosage is needed and what long-term problems the treatment might cause. People with chronic leukemia take dasatinib for years with few serious ill effects.

In another recent study, scientists used oxygen therapy to tackle senescent cells. Thirty-five adults ages 64 and older received oxygen therapy in a pressurized chamber. After 60 daily sessions, they showed a decrease in senescent cells and improvement in the length of DNA segments called telomeres. Shortened segments of telomeres are thought to be another marker of aging.

Researchers are also looking to the gene-editing technology CRISPR for anti-aging treatments, but the testing is only in mice so far.

Dr. Barzilai hopes that if the metformin trial succeeds, it will open the floodgates to a wave of new drugs that can stop or reverse human aging. Some of the major players in this field include Juvenescence, AgeX Therapeutics, LyGenesis, and Life Biosciences, which Dr. Barzilai founded.

“Until aging is seen as preventable, health plans won’t have to pay for this type of treatment,” he says. And if health plans won’t cover aging, pharmaceutical companies have little incentive to invest in drug development.

That may be the only thing standing between humans and unprecedented lifespans. The Census Bureau projects that Americans born in 2060 should live an average of 85.6 years, up from 78.7 years in 2018. Dr. De Grey’s prediction tops that mark by a factor of about 50. He believes that the life expectancy for someone born in 2100 may well be 5,000 years.

Dr. Barzilai, for his part, has a prediction that’s seemingly more modest.

“We die at 80. Getting an additional 35 years is relatively low-hanging fruit,” he says. “But I don’t believe that is a fixed limit.”

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

Heart disease. Cancer. Diabetes. Dementia.

Researchers spend billions of dollars every year trying to eradicate these medical scourges.

Yet even if we discover cures to these and all other chronic conditions, it won’t change our ultimate prognosis: death.

“That’s because you haven’t stopped aging,” says Jay Olshansky, PhD, a professor of epidemiology and biostatistics at the University of Illinois at Chicago School of Public Health.

But what if we could? What if we are trying to extend longevity in the wrong way? Instead of focusing on diseases, should we take aim at aging itself?

Some scientists think so. Fueled in part by a billion dollars of investor money, they are attempting to reverse-engineer your molecular biological clock. Their goal? To eliminate not merely diseases that kill people, but to prevent death itself. 
 

Hacking the code for immortality

Aubrey de Grey, PhD, a biomedical gerontologist, has drawn wide attention for his belief that the first person who will live to be 1,000 years old is already among us. 

He believes there’s no cap on how long we can live, depending on what medicines we develop in the future.

“The whole idea is that there would not be a limit on how long we can keep people healthy,” Dr. de Grey says. He’s the chief science officer and co-founder of the SENS Research Foundation, which funds research on how to put the brakes on aging.

Dr. De Grey’s view, in theory, isn’t so far-fetched.

Scientists have studied the immortal jellyfish, Turritopsis dohrnii. It’s the only animal that can cheat death by reverting from adulthood back to its polyp stage when threatened with danger or starvation.

Other clues to possible eternal life also may exist underwater. Certain marine clams can live more than 500 years. And lobsters stock a seemingly limitless supply of a youthful enzyme that has some scientists wondering if the crustacean, under the best conditions, just might live forever.

Among humans, researchers have been studying “super-agers” – people who not only live exceptionally long, but also do so without many of the chronic diseases that plague their peers. That’s even though they share some of the same bad habits as everyone else.

“They are making it past the age of 80 with their minds completely intact. That’s what’s so unusual,” Dr. Olshansky says. The rest of their bodies are doing better than those of average 80-year-olds, too.

People who reached ages 95 to 112 got cancer, heart disease, diabetes, osteoporosis, and stroke up to 24 years later than those with average lifespans, data show. Figuring out why might pave the way for targeted gene therapy to mimic the DNA of these nonagenarians and centenarians.

“There’s likely to be secrets contained within their genome that are eventually discovered that will help us develop therapeutic interventions to mimic the effects of decelerated aging,” Dr. Olshansky says.

Treating aging this way may offer a bigger payoff than targeting individual diseases. That’s because even if you manage to dodge any illnesses, there’s ultimately no escaping old age.

“Longevity is a side effect of health,” Dr. de Grey says. “If we can keep people healthy, then their likelihood of dying is reduced.”
 

Aging as a preventable condition

In 2015, Michael Cantor was prescribed metformin for prediabetes. Once that was under control, his doctor said Mr. Cantor could quit the drug. But Mr. Cantor had heard about studies testing it as an anti-aging drug. The 62-year-old Connecticut-based attorney asked if he could stay on it. A year ago Cantor’s wife, Shari, who is mayor of West Hartford, Conn., started to take metformin, too.

“I read the articles, they made a lot of sense to me, and with the number of people that have been taking this drug worldwide for decades, I felt like there was nothing to lose,” he says.

The couple can’t say if their daily doses have led to any changes in how they look or feel. After all, they’re taking the pills not to treat current ailments but to prevent ones in the future.

They may have answers soon. Nir Barzilai, MD, director of the National Institutes of Health’s Nathan Shock Centers of Excellence in the Basic Biology of Aging, is leading a study that hopes to prove aging is a preventable health condition. The TAME (Targeting Aging with Metformin) study is designed to do this by demonstrating that metformin, a cheap and widely prescribed pill for diabetes, may also be an anti-aging elixir.

The TAME trial is currently in phase III – typically the final step of research into any treatment before drugmakers can apply for FDA approval.

Earlier studies found that people with type 2 diabetes who take metformin have lower death rates from any cause, compared to peers who don’t take the drug. Metformin also seems to help curb the incidence of age-related diseases, including heart disease, dementia, and Alzheimer›s. It also may lower the risk of many types of cancer as well as raise the chances of survival. Observations made since the beginning of the COVID-19 pandemic suggest that people who get the virus while taking metformin are less likely to land in the hospital or die from it.

It’s not clear exactly how metformin works to do all that. The compound was originally derived from Galega officinalis, also known as goat’s rue, a perennial plant used as medicine since medieval times.

Dr. Barzilai says he hopes to prove that aging is a preventable condition.

“If the results are what they think they will be, the whole world could go on metformin and extend life for everybody – extend your good quality of life,” Dr. Barzilai says. “That’s what we all want. Every extra year that we could get where we’re still vigorous and vital would be amazing.”

Long life versus healthy life

Some researchers argue that only the “healthspan” – the period of life free of illness – is worth extending. Of course, a healthy lifestyle can add years to most people’s lives and actually improve cellular aging. Some of the biggest payoffs come from quitting or never smoking, logging more than 5½ hours of physical activity per week, and keeping a normal weight.

Drugs may be able to do that as well by interrupting common markers of aging, including telomere length, inflammation, oxidative stress, and slower cell metabolism.

“You don’t have to target all of these hallmarks to get improvement” in healthspans, says Dr. Barzilai, who also is director of the Institute for Aging Research at the Albert Einstein College of Medicine in the Bronx and scientific director of the American Federation for Aging Research.

“If you target one, you show benefit in the others.”

The medical term for growing old is senescence. Buffeted by DNA damage and stresses, your cells deteriorate and eventually stop multiplying, but don’t die.

That slowdown may have big consequences for your health. Your genes become more likely to get mutations, which can pave the way for cancer. Mitochondria, which produce energy in the cell, struggle to fuel your body. That can damage cells and cause chronic inflammation, which plays a part in diabetes, arthritis, ulcerative colitis, and many other diseases.

One major hallmark of aging is the growing stockpile of these senescent cells. Damaged cells become deactivated as a way to protect your body from harmful or uncontrolled cell division. But like the rotten apple that spoils the whole bunch, senescent cells encourage their neighbors to turn dysfunctional, too. They also emit proteins that trigger inflammation. Your body naturally removes these dormant cells. But older immune systems have a harder time cleaning up, so the senescent cells are more likely to hang around.

Flushing out this accumulated debris may be one way to avert aging, some experts say.

Dr. De Grey also believes that could be done with drugs.

“These therapies would actually repair [cellular] damage,” he says. “They’ll eliminate damage from the body by resetting or turning back the clock.”

James Kirkland, MD, PhD, of the Mayo Clinic, is one researcher exploring this theory. He gave a mixture of the cancer drug dasatinib and a plant pigment called quercetin to people with diabetic kidney disease. Quercetin is an antioxidant that gives grapes, tomatoes, and other fruits and vegetables their flavor.

A small phase I clinical trial showed that the dasatinib-quercetin combination got rid of senescent cells in the tissues of people with the disease.

The researchers don’t know yet if the results will translate into prolonged youth. They also don’t know how high a dosage is needed and what long-term problems the treatment might cause. People with chronic leukemia take dasatinib for years with few serious ill effects.

In another recent study, scientists used oxygen therapy to tackle senescent cells. Thirty-five adults ages 64 and older received oxygen therapy in a pressurized chamber. After 60 daily sessions, they showed a decrease in senescent cells and improvement in the length of DNA segments called telomeres. Shortened segments of telomeres are thought to be another marker of aging.

Researchers are also looking to the gene-editing technology CRISPR for anti-aging treatments, but the testing is only in mice so far.

Dr. Barzilai hopes that if the metformin trial succeeds, it will open the floodgates to a wave of new drugs that can stop or reverse human aging. Some of the major players in this field include Juvenescence, AgeX Therapeutics, LyGenesis, and Life Biosciences, which Dr. Barzilai founded.

“Until aging is seen as preventable, health plans won’t have to pay for this type of treatment,” he says. And if health plans won’t cover aging, pharmaceutical companies have little incentive to invest in drug development.

That may be the only thing standing between humans and unprecedented lifespans. The Census Bureau projects that Americans born in 2060 should live an average of 85.6 years, up from 78.7 years in 2018. Dr. De Grey’s prediction tops that mark by a factor of about 50. He believes that the life expectancy for someone born in 2100 may well be 5,000 years.

Dr. Barzilai, for his part, has a prediction that’s seemingly more modest.

“We die at 80. Getting an additional 35 years is relatively low-hanging fruit,” he says. “But I don’t believe that is a fixed limit.”

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

Heart disease. Cancer. Diabetes. Dementia.

Researchers spend billions of dollars every year trying to eradicate these medical scourges.

Yet even if we discover cures to these and all other chronic conditions, it won’t change our ultimate prognosis: death.

“That’s because you haven’t stopped aging,” says Jay Olshansky, PhD, a professor of epidemiology and biostatistics at the University of Illinois at Chicago School of Public Health.

But what if we could? What if we are trying to extend longevity in the wrong way? Instead of focusing on diseases, should we take aim at aging itself?

Some scientists think so. Fueled in part by a billion dollars of investor money, they are attempting to reverse-engineer your molecular biological clock. Their goal? To eliminate not merely diseases that kill people, but to prevent death itself. 
 

Hacking the code for immortality

Aubrey de Grey, PhD, a biomedical gerontologist, has drawn wide attention for his belief that the first person who will live to be 1,000 years old is already among us. 

He believes there’s no cap on how long we can live, depending on what medicines we develop in the future.

“The whole idea is that there would not be a limit on how long we can keep people healthy,” Dr. de Grey says. He’s the chief science officer and co-founder of the SENS Research Foundation, which funds research on how to put the brakes on aging.

Dr. De Grey’s view, in theory, isn’t so far-fetched.

Scientists have studied the immortal jellyfish, Turritopsis dohrnii. It’s the only animal that can cheat death by reverting from adulthood back to its polyp stage when threatened with danger or starvation.

Other clues to possible eternal life also may exist underwater. Certain marine clams can live more than 500 years. And lobsters stock a seemingly limitless supply of a youthful enzyme that has some scientists wondering if the crustacean, under the best conditions, just might live forever.

Among humans, researchers have been studying “super-agers” – people who not only live exceptionally long, but also do so without many of the chronic diseases that plague their peers. That’s even though they share some of the same bad habits as everyone else.

“They are making it past the age of 80 with their minds completely intact. That’s what’s so unusual,” Dr. Olshansky says. The rest of their bodies are doing better than those of average 80-year-olds, too.

People who reached ages 95 to 112 got cancer, heart disease, diabetes, osteoporosis, and stroke up to 24 years later than those with average lifespans, data show. Figuring out why might pave the way for targeted gene therapy to mimic the DNA of these nonagenarians and centenarians.

“There’s likely to be secrets contained within their genome that are eventually discovered that will help us develop therapeutic interventions to mimic the effects of decelerated aging,” Dr. Olshansky says.

Treating aging this way may offer a bigger payoff than targeting individual diseases. That’s because even if you manage to dodge any illnesses, there’s ultimately no escaping old age.

“Longevity is a side effect of health,” Dr. de Grey says. “If we can keep people healthy, then their likelihood of dying is reduced.”
 

Aging as a preventable condition

In 2015, Michael Cantor was prescribed metformin for prediabetes. Once that was under control, his doctor said Mr. Cantor could quit the drug. But Mr. Cantor had heard about studies testing it as an anti-aging drug. The 62-year-old Connecticut-based attorney asked if he could stay on it. A year ago Cantor’s wife, Shari, who is mayor of West Hartford, Conn., started to take metformin, too.

“I read the articles, they made a lot of sense to me, and with the number of people that have been taking this drug worldwide for decades, I felt like there was nothing to lose,” he says.

The couple can’t say if their daily doses have led to any changes in how they look or feel. After all, they’re taking the pills not to treat current ailments but to prevent ones in the future.

They may have answers soon. Nir Barzilai, MD, director of the National Institutes of Health’s Nathan Shock Centers of Excellence in the Basic Biology of Aging, is leading a study that hopes to prove aging is a preventable health condition. The TAME (Targeting Aging with Metformin) study is designed to do this by demonstrating that metformin, a cheap and widely prescribed pill for diabetes, may also be an anti-aging elixir.

The TAME trial is currently in phase III – typically the final step of research into any treatment before drugmakers can apply for FDA approval.

Earlier studies found that people with type 2 diabetes who take metformin have lower death rates from any cause, compared to peers who don’t take the drug. Metformin also seems to help curb the incidence of age-related diseases, including heart disease, dementia, and Alzheimer›s. It also may lower the risk of many types of cancer as well as raise the chances of survival. Observations made since the beginning of the COVID-19 pandemic suggest that people who get the virus while taking metformin are less likely to land in the hospital or die from it.

It’s not clear exactly how metformin works to do all that. The compound was originally derived from Galega officinalis, also known as goat’s rue, a perennial plant used as medicine since medieval times.

Dr. Barzilai says he hopes to prove that aging is a preventable condition.

“If the results are what they think they will be, the whole world could go on metformin and extend life for everybody – extend your good quality of life,” Dr. Barzilai says. “That’s what we all want. Every extra year that we could get where we’re still vigorous and vital would be amazing.”

Long life versus healthy life

Some researchers argue that only the “healthspan” – the period of life free of illness – is worth extending. Of course, a healthy lifestyle can add years to most people’s lives and actually improve cellular aging. Some of the biggest payoffs come from quitting or never smoking, logging more than 5½ hours of physical activity per week, and keeping a normal weight.

Drugs may be able to do that as well by interrupting common markers of aging, including telomere length, inflammation, oxidative stress, and slower cell metabolism.

“You don’t have to target all of these hallmarks to get improvement” in healthspans, says Dr. Barzilai, who also is director of the Institute for Aging Research at the Albert Einstein College of Medicine in the Bronx and scientific director of the American Federation for Aging Research.

“If you target one, you show benefit in the others.”

The medical term for growing old is senescence. Buffeted by DNA damage and stresses, your cells deteriorate and eventually stop multiplying, but don’t die.

That slowdown may have big consequences for your health. Your genes become more likely to get mutations, which can pave the way for cancer. Mitochondria, which produce energy in the cell, struggle to fuel your body. That can damage cells and cause chronic inflammation, which plays a part in diabetes, arthritis, ulcerative colitis, and many other diseases.

One major hallmark of aging is the growing stockpile of these senescent cells. Damaged cells become deactivated as a way to protect your body from harmful or uncontrolled cell division. But like the rotten apple that spoils the whole bunch, senescent cells encourage their neighbors to turn dysfunctional, too. They also emit proteins that trigger inflammation. Your body naturally removes these dormant cells. But older immune systems have a harder time cleaning up, so the senescent cells are more likely to hang around.

Flushing out this accumulated debris may be one way to avert aging, some experts say.

Dr. De Grey also believes that could be done with drugs.

“These therapies would actually repair [cellular] damage,” he says. “They’ll eliminate damage from the body by resetting or turning back the clock.”

James Kirkland, MD, PhD, of the Mayo Clinic, is one researcher exploring this theory. He gave a mixture of the cancer drug dasatinib and a plant pigment called quercetin to people with diabetic kidney disease. Quercetin is an antioxidant that gives grapes, tomatoes, and other fruits and vegetables their flavor.

A small phase I clinical trial showed that the dasatinib-quercetin combination got rid of senescent cells in the tissues of people with the disease.

The researchers don’t know yet if the results will translate into prolonged youth. They also don’t know how high a dosage is needed and what long-term problems the treatment might cause. People with chronic leukemia take dasatinib for years with few serious ill effects.

In another recent study, scientists used oxygen therapy to tackle senescent cells. Thirty-five adults ages 64 and older received oxygen therapy in a pressurized chamber. After 60 daily sessions, they showed a decrease in senescent cells and improvement in the length of DNA segments called telomeres. Shortened segments of telomeres are thought to be another marker of aging.

Researchers are also looking to the gene-editing technology CRISPR for anti-aging treatments, but the testing is only in mice so far.

Dr. Barzilai hopes that if the metformin trial succeeds, it will open the floodgates to a wave of new drugs that can stop or reverse human aging. Some of the major players in this field include Juvenescence, AgeX Therapeutics, LyGenesis, and Life Biosciences, which Dr. Barzilai founded.

“Until aging is seen as preventable, health plans won’t have to pay for this type of treatment,” he says. And if health plans won’t cover aging, pharmaceutical companies have little incentive to invest in drug development.

That may be the only thing standing between humans and unprecedented lifespans. The Census Bureau projects that Americans born in 2060 should live an average of 85.6 years, up from 78.7 years in 2018. Dr. De Grey’s prediction tops that mark by a factor of about 50. He believes that the life expectancy for someone born in 2100 may well be 5,000 years.

Dr. Barzilai, for his part, has a prediction that’s seemingly more modest.

“We die at 80. Getting an additional 35 years is relatively low-hanging fruit,” he says. “But I don’t believe that is a fixed limit.”

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