LAS VEGAS – Cases of cutaneous squamous cell carcinoma (cSCC) are on the rise and are associated with mortality rates similar to melanoma. But even as cSCC draws more attention, two popular staging systems still need refinement, a hematologist-oncologist told dermatologist colleagues.

Both staging systems can be helpful, however, Guilherme Rabinowits, MD, said at Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar. “The best thing to do is combine both,” he noted, referring to the staging system developed by the Brigham and Women’s Hospital (BWH) and staging systems released in the 7th and 8th editions of the American Joint Committee on Cancer Staging Manual (AJCC 7 and AJCC 8; the latter focuses on head and neck only).

Cutaneous SCC has become a “huge health care burden,” said Dr. Rabinowits of the Miami Cancer Institute/Baptist Health South Florida and Florida International University, Miami. He referred to Medicare data suggesting that cSCC has become as common as basal cell carcinoma (JAMA Dermatol. 2015 Oct;151[10]:1081-6).

While most patients with cSCC have a positive prognosis, he added, the 5-year survival rate among those with the most aggressive disease is only 25%.

As he pointed out, staging systems provide insight into prognosis and treatment, guide appropriate monitoring, and give a common language to clinicians around the world. “When I talk about stage 3, we all understand who we’re talking about,” he said.

Dr. Rabinowits said he formerly worked at BWH so he is especially comfortable with its staging system. It can be appropriate to use both the BWH and AJCC systems at once, he said, noting, however, that studies suggest that the BWH system is superior.

An analysis released in 2014, for example, found that most poor outcomes occurred in patients whose tumors had been rated at lower stages – suggesting less risk – in the AJCC 7 system (J Clin Oncol 2014 Feb 1;32[4]:327-4).

In contrast, the 5% of tumors that were rated at the highest stages in the BWH system – with the highest level of perceived risk – accounted for 70% of nodal metastases and 83% of disease-specific deaths. This group may deserve extra attention in terms of staging and adjuvant treatment in order to improve outcomes, he said.

A study published this year, which compared the BWH and AJCC 8 staging systems, found that they had the same negative predictive value (0.99), while the BWH system showed higher positive predictive value (0.30 vs. 0.17). “Use of BWH tumor classification may minimize the number of patients recommended for radiologic evaluation, close surveillance, and possible adjuvant therapy while still identifying most patients at risk for recurrence, metastasis, and death,” the authors wrote (JAMA Dermatol. 2019 Jul 1;155[7]: 819-25).

As for treatment of localized disease in high-risk patients, Dr. Rabinowits advised turning to a multidisciplinary team for guidance because there are limited prospective randomized data.

Dr. Rabinowits discloses scientific advisory board/consultant relationships (Merck, Regeneron, Sanofi, EMD Serono, Pfizer, and Castle) and shares in Regeneron and Syros Pharmaceuticals. He spoke during a forum on cutaneous malignancies at the meeting.

SDEF and this news organization are owned by the same parent company.

LAS VEGAS – Cases of cutaneous squamous cell carcinoma (cSCC) are on the rise and are associated with mortality rates similar to melanoma. But even as cSCC draws more attention, two popular staging systems still need refinement, a hematologist-oncologist told dermatologist colleagues.

Both staging systems can be helpful, however, Guilherme Rabinowits, MD, said at Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar. “The best thing to do is combine both,” he noted, referring to the staging system developed by the Brigham and Women’s Hospital (BWH) and staging systems released in the 7th and 8th editions of the American Joint Committee on Cancer Staging Manual (AJCC 7 and AJCC 8; the latter focuses on head and neck only).

Cutaneous SCC has become a “huge health care burden,” said Dr. Rabinowits of the Miami Cancer Institute/Baptist Health South Florida and Florida International University, Miami. He referred to Medicare data suggesting that cSCC has become as common as basal cell carcinoma (JAMA Dermatol. 2015 Oct;151[10]:1081-6).

While most patients with cSCC have a positive prognosis, he added, the 5-year survival rate among those with the most aggressive disease is only 25%.

As he pointed out, staging systems provide insight into prognosis and treatment, guide appropriate monitoring, and give a common language to clinicians around the world. “When I talk about stage 3, we all understand who we’re talking about,” he said.

Dr. Rabinowits said he formerly worked at BWH so he is especially comfortable with its staging system. It can be appropriate to use both the BWH and AJCC systems at once, he said, noting, however, that studies suggest that the BWH system is superior.

