Immunology and Rheumatology Faculty Reach Across Divisions to Fight Disease

Baldeep Singh, MD, with staff at Samaritan House

Sarcoidosis is a rare disease that can manifest in various ways.

Immunology and Rheumatology Faculty Reach Across Divisions to Fight Disease

Sarcoidosis is a rare disease that can manifest in various ways.

Immunology and Rheumatology Faculty Reach Across Divisions to Fight Disease

In many ways, modern medicine is getting more intimate in scope: Think targeted cell-based therapies or interventions tailored to the microbiome. But in another sense, its scope is also getting broader: More and more frequently, doctors from various specialties are realizing how important interdisciplinary care is to fight diseases and care for patients. The immunology and rheumatology division is a perfect illustration of this principle. Among others, both Matt Baker, MD, MS, clinical assistant professor of immunology and rheumatology, and Tamiko Katsumoto, MD, clinical assistant professor of immunology and rheumatology, are working collaboratively with other divisions on research and patient care.

A Hub to Treat Sarcoidosis
Baker “really fell in love with immunology” when he worked in a lab at the National Institutes of Health before attending medical school at Harvard. His path to medicine was unusual: He grew up in a tiny town in Oregon, living in a log house and attending the local high school, where they had classes in “hatchet throwing and log rolling.”

He remembers being struck by the role that his father (the town dentist) and the town doctors played. “It was very Rockwellian—seeing them take care of entire families or running down to help when there was an injury at a sporting event,” Baker explains, “so I always had this idea that I would go into medicine.” After internal medicine training, he chose to specialize in rheumatology. “Ten or 20 years ago, many of the other fields within medicine weren’t really focused on the immune system,” Baker says. “But now it’s clearly involved in just about everything. It was, and is, a really exciting time to be in the field.”

His work eventually led him to Stanford, where he’s become one of the go-to doctors on the West Coast for sarcoidosis, a rare disease that can manifest in various ways, including fibrotic lung disease, lymph node enlargement, and life-threatening problems in the heart. Ron Witteles, MD, associate professor of cardiovascular medicine, often referred his sarcoidosis patients with cardiac involvement to Baker. 

Soon Baker and Witteles were co-managing close to 20 patients. “There was a need to bring people together around sarcoidosis,” Baker explains. They wanted to “formalize and standardize” their practice.

At first, this included capturing patient information in a database and collecting samples from willing patients to use for future studies. It snowballed from there—cardiac sarcoidosis is a rare form of the disease; it’s more common to see pulmonary problems. So Baker and Witteles started to include pulmonologists (including Rishi Raj, MD, clinical professor of pulmonary and critical care medicine) in their work. From there, it transformed into what is now known as the Stanford Multidisciplinary Sarcoidosis Program, co-directed by Baker, Witteles, and Raj and staffed by Emily Braley, RN. The program began in June 2019, and as the only program of its kind in Northern California, it’s become a hub for sarcoidosis patients.

As part of the program, doctors try to coordinate their clinic days so they can see patients together or at least ensure that the patients can see all the different subspecialists they need to in one day. Baker and his colleagues hope to develop their own algorithm and practice guidelines for the diagnosis and management of sarcoidosis.

Baker is also collecting patient samples to investigate specific cell types that might be involved in sarcoidosis pathogenesis, and he’s recruiting for a study to determine the effectiveness of a drug approved for rheumatoid arthritis in sarcoidosis patients.

The far-reaching ambition of the program is a simple one. “A lot of people come from far away,” Baker says, “so we want to make their visits efficient. Our goal is to be able to provide the best collaborative care possible.”

Matt Baker, MD, MS (right), talks with a patient.

In many ways, modern medicine is getting more intimate in scope: Think targeted cell-based therapies or interventions tailored to the microbiome. But in another sense, its scope is also getting broader: More and more frequently, doctors from various specialties are realizing how important interdisciplinary care is to fight diseases and care for patients. The immunology and rheumatology division is a perfect illustration of this principle. Among others, both Matt Baker, MD, MS, clinical assistant professor of immunology and rheumatology, and Tamiko Katsumoto, MD, clinical assistant professor of immunology and rheumatology, are working collaboratively with other divisions on research and patient care.

A Hub to Treat Sarcoidosis

Baker “really fell in love with immunology” when he worked in a lab at the National Institutes of Health before attending medical school at Harvard. His path to medicine was unusual: He grew up in a tiny town in Oregon, living in a log house and attending the local high school, where they had classes in “hatchet throwing and log rolling.” He remembers being struck by the role that his father (the town dentist) and the town doctors played. “It was very Rockwellian—seeing them take care of entire families or running down to help when there was an injury at a sporting event,” Baker explains, “so I always had this idea that I would go into medicine.” After internal medicine training, he chose to specialize in rheumatology. “Ten or 20 years ago, many of the other fields within medicine weren’t really focused on the immune system,” Baker says. “But now it’s clearly involved in just about everything. It was, and is, a really exciting time to be in the field.”

His work eventually led him to Stanford, where he’s become one of the go-to doctors on the West Coast for sarcoidosis, a rare disease that can manifest in various ways, including fibrotic lung disease, lymph node enlargement, and life-threatening problems in the heart. Ron Witteles, MD, associate professor of cardiovascular medicine, often referred his sarcoidosis patients with cardiac involvement to Baker. Soon Baker and Witteles were co-managing close to 20 patients. “There was a need to bring people together around sarcoidosis,” Baker explains. They wanted to “formalize and standardize” their practice.

Matt Baker, MD, MS (right), talks with a patient.

At first, this included capturing patient information in a database and collecting samples from willing patients to use for future studies. It snowballed from there—cardiac sarcoidosis is a rare form of the disease; it’s more common to see pulmonary problems. So Baker and Witteles started to include pulmonologists (including Rishi Raj, MD, clinical professor of pulmonary and critical care medicine) in their work. From there, it transformed into what is now known as the Stanford Multidisciplinary Sarcoidosis Program, co-directed by Baker, Witteles, and Raj and staffed by Emily Braley, RN. The program began in June 2019, and as the only program of its kind in Northern California, it’s become a hub for sarcoidosis patients.

As part of the program, doctors try to coordinate their clinic days so they can see patients together or at least ensure that the patients can see all the different subspecialists they need to in one day. Baker and his colleagues hope to develop their own algorithm and practice guidelines for the diagnosis and management of sarcoidosis.

Baker is also collecting patient samples to investigate specific cell types that might be involved in sarcoidosis pathogenesis, and he’s recruiting for a study to determine the effectiveness of a drug approved for rheumatoid arthritis in sarcoidosis patients.

The far-reaching ambition of the program is a simple one. “A lot of people come from far away,” Baker says, “so we want to make their visits efficient. Our goal is to be able to provide the best collaborative care possible.”

Tamiko Katsumoto, MD, explains her work.

A Working Group for Adverse Events
Katsumoto also preaches the benefits of interdisciplinary work. She always had “a profound love of internal medicine,” and when the time came to choose her specialty, she found herself torn between oncology and immunology and rheumatology. Ultimately she chose immunology and rheumatology, but as she points out, in many ways her career has now come full circle: After years at UC-San Francisco, then Genentech, and now Stanford, her work has resulted in the creation of a new interdisciplinary project: the Immune-Related Toxicity Group.

The idea for this group arose from the growing trend of applying immunology to cancer treatments, and in Katsumoto’s case, the use of checkpoint inhibitors to fight tumors. As Katsumoto explains, “Normally, the immune system is capable of identifying a tumor and mounting a productive response against it. When cancer develops, often the tumor evolves mechanisms of resisting immune attack.” The checkpoint inhibitors administered by doctors then block the resistance mechanism of the tumor, thereby “unleashing the immune system by taking the brakes off” and allowing the immune system to recognize and attack the tumor. Checkpoint inhibitors have generated impressive long-term responses in some patients, but there’s a secondary issue. When you take the brakes off the immune system, it leaves the patient vulnerable to “immune-related adverse events.”

“Sometimes you get collateral damage to your own internal organs,” Katsumoto says. That’s where she and her colleagues in medicine—jokingly referred to as “the cleanup crew”—come in, and how she first got the idea for the group.

Katsumoto realized while treating these adverse events that there were still knowledge gaps, despite the existence of several guidelines. Clinical questions frequently arise, such as how to optimally manage these adverse events, whether it’s safe to restart the checkpoint inhibitor, and whether it’s safe to use checkpoint inhibitors in patients with pre-existing autoimmunity. Katsumoto wondered about creating a working group, akin to a tumor board, that could provide consultative services, a database, and even a biobank for all these adverse events. As Katsumoto puts it, “It became clear that there was a need for us to come together as a larger multidisciplinary group to really discuss these cases and learn from each other.”

The group is still in its infancy, but Katsumoto has identified interested parties from various disciplines (including oncology, dermatology, gastroenterology, pulmonary medicine, endocrinology, nephrology, hepatology, and neurology), and she’s already getting referrals for patients from colleagues. She’s also involved in a large multisite NIH trial seeking to discover whether patients with pre-existing autoimmunity can safely use checkpoint inhibitor therapy. Another major project involves biomarkers: If doctors can discover which biomarkers identify patients who will respond negatively to checkpoint inhibitor therapy, they can identify problems before any therapy is administered.

She’s hoping to convene the group as a resource for doctors in this rapidly changing field. “This could be a springboard for a lot of collaborative research projects,” Katsumoto envisions. She also hopes that identifying “point people” in various divisions can help improve clinical care.

The Immune-Related Toxicity Group is a relatively new idea for Katsumoto, but her goals for the project prove her determination, and her collaborators are just as eager. “The use of checkpoint inhibitor therapy is growing, almost exponentially. More and more medications are getting approved for new indications every day,” Katsumoto says. And that only proves the greater need for collaboration. As Katsumoto asserts, “The field is growing in real time. We need to band together.”

A Working Group for Adverse Events
Katsumoto also preaches the benefits of interdisciplinary work. She always had “a profound love of internal medicine,” and when the time came to choose her specialty, she found herself torn between oncology and immunology and rheumatology. Ultimately she chose immunology and rheumatology, but as she points out, in many ways her career has now come full circle: After years at UC-San Francisco, then Genentech, and now Stanford, her work has resulted in the creation of a new interdisciplinary project: the Immune-Related Toxicity Group.

The idea for this group arose from the growing trend of applying immunology to cancer treatments, and in Katsumoto’s case, the use of checkpoint inhibitors to fight tumors. As Katsumoto explains, “Normally, the immune system is capable of identifying a tumor and mounting a productive response against it. When cancer develops, often the tumor evolves mechanisms of resisting immune attack.” The checkpoint inhibitors administered by doctors then block the resistance mechanism of the tumor, thereby “unleashing the immune system by taking the brakes off” and allowing the immune system to recognize and attack the tumor. Checkpoint inhibitors have generated impressive long-term responses in some patients, but there’s a secondary issue. When you take the brakes off the immune system, it leaves the patient vulnerable to “immune-related adverse events.”

“Sometimes you get collateral damage to your own internal organs,” Katsumoto says. That’s where she and her colleagues in medicine—jokingly referred to as “the cleanup crew”—come in, and how she first got the idea for the group.

Tamiko Katsumoto, MD, explains her work.

Katsumoto realized while treating these adverse events that there were still knowledge gaps, despite the existence of several guidelines. Clinical questions frequently arise, such as how to optimally manage these adverse events, whether it’s safe to restart the checkpoint inhibitor, and whether it’s safe to use checkpoint inhibitors in patients with pre-existing autoimmunity. Katsumoto wondered about creating a working group, akin to a tumor board, that could provide consultative services, a database, and even a biobank for all these adverse events. As Katsumoto puts it, “It became clear that there was a need for us to come together as a larger multidisciplinary group to really discuss these cases and learn from each other.”

The group is still in its infancy, but Katsumoto has identified interested parties from various disciplines (including oncology, dermatology, gastroenterology, pulmonary medicine, endocrinology, nephrology, hepatology, and neurology), and she’s already getting referrals for patients from colleagues. She’s also involved in a large multisite NIH trial seeking to discover whether patients with pre-existing autoimmunity can safely use checkpoint inhibitor therapy. Another major project involves biomarkers: If doctors can discover which biomarkers identify patients who will respond negatively to checkpoint inhibitor therapy, they can identify problems before any therapy is administered.

She’s hoping to convene the group as a resource for doctors in this rapidly changing field. “This could be a springboard for a lot of collaborative research projects,” Katsumoto envisions. She also hopes that identifying “point people” in various divisions can help improve clinical care.

The Immune-Related Toxicity Group is a relatively new idea for Katsumoto, but her goals for the project prove her determination, and her collaborators are just as eager. “The use of checkpoint inhibitor therapy is growing, almost exponentially. More and more medications are getting approved for new indications every day,” Katsumoto says. And that only proves the greater need for collaboration. As Katsumoto asserts, “The field is growing in real time. We need to band together.”

CREDENCE Brings Together Multiple Groups in Successful Trial

Baldeep Singh, MD, with staff at Samaritan House

Sun Kim, MD, MS, a principal investigator for CREDENCE, examines a patient with Type 2 diabetes.

CREDENCE Brings Together Multiple Groups in Successful Trial

Sun Kim, MD, MS, a principal investigator for CREDENCE, examines a patient with Type 2 diabetes.

CREDENCE Brings Together Multiple Groups in Successful Trial

Sun Kim, MD, MS, associate professor of endocrinology, was a principal investigator at Stanford for a recent randomized, placebo-controlled clinical trial of the drug canagliflozin, which is a sodium glucose co-transporter 2 inhibitor. This class of drug for Type 2 diabetes controls high blood sugar while lowering the risk of death from heart attack or stroke in patients who also have heart disease.

Canagliflozin was approved by the Food and Drug Administration based on the CANagliflozin cardioVascular Assessment Study, or CANVAS, which assessed the drug in patients with or at high risk of cardiovascular disease. Patients were excluded unless they had “almost normal kidneys,” according to Tara Chang, MD, associate professor of nephrology, who is director of clinical research for the division of nephrology.

Yet patients with Type 2 diabetes are at high risk for kidney disease, so testing the drug in diabetic patients with kidney disease became the aim of another clinical trial, CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy).

“What made us so excited about CREDENCE was that we focused on people with advanced kidney disease,” says Chang. “CREDENCE was a sicker population than CANVAS with regard to kidney disease, and canagliflozin worked amazingly well.”

The primary composite end point of the study included end-stage kidney disease, doubling of serum creatinine, or renal or cardiovascular death. End-stage kidney disease was defined as needing dialysis, getting a kidney transplant, or having kidney function less than 15% of normal. 

In the end, says Chang, “People randomized to canagliflozin had a 30% lower rate of this primary outcome compared with patients who were randomized to placebo.”

That was a home run: The trial was ended early because of benefit, a rarity. It is the first trial in nearly 20 years to identify a therapy that slows progression to renal failure in patients with Type 2 diabetes.

A few years ago, says Kim, Stanford’s Department of Medicine participated in few clinical trials. “Stanford has a long history of strength in basic science research,” she explains, “and we have really great mechanistic and physiology studies. But we weren’t focusing much on clinical trials. The infrastructure to support clinical research was very cumbersome; just simple Institutional Review Board approval was very time-consuming.”

Sun Kim, MD, MS, associate professor of endocrinology, was a principal investigator at Stanford for a recent randomized, placebo-controlled clinical trial of the drug canagliflozin, which is a sodium glucose co-transporter 2 inhibitor. This class of drug for Type 2 diabetes controls high blood sugar while lowering the risk of death from heart attack or stroke in patients who also have heart disease.

Canagliflozin was approved by the Food and Drug Administration based on the CANagliflozin cardioVascular Assessment Study, or CANVAS, which assessed the drug in patients with or at high risk of cardiovascular disease. Patients were excluded unless they had “almost normal kidneys,” according to Tara Chang, MD, associate professor of nephrology, who is director of clinical research for the division of nephrology.

Yet patients with Type 2 diabetes are at high risk for kidney disease, so testing the drug in diabetic patients with kidney disease became the aim of another clinical trial, CREDENCE (Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy).

“What made us so excited about CREDENCE was that we focused on people with advanced kidney disease,” says Chang. “CREDENCE was a sicker population than CANVAS with regard to kidney disease, and canagliflozin worked amazingly well.”

The primary composite end point of the study included end-stage kidney disease, doubling of serum creatinine, or renal or cardiovascular death. End-stage kidney disease was defined as needing dialysis, getting a kidney transplant, or having kidney function less than 15% of normal. In the end, says Chang, “People randomized to canagliflozin had a 30% lower rate of this primary outcome compared with patients who were randomized to placebo.”

That was a home run: The trial was ended early because of benefit, a rarity. It is the first trial in nearly 20 years to identify a therapy that slows progression to renal failure in patients with Type 2 diabetes.

A few years ago, says Kim, Stanford’s Department of Medicine participated in few clinical trials. “Stanford has a long history of strength in basic science research,” she explains, “and we have really great mechanistic and physiology studies. But we weren’t focusing much on clinical trials. The infrastructure to support clinical research was very cumbersome; just simple Institutional Review Board approval was very time-consuming.”

Then Ken Mahaffey, MD, professor of cardiovascular medicine, started up the Stanford Center for Clinical Research, and the department began to grow its participation in clinical trials. Kim mentions a few pain points that have eased in recent years: “Ken streamlined a lot of logistics and helped with operational aspects of the larger programs for grant and proposal submissions.”

Much of the reward of participating in CREDENCE for Kim was working with a team to design and conduct the trial, including other Stanford researchers with important roles: Mahaffey as the overall study co-principal investigator with Vlado Perkovic from Australia as well as Chang and Glenn Chertow, MD, MPH, professor of nephrology, as national leaders in the United States responsible for site recruitment and retention and data quality. Mahaffey also co-led and Chang was a member of the event adjudication committee.

Kim affectionately calls her partnership with Mahaffey and Chang the CKD (cardiology, kidney, diabetes) group. As a caregiver, she says, “It’s exciting to tell a patient that this drug can control glucose, and it has other benefits like helping the kidneys and the heart.”

The CREDENCE database is a rich one, and abstracts are already underway for upcoming meetings in endocrinology, nephrology, and cardiology to inform the medical community about the striking results.

Then Ken Mahaffey, MD, professor of cardiovascular medicine, started up the Stanford Center for Clinical Research, and the department began to grow its participation in clinical trials. Kim mentions a few pain points that have eased in recent years: “Ken streamlined a lot of logistics and helped with operational aspects of the larger programs for grant and proposal submissions.”

Much of the reward of participating in CREDENCE for Kim was working with a team to design and conduct the trial, including other Stanford researchers with important roles: Mahaffey as the overall study co-principal investigator with Vlado Perkovic from Australia as well as Chang and Glenn Chertow, MD, MPH, professor of nephrology, as national leaders in the United States responsible for site recruitment and retention and data quality. Mahaffey also co-led and Chang was a member of the event adjudication committee.

Kim affectionately calls her partnership with Mahaffey and Chang the CKD (cardiology, kidney, diabetes) group. As a caregiver, she says, “It’s exciting to tell a patient that this drug can control glucose, and it has other benefits like helping the kidneys and the heart.”

The CREDENCE database is a rich one, and abstracts are already underway for upcoming meetings in endocrinology, nephrology, and cardiology to inform the medical community about the striking results.

New Approaches to Tobacco Control

Baldeep Singh, MD, with staff at Samaritan House

New Approaches to Tobacco Control

New Approaches to Tobacco Control

The tobacco products of today are not just your grandfather’s unfiltered Lucky Strikes or Camels, but rather natural and organic cigarettes, confectionary-flavored e-cigarettes and vapes, and emerging heated tobacco products. Jodi Prochaska, PhD, MPH, associate professor of medicine with the Stanford Prevention Research Center, is making seminal contributions to the rapidly changing field of tobacco control.

Prochaska has over a dozen active grants, all directed at addressing tobacco and nicotine use, from evaluations of novel treatments to study of policy dissemination to advances in medical education.

Tobacco Use in Alaska
Prochaska’s most scenic project is centered in the Norton Sound region, an inlet in the Bering Sea off the west coast of Alaska. Funded by the National Heart, Lung, and Blood Institute, the Healing and Empowering Alaskan Lives Toward Healthy Hearts (HEALTHH) project uses telemedicine to address significant inequities in tobacco use and tobacco-related disease in the region. About half of Alaska Native men and a third of Alaska Native women smoke—a level of prevalence that hasn’t been seen in the continental United States since the 1960s. “It’s a very high smoking prevalence in a remote location, without easy access to treatment. Developing partnerships and trust is critical,” Prochaska states.

The HEALTHH project works closely with the local tribal health council, in collaboration with a team in Anchorage, including two doctoral students of Alaska Native heritage who received their own fellowship awards on the project.

Launched in 2012, the HEALTHH team has made over 125 trips to the Norton Sound region. “Half the 299 participants are randomized to telemedicine-based counseling for quitting smoking and exercising, and half are randomized to telemedicine-based counseling for a heart-healthy Native diet and compliance with medications for hypertension and/or high cholesterol,” Prochaska explains. Though too early for outcome results, Prochaska says, “The telemedicine treatment approach has been rated highly, and participants are sharing their successes.”

The tobacco products of today are not just your grandfather’s unfiltered Lucky Strikes or Camels, but rather natural and organic cigarettes, confectionary-flavored e-cigarettes and vapes, and emerging heated tobacco products. Jodi Prochaska, PhD, MPH, associate professor of medicine with the Stanford Prevention Research Center, is making seminal contributions to the rapidly changing field of tobacco control.

Prochaska has over a dozen active grants, all directed at addressing tobacco and nicotine use, from evaluations of novel treatments to study of policy dissemination to advances in medical education.

Tobacco Use in Alaska
Prochaska’s most scenic project is centered in the Norton Sound region, an inlet in the Bering Sea off the west coast of Alaska. Funded by the National Heart, Lung, and Blood Institute, the Healing and Empowering Alaskan Lives Toward Healthy Hearts (HEALTHH) project uses telemedicine to address significant inequities in tobacco use and tobacco-related disease in the region. About half of Alaska Native men and a third of Alaska Native women smoke—a level of prevalence that hasn’t been seen in the continental United States since the 1960s. “It’s a very high smoking prevalence in a remote location, without easy access to treatment. Developing partnerships and trust is critical,” Prochaska states.

The HEALTHH project works closely with the local tribal health council, in collaboration with a team in Anchorage, including two doctoral students of Alaska Native heritage who received their own fellowship awards on the project.

Launched in 2012, the HEALTHH team has made over 125 trips to the Norton Sound region. “Half the 299 participants are randomized to telemedicine-based counseling for quitting smoking and exercising, and half are randomized to telemedicine-based counseling for a heart-healthy Native diet and compliance with medications for hypertension and/or high cholesterol,” Prochaska explains. Though too early for outcome results, Prochaska says, “The telemedicine treatment approach has been rated highly, and participants are sharing their successes.”

The Challenge of Vaping
As for e-cigarettes, Prochaska notes, “The science is trying to catch up with the unregulated free-market growth of e-cigarettes, and there’s a huge gap in training for clinicians in terms of best practice for when a patient asks about vaping.” She and her colleagues created a free online CME course to help clinicians work through scenarios with patients asking about e-cigarettes. From an earlier project, Prochaska and her colleagues, in collaboration with HealthTap, studied hundreds of patient-doctor interactions on e-cigarettes, then designed and evaluated a highly interactive course to address the most prevalent concerns. Prochaska describes the course as “a non-linear, Go-Pro, first-person, choose-your-own-adventure, clinician-led experience.” She explains, “The course features a day in the life of a clinician—exposed to media reports on e-cigarettes; in the exam room, encountering patient questions about vaping; and venturing out to visit a virtual vape shop.” So far, over 1,000 health care providers from 70 nations have taken the course. Knowledge scores have significantly improved, and course ratings have been high.

Prochaska is also the faculty director for the Department of Medicine’s Master of Science (MS) Program in Community Health and Prevention Research. She teaches a highly rated course on theories of behavior change and community-based interventions.

Prochaska is a product of social scientists who emphasized “higher education, service to the community, and well-being.” Her father, James Prochaska, developed one of the field’s leading theories of behavior change. Her early start, with an emphasis on “encouragement to ask questions and seek out answers,” has served her well through two decades in the tobacco control field and will continue to help her pursue solutions on the increasingly complicated tobacco frontier.

The Challenge of Vaping
As for e-cigarettes, Prochaska notes, “The science is trying to catch up with the unregulated free-market growth of e-cigarettes, and there’s a huge gap in training for clinicians in terms of best practice for when a patient asks about vaping.” She and her colleagues created a free online CME course to help clinicians work through scenarios with patients asking about e-cigarettes. From an earlier project, Prochaska and her colleagues, in collaboration with HealthTap, studied hundreds of patient-doctor interactions on e-cigarettes, then designed and evaluated a highly interactive course to address the most prevalent concerns. Prochaska describes the course as “a non-linear, Go-Pro, first-person, choose-your-own-adventure, clinician-led experience.” She explains, “The course features a day in the life of a clinician—exposed to media reports on e-cigarettes; in the exam room, encountering patient questions about vaping; and venturing out to visit a virtual vape shop.” So far, over 1,000 health care providers from 70 nations have taken the course. Knowledge scores have significantly improved, and course ratings have been high.

Prochaska is also the faculty director for the Department of Medicine’s Master of Science (MS) Program in Community Health and Prevention Research. She teaches a highly rated course on theories of behavior change and community-based interventions.

Prochaska is a product of social scientists who emphasized “higher education, service to the community, and well-being.” Her father, James Prochaska, developed one of the field’s leading theories of behavior change. Her early start, with an emphasis on “encouragement to ask questions and seek out answers,” has served her well through two decades in the tobacco control field and will continue to help her pursue solutions on the increasingly complicated tobacco frontier.

Regulatory T Cells Join the Mainstream

Baldeep Singh, MD, with staff at Samaritan House

Everett Meyer, MD, PhD, leads a team that replaces immunosuppressive agents with T regulatory cells for patients with specific cancers.

Regulatory T Cells Join the Mainstream

Everett Meyer, MD, PhD, leads a team that replaces immunosuppressive agents with T regulatory cells for patients with specific cancers.

Regulatory T Cells Join the Mainstream

Just 70 years ago, cancers of the blood were essentially untreatable while other cancers, of solid organs for instance, could be cut out with surgery or burned out with radiation. Eventually chemotherapeutic agents became capable of killing a cancer without killing the patient, but they were brutal. Then along came blood and marrow transplantation which could give patients a new lease on life. However, they required immunosuppressive agents to keep the patient’s immune system from rejecting the transplant—and those came with serious side effects. Consistent steps forward but always with asterisks.

Today some high-risk patients at Stanford with severe cancers, including leukemias, lymphoma, and myelodysplastic syndrome, are enrolled in a Phase 2 randomized clinical trial in which they forgo immunosuppression in favor of treatment with T regulatory cells, known as T regs, thanks to work by a team led by Everett Meyer, MD, PhD, assistant professor of blood and marrow transplantation.

Progress has been slow and steady. According to Meyer, “It’s actually been a 20-year effort. The proof of concept was done in 2003, and the trial itself opened in 2011.

After I joined as faculty in 2015 and the person who had opened the trial left, I revamped it and did some basic science to fix some problems. Once we reopened the trial we had pretty good success.”

Patients in the trial are quite sick, Meyer explains, and their course is rigorous: “They’ve either failed an initial therapy or they’re so high risk that we expect their disease to come back. They need a bone marrow transplant, and we have to get donor grafts into them and then prevent their grafts from causing graft-versus-host disease, a major complication.

Just 70 years ago, cancers of the blood were essentially untreatable while other cancers, of solid organs for instance, could be cut out with surgery or burned out with radiation. Eventually chemotherapeutic agents became capable of killing a cancer without killing the patient, but they were brutal. Then along came blood and marrow transplantation which could give patients a new lease on life. However, they required immunosuppressive agents to keep the patient’s immune system from rejecting the transplant—and those came with serious side effects. Consistent steps forward but always with asterisks.

Today some high-risk patients at Stanford with severe cancers, including leukemias, lymphoma, and myelodysplastic syndrome, are enrolled in a Phase 2 randomized clinical trial in which they forgo immunosuppression in favor of treatment with T regulatory cells, known as T regs, thanks to work by a team led by Everett Meyer, MD, PhD, assistant professor of blood and marrow transplantation.

Progress has been slow and steady. According to Meyer, “It’s actually been a 20-year effort. The proof of concept was done in 2003, and the trial itself opened in 2011. After I joined as faculty in 2015 and the person who had opened the trial left, I revamped it and did some basic science to fix some problems. Once we reopened the trial we had pretty good success.”

Patients in the trial are quite sick, Meyer explains, and their course is rigorous: “They’ve either failed an initial therapy or they’re so high risk that we expect their disease to come back. They need a bone marrow transplant, and we have to get donor grafts into them and then prevent their grafts from causing graft-versus-host disease, a major complication. We also need to allow their new donor immune system the space and freedom to attack and kill the cancer. That graft-versus-leukemia effect is the secret sauce of our transplant.”

Once a patient receives a bone marrow transplant, T regs attempt to teach the patient’s new immune system how to regrow in a way that will help the anti-leukemia response and prevent complications. Using immunosuppressive medications, on the other hand, is a “strategy that essentially says we’re going to cripple the immune system just enough to make it work,” according to Meyer.

Not all patients in the ongoing randomized trial get to skip immunosuppressive medications. Only half the patients get T regs alone while the other half get T regs plus a single-agent immunosuppressive. By comparing the two groups, Meyer will be able “to understand how effective these T regulatory cells are. So far, we’ve seen very few mild cases of graft-versus-host disease in the 17 patients we’ve treated.”

T regulatory cells have shown promise in newer frontiers such as solid organ transplant and islet tolerance, and the treatment of autoimmune disorders such as rheumatic disease or Type 1 diabetes. Meyer considers himself fortunate to have collaborators in many divisions: Seung Kim, MD, PhD, professor of developmental biology; Justin Annes, MD, PhD, assistant professor of endocrinology; Sam Strober, MD, professor of rheumatology and immunology; Robert Negrin, MD, professor and chief of blood and marrow transplantation; and Judith Shizuru, MD, professor of blood and marrow transplantation, have been “guiding forces.”

He is especially pleased to work with “the people who do cell therapy, because they’re the quiet, unsung, committed heroes moving things forward. I know certain things, but I know I don’t know more. And they do. Being able to interact with them is a gift.”

“It’s nice to talk to students and fellows, tell them this is the future, and wonder how much further they’re going to take it.”

We also need to allow their new donor immune system the space and freedom to attack and kill the cancer. That graft-versus-leukemia effect is the secret sauce of our transplant.”

Once a patient receives a bone marrow transplant, T regs attempt to teach the patient’s new immune system how to regrow in a way that will help the anti-leukemia response and prevent complications. Using immunosuppressive medications, on the other hand, is a “strategy that essentially says we’re going to cripple the immune system just enough to make it work,” according to Meyer.

Not all patients in the ongoing randomized trial get to skip immunosuppressive medications. Only half the patients get T regs alone while the other half get T regs plus a single-agent immunosuppressive. By comparing the two groups, Meyer will be able “to understand how effective these T regulatory cells are. So far, we’ve seen very few mild cases of graft-versus-host disease in the 17 patients we’ve treated.”

T regulatory cells have shown promise in newer frontiers such as solid organ transplant and islet tolerance, and the treatment of autoimmune disorders such as rheumatic disease or Type 1 diabetes. Meyer considers himself fortunate to have collaborators in many divisions: Seung Kim, MD, PhD, professor of developmental biology; Justin Annes, MD, PhD, assistant professor of endocrinology; Sam Strober, MD, professor of rheumatology and immunology; Robert Negrin, MD, professor and chief of blood and marrow transplantation; and Judith Shizuru, MD, professor of blood and marrow transplantation, have been “guiding forces.”

He is especially pleased to work with “the people who do cell therapy, because they’re the quiet, unsung, committed heroes moving things forward. I know certain things, but I know I don’t know more. And they do. Being able to interact with them is a gift.”

“It’s nice to talk to students and fellows, tell them this is the future, and wonder how much further they’re going to take it.”

Diagnosing Lung Disease with Help from Computers

Baldeep Singh, MD, with staff at Samaritan House

Joe Hsu, MD (left) and Husham Sharifi, MD, discuss diagnostic techniques using machine learning.

Diagnosing Lung Disease with Help from Computers

Joe Hsu, MD (left) and Husham Sharifi, MD, discuss diagnostic techniques using machine learning.

Diagnosing Lung Disease with Help from Computers

APPLYING MACHINE LEARNING ALGORITHMS TO PATIENT DATA IS HELPING STANFORD RESEARCHERS BETTER DIAGNOSE AND TREAT LUNG DISEASE.

Parts of medicine can be trial and error—if one drug doesn’t work, try another; if a diagnosis isn’t leading to a cure, maybe the diagnosis is wrong. But eliminating that trial and error, through more informed diagnostic tests, saves time for both clinicians and patients. In the division of pulmonary, allergy and critical care medicine, machine learning algorithms are now guiding those more personalized treatment decisions.

“We’re at a critical juncture in pulmonary medicine, where innovative analysis approaches are needed to handle the large number of patient samples and clinical variables we are collecting for research,” says Andrew Sweatt, MD, a clinical assistant professor of pulmonary, allergy, and critical care medicine. “Machine learning is a promising tool that can help us with most of this high-throughput data.”

In machine learning, a computer program sifts through data—whether it’s information on the levels of different molecules in a blood sample or scans of the lungs—and finds otherwise hidden patterns. Often, such programs can do a better job than the human eye at spotting structure in the data, finding correlations between data and patient outcomes, or pinpointing groups of variables that set some patients apart.

“We’re not trying to replace doctors, but with machine learning, there’s a huge potential for augmenting clinical decisions by physicians,” says Husham Sharifi, MD, instructor of pulmonary, allergy, and critical care medicine.

Guiding the Treatment of a Rare Disease
Many patients with pulmonary arterial hypertension (PAH) have other underlying diseases—scleroderma, lupus, cirrhosis, congenital heart disease, or HIV, to name a few.

Others have been exposed to drugs or toxins, such as methamphetamine. And in roughly a third to half of patients, the rare lung disease appears without any explanation. In all cases, though, the underlying disease is the same: The small arteries that carry blood through the lungs narrow over time due to structural changes. This progression leads to high blood pressure in the lungs and places strain on the heart.

“It’s a very aggressive disease, and there’s a lot of room to improve patient outcomes,” says Sweatt.

Without treatment, nearly half of all patients die within five years of their diagnosis. Over the past decade, several drugs have been approved to treat PAH. The treatments don’t consistently work in all patients, however, although they all have the same mechanism—to relax and open blood vessels.

 

APPLYING MACHINE LEARNING ALGORITHMS TO PATIENT DATA IS HELPING STANFORD RESEARCHERS BETTER DIAGNOSE AND TREAT LUNG DISEASE.

Parts of medicine can be trial and error—if one drug doesn’t work, try another; if a diagnosis isn’t leading to a cure, maybe the diagnosis is wrong. But eliminating that trial and error, through more informed diagnostic tests, saves time for both clinicians and patients. In the division of pulmonary, allergy and critical care medicine, machine learning algorithms are now guiding those more personalized treatment decisions.

“We’re at a critical juncture in pulmonary medicine, where innovative analysis approaches are needed to handle the large number of patient samples and clinical variables we are collecting for research,” says Andrew Sweatt, MD, a clinical assistant professor of pulmonary, allergy, and critical care medicine. “Machine learning is a promising tool that can help us with most of this high-throughput data.”

In machine learning, a computer program sifts through data—whether it’s information on the levels of different molecules in a blood sample or scans of the lungs—and finds otherwise hidden patterns. Often, such programs can do a better job than the human eye at spotting structure in the data, finding correlations between data and patient outcomes, or pinpointing groups of variables that set some patients apart.

“We’re not trying to replace doctors, but with machine learning, there’s a huge potential for augmenting clinical decisions by physicians,” says Husham Sharifi, MD, instructor of pulmonary, allergy, and critical care medicine.

Guiding the Treatment of a Rare Disease
Many patients with pulmonary arterial hypertension (PAH) have other underlying diseases—scleroderma, lupus, cirrhosis, congenital heart disease, or HIV, to name a few. Others have been exposed to drugs or toxins, such as methamphetamine. And in roughly a third to half of patients, the rare lung disease appears without any explanation. In all cases, though, the underlying disease is the same: The small arteries that carry blood through the lungs narrow over time due to structural changes. This progression leads to high blood pressure in the lungs and places strain on the heart.

“It’s a very aggressive disease, and there’s a lot of room to improve patient outcomes,” says Sweatt.

Without treatment, nearly half of all patients die within five years of their diagnosis. Over the past decade, several drugs have been approved to treat PAH. The treatments don’t consistently work in all patients, however, although they all have the same mechanism—to relax and open blood vessels.

A large body of research has suggested that there’s a component of PAH that’s mediated by the immune system, and new drugs are in development to target this inflammation. Sweatt wanted to know whether some patients would be better helped by these new drugs. Until now, PAH has been grouped into subtypes based on the patient’s underlying predisposition, and all subtypes have been treated the same.

Sweatt and his colleagues collected blood samples from 385 PAH patients and measured levels of 48 immune proteins and signaling molecules. Then they let a machine-learning program parse the data set.

“My goal was to remain agnostic by avoiding common pre-conceived notions about the disease, and instead let the molecular data alone tell the story,” says Sweatt.

It worked—the program revealed four previously unknown subtypes of PAH based on the immune profiles of the patients. One-third of the patients studied had minimal inflammation, suggesting that drugs targeting the immune system may not be helpful for them. The three other groups were each distinguished by their unique inflammatory signatures in the blood.

Importantly, the clinical disease severity and risk of death also differed among the four subgroups.

“What really stood out is that these immune phenotypes were completely independent of the cause of PAH,” says Sweatt. In other words, patients who had underlying immune diseases like lupus or scleroderma were just as likely to be in each subcategory of PAH as patients with no underlying disease. “It means we really detected a hidden system for classifying patients that is highly relevant to underlying disease biology and clinical outcomes,” he says.

The data suggest that different types of immune drugs may work against PAH for different patients, but more work is needed to determine whether the new immune subtypes can help guide treatment. Sweatt’s research has been recognized as an innovative first step toward precision medicine in PAH. Building on this foundational work, Sweatt also has additional machine learning–based studies planned to better understand the biological underpinnings and therapy ramifications of each immune subtype.

It was seeing things that the eye couldn’t necessarily pick up on and improving the diagnosis

Narrowing Down a Diagnosis
Another challenge involves graft-versus-host disease of the lungs—also known as bronchiolitis obliterans syndrome (BOS). In that case, the challenge is not differentiating subtypes of patients, but diagnosing them in the first place. Graft-versus-host disease is a complication of a bone marrow or blood stem cell transplant in which the donated bone marrow or stem cells start attacking the body. But BOS can closely resemble other common complications of a transplant, including infections and inflammatory disorders.

“All these types of lung disease are poorly defined,” says Joe Hsu, MD, an assistant professor of pulmonary, allergy, and critical care medicine. “The way we typically diagnose graft-versus-host disease is to look for everything else and, if we don’t find anything else, diagnose that.”

Hsu and Sharifi wanted to do better at diagnosing BOS. They started collecting CT scans from patients with BOS as well as from transplant patients who had similar symptoms but did not have BOS. Then they used a machine learning approach—telling a computer program which cases were which and letting it learn how to differentiate them.

The machine, it turned out, became so good at telling BOS apart from other lung diseases that it was even slightly better than thoracic radiologists, who regularly read CT scans of the chest. The program learned to differentiate normal lung, mild BOS, severe BOS, and alternative diagnoses.

“It was seeing things that the eye couldn’t necessarily pick up on and improving the diagnosis quite a bit,” says Hsu.

Since each diagnosis is treated differently, fast and easy diagnosis is critical. Hsu and Sharifi say in the future, similar programs might be able to differentiate other diagnoses as well, such as chronic obstructive pulmonary disease (COPD). Pulmonology, Sharifi points out, is full of numerical and imaging data that can be leveraged with machine learning.

“For a lot of other aspects of medicine, it’s a bigger challenge to integrate artificial intelligence because clinical notes can be so messy and unstructured,” he says. “But this is a good example of where algorithmic and computational analysis can be used hand in hand with a doctor’s advanced training and experience.”

A large body of research has suggested that there’s a component of PAH that’s mediated by the immune system, and new drugs are in development to target this inflammation. Sweatt wanted to know whether some patients would be better helped by these new drugs. Until now, PAH has been grouped into subtypes based on the patient’s underlying predisposition, and all subtypes have been treated the same.

Sweatt and his colleagues collected blood samples from 385 PAH patients and measured levels of 48 immune proteins and signaling molecules. Then they let a machine-learning program parse the data set.

“My goal was to remain agnostic by avoiding common pre-conceived notions about the disease, and instead let the molecular data alone tell the story,” says Sweatt.

It worked—the program revealed four previously unknown subtypes of PAH based on the immune profiles of the patients. One-third of the patients studied had minimal inflammation, suggesting that drugs targeting the immune system may not be helpful for them. The three other groups were each distinguished by their unique inflammatory signatures in the blood.

Importantly, the clinical disease severity and risk of death also differed among the four subgroups.

“What really stood out is that these immune phenotypes were completely independent of the cause of PAH,” says Sweatt. In other words, patients who had underlying immune diseases like lupus or scleroderma were just as likely to be in each subcategory of PAH as patients with no underlying disease. “It means we really detected a hidden system for classifying patients that is highly relevant to underlying disease biology and clinical outcomes,” he says.

The data suggest that different types of immune drugs may work against PAH for different patients, but more work is needed to determine whether the new immune subtypes can help guide treatment. Sweatt’s research has been recognized as an innovative first step toward precision medicine in PAH. Building on this foundational work, Sweatt also has additional machine learning–based studies planned to better understand the biological underpinnings and therapy ramifications of each immune subtype.

It was seeing things that the eye couldn’t necessarily pick up on and improving the diagnosis

Narrowing Down a Diagnosis
Another challenge involves graft-versus-host disease of the lungs—also known as bronchiolitis obliterans syndrome (BOS). In that case, the challenge is not differentiating subtypes of patients, but diagnosing them in the first place. Graft-versus-host disease is a complication of a bone marrow or blood stem cell transplant in which the donated bone marrow or stem cells start attacking the body. But BOS can closely resemble other common complications of a transplant, including infections and inflammatory disorders.

“All these types of lung disease are poorly defined,” says Joe Hsu, MD, an assistant professor of pulmonary, allergy, and critical care medicine. “The way we typically diagnose graft-versus-host disease is to look for everything else and, if we don’t find anything else, diagnose that.”

Hsu and Sharifi wanted to do better at diagnosing BOS. They started collecting CT scans from patients with BOS as well as from transplant patients who had similar symptoms but did not have BOS. Then they used a machine learning approach—telling a computer program which cases were which and letting it learn how to differentiate them.

The machine, it turned out, became so good at telling BOS apart from other lung diseases that it was even slightly better than thoracic radiologists, who regularly read CT scans of the chest. The program learned to differentiate normal lung, mild BOS, severe BOS, and alternative diagnoses.

“It was seeing things that the eye couldn’t necessarily pick up on and improving the diagnosis quite a bit,” says Hsu.

Since each diagnosis is treated differently, fast and easy diagnosis is critical. Hsu and Sharifi say in the future, similar programs might be able to differentiate other diagnoses as well, such as chronic obstructive pulmonary disease (COPD). Pulmonology, Sharifi points out, is full of numerical and imaging data that can be leveraged with machine learning.

“For a lot of other aspects of medicine, it’s a bigger challenge to integrate artificial intelligence because clinical notes can be so messy and unstructured,” he says. “But this is a good example of where algorithmic and computational analysis can be used hand in hand with a doctor’s advanced training and experience.”