An analysis released in 2014, for example, found that most poor outcomes occurred in patients whose tumors had been rated at lower stages – suggesting less risk – in the AJCC 7 system (J Clin Oncol 2014 Feb 1;32[4]:327-4).

In contrast, the 5% of tumors that were rated at the highest stages in the BWH system – with the highest level of perceived risk – accounted for 70% of nodal metastases and 83% of disease-specific deaths. This group may deserve extra attention in terms of staging and adjuvant treatment in order to improve outcomes, he said.

A study published this year, which compared the BWH and AJCC 8 staging systems, found that they had the same negative predictive value (0.99), while the BWH system showed higher positive predictive value (0.30 vs. 0.17). “Use of BWH tumor classification may minimize the number of patients recommended for radiologic evaluation, close surveillance, and possible adjuvant therapy while still identifying most patients at risk for recurrence, metastasis, and death,” the authors wrote (JAMA Dermatol. 2019 Jul 1;155[7]: 819-25).

As for treatment of localized disease in high-risk patients, Dr. Rabinowits advised turning to a multidisciplinary team for guidance because there are limited prospective randomized data.

Dr. Rabinowits discloses scientific advisory board/consultant relationships (Merck, Regeneron, Sanofi, EMD Serono, Pfizer, and Castle) and shares in Regeneron and Syros Pharmaceuticals. He spoke during a forum on cutaneous malignancies at the meeting.

SDEF and this news organization are owned by the same parent company.

LAS VEGAS – Cases of cutaneous squamous cell carcinoma (cSCC) are on the rise and are associated with mortality rates similar to melanoma. But even as cSCC draws more attention, two popular staging systems still need refinement, a hematologist-oncologist told dermatologist colleagues.

Both staging systems can be helpful, however, Guilherme Rabinowits, MD, said at Skin Disease Education Foundation’s annual Las Vegas Dermatology Seminar. “The best thing to do is combine both,” he noted, referring to the staging system developed by the Brigham and Women’s Hospital (BWH) and staging systems released in the 7th and 8th editions of the American Joint Committee on Cancer Staging Manual (AJCC 7 and AJCC 8; the latter focuses on head and neck only).

Cutaneous SCC has become a “huge health care burden,” said Dr. Rabinowits of the Miami Cancer Institute/Baptist Health South Florida and Florida International University, Miami. He referred to Medicare data suggesting that cSCC has become as common as basal cell carcinoma (JAMA Dermatol. 2015 Oct;151[10]:1081-6).

While most patients with cSCC have a positive prognosis, he added, the 5-year survival rate among those with the most aggressive disease is only 25%.

As he pointed out, staging systems provide insight into prognosis and treatment, guide appropriate monitoring, and give a common language to clinicians around the world. “When I talk about stage 3, we all understand who we’re talking about,” he said.

Dr. Rabinowits said he formerly worked at BWH so he is especially comfortable with its staging system. It can be appropriate to use both the BWH and AJCC systems at once, he said, noting, however, that studies suggest that the BWH system is superior.

An analysis released in 2014, for example, found that most poor outcomes occurred in patients whose tumors had been rated at lower stages – suggesting less risk – in the AJCC 7 system (J Clin Oncol 2014 Feb 1;32[4]:327-4).

In contrast, the 5% of tumors that were rated at the highest stages in the BWH system – with the highest level of perceived risk – accounted for 70% of nodal metastases and 83% of disease-specific deaths. This group may deserve extra attention in terms of staging and adjuvant treatment in order to improve outcomes, he said.

A study published this year, which compared the BWH and AJCC 8 staging systems, found that they had the same negative predictive value (0.99), while the BWH system showed higher positive predictive value (0.30 vs. 0.17). “Use of BWH tumor classification may minimize the number of patients recommended for radiologic evaluation, close surveillance, and possible adjuvant therapy while still identifying most patients at risk for recurrence, metastasis, and death,” the authors wrote (JAMA Dermatol. 2019 Jul 1;155[7]: 819-25).

As for treatment of localized disease in high-risk patients, Dr. Rabinowits advised turning to a multidisciplinary team for guidance because there are limited prospective randomized data.

Dr. Rabinowits discloses scientific advisory board/consultant relationships (Merck, Regeneron, Sanofi, EMD Serono, Pfizer, and Castle) and shares in Regeneron and Syros Pharmaceuticals. He spoke during a forum on cutaneous malignancies at the meeting.

SDEF and this news organization are owned by the same parent company.

While lung cancer is generally on the decline among both sexes, men have a ways to go to catch up with women, according to the Centers for Disease Control and Prevention.

From 2007 to 2016, rates dropped among both sexes in metropolitan and nonmetropolitan areas, according to Mary Elizabeth O’Neil, MPH, and colleagues. Their report is in Morbidity and Mortality Weekly Report (MMWR Morb Mortal Wkly Rep. 2019 Nov 8;68[44];993-8). But lung cancer incidence in 2016 was still 40% higher among men than among women, said Ms. O’Neil, an epidemiologist at the CDC.

Rather than narrowly focusing on the “just stop smoking” message, “a comprehensive approach to lung cancer prevention and control includes such population-based strategies as screening for tobacco dependence, promoting tobacco cessation, implementing comprehensive smoke-free laws, testing all homes for radon and using proven methods to lower high radon levels, and reducing exposure to lung carcinogens such as asbestos.” According to the authors of the report, “increasing the implementation of these strategies, particularly among persons living in nonmetropolitan counties, might help to reduce disparities in the decline of lung cancer incidence.”

The recommendation is based on data extracted from the U.S. Cancer Statistics Database for 2007-2016. The data cover 97% of the population.

In nonmetropolitan counties in 2007, incidence rates among men were 60% higher (99 vs. 61 per 100,000). Although rates decreased in both sexes, they were still elevated compared with women in 2016 (82 vs. 58 per 100,000; 40%).

Over the 10-year period, the rate declined more among men than among women (–2.9% vs. –1.5%) in metropolitan areas. The pattern repeated in nonmetropolitan areas (–2.1% and –0.5%, respectively).

There were different declines in different age groups by region, the authors noted.

Men aged 45-54 years in metropolitan areas experienced the largest decline (–5.2%).

Among women, the largest decline occurred in metropolitan areas among those aged 35-44 years (–5%). In nonmetropolitan areas, women in this age group experienced a 3.6% decline and women aged 65-74 years, a 1.3% decline.

Among persons aged 35-54 years, incidence rates in nonmetropolitan and metropolitan counties did not differ by sex but were higher in nonmetropolitan counties than in metropolitan counties.

There were also overall changes in smoking patterns. According to 2017 data from the National Health Interview Survey data, more adults in metropolitan areas than nonmetropolitan areas smoked (23% versus 13%) but fewer had tried to quit (50% vs. 56%). Successful quitting attempts also were lower (5% vs. 9%).

Although it is a large contributing factor, smoking is not the only risk factor for lung cancer, the authors wrote. About 10%-15% of lung cancer patients have never smoked tobacco. Nonsmoked tobacco products and second-hand exposure to cigarette smoke are risks, as are indoor radon and asbestos exposure.

Clinicians can help improve this scenario by screening at each office visit, the authors said. The recommendation is based on U.S. Preventive Services Task Force guidance.

“Lung cancer screening is recommended for adults at high risk for developing lung cancer because of their age and cigarette smoking history. Screening efforts can identify lung cancer in its early stages and provide an important opportunity to promote tobacco smoking cessation.”

However, lack of insurance among residents of nonmetropolitan areas may hamper access to these services, they said. In those regions, “a higher percentage of residents aged less than 65 years report being uninsured compared with those in metropolitan areas.”

msullivan@mdedge.com

SOURCE: O’Neil ME et al. MMWR Morb Mortal Wkly Rep. 2019 Nov 8: 68(44);993-8.

While lung cancer is generally on the decline among both sexes, men have a ways to go to catch up with women, according to the Centers for Disease Control and Prevention.

From 2007 to 2016, rates dropped among both sexes in metropolitan and nonmetropolitan areas, according to Mary Elizabeth O’Neil, MPH, and colleagues. Their report is in Morbidity and Mortality Weekly Report (MMWR Morb Mortal Wkly Rep. 2019 Nov 8;68[44];993-8). But lung cancer incidence in 2016 was still 40% higher among men than among women, said Ms. O’Neil, an epidemiologist at the CDC.

Rather than narrowly focusing on the “just stop smoking” message, “a comprehensive approach to lung cancer prevention and control includes such population-based strategies as screening for tobacco dependence, promoting tobacco cessation, implementing comprehensive smoke-free laws, testing all homes for radon and using proven methods to lower high radon levels, and reducing exposure to lung carcinogens such as asbestos.” According to the authors of the report, “increasing the implementation of these strategies, particularly among persons living in nonmetropolitan counties, might help to reduce disparities in the decline of lung cancer incidence.”

The recommendation is based on data extracted from the U.S. Cancer Statistics Database for 2007-2016. The data cover 97% of the population.

In nonmetropolitan counties in 2007, incidence rates among men were 60% higher (99 vs. 61 per 100,000). Although rates decreased in both sexes, they were still elevated compared with women in 2016 (82 vs. 58 per 100,000; 40%).

Over the 10-year period, the rate declined more among men than among women (–2.9% vs. –1.5%) in metropolitan areas. The pattern repeated in nonmetropolitan areas (–2.1% and –0.5%, respectively).

There were different declines in different age groups by region, the authors noted.

Men aged 45-54 years in metropolitan areas experienced the largest decline (–5.2%).

Among women, the largest decline occurred in metropolitan areas among those aged 35-44 years (–5%). In nonmetropolitan areas, women in this age group experienced a 3.6% decline and women aged 65-74 years, a 1.3% decline.

Among persons aged 35-54 years, incidence rates in nonmetropolitan and metropolitan counties did not differ by sex but were higher in nonmetropolitan counties than in metropolitan counties.

There were also overall changes in smoking patterns. According to 2017 data from the National Health Interview Survey data, more adults in metropolitan areas than nonmetropolitan areas smoked (23% versus 13%) but fewer had tried to quit (50% vs. 56%). Successful quitting attempts also were lower (5% vs. 9%).

Although it is a large contributing factor, smoking is not the only risk factor for lung cancer, the authors wrote. About 10%-15% of lung cancer patients have never smoked tobacco. Nonsmoked tobacco products and second-hand exposure to cigarette smoke are risks, as are indoor radon and asbestos exposure.

Clinicians can help improve this scenario by screening at each office visit, the authors said. The recommendation is based on U.S. Preventive Services Task Force guidance.

“Lung cancer screening is recommended for adults at high risk for developing lung cancer because of their age and cigarette smoking history. Screening efforts can identify lung cancer in its early stages and provide an important opportunity to promote tobacco smoking cessation.”

However, lack of insurance among residents of nonmetropolitan areas may hamper access to these services, they said. In those regions, “a higher percentage of residents aged less than 65 years report being uninsured compared with those in metropolitan areas.”

msullivan@mdedge.com

SOURCE: O’Neil ME et al. MMWR Morb Mortal Wkly Rep. 2019 Nov 8: 68(44);993-8.

While lung cancer is generally on the decline among both sexes, men have a ways to go to catch up with women, according to the Centers for Disease Control and Prevention.

From 2007 to 2016, rates dropped among both sexes in metropolitan and nonmetropolitan areas, according to Mary Elizabeth O’Neil, MPH, and colleagues. Their report is in Morbidity and Mortality Weekly Report (MMWR Morb Mortal Wkly Rep. 2019 Nov 8;68[44];993-8). But lung cancer incidence in 2016 was still 40% higher among men than among women, said Ms. O’Neil, an epidemiologist at the CDC.

Rather than narrowly focusing on the “just stop smoking” message, “a comprehensive approach to lung cancer prevention and control includes such population-based strategies as screening for tobacco dependence, promoting tobacco cessation, implementing comprehensive smoke-free laws, testing all homes for radon and using proven methods to lower high radon levels, and reducing exposure to lung carcinogens such as asbestos.” According to the authors of the report, “increasing the implementation of these strategies, particularly among persons living in nonmetropolitan counties, might help to reduce disparities in the decline of lung cancer incidence.”

The recommendation is based on data extracted from the U.S. Cancer Statistics Database for 2007-2016. The data cover 97% of the population.

In nonmetropolitan counties in 2007, incidence rates among men were 60% higher (99 vs. 61 per 100,000). Although rates decreased in both sexes, they were still elevated compared with women in 2016 (82 vs. 58 per 100,000; 40%).

Over the 10-year period, the rate declined more among men than among women (–2.9% vs. –1.5%) in metropolitan areas. The pattern repeated in nonmetropolitan areas (–2.1% and –0.5%, respectively).

There were different declines in different age groups by region, the authors noted.

Men aged 45-54 years in metropolitan areas experienced the largest decline (–5.2%).

Among women, the largest decline occurred in metropolitan areas among those aged 35-44 years (–5%). In nonmetropolitan areas, women in this age group experienced a 3.6% decline and women aged 65-74 years, a 1.3% decline.

Among persons aged 35-54 years, incidence rates in nonmetropolitan and metropolitan counties did not differ by sex but were higher in nonmetropolitan counties than in metropolitan counties.

There were also overall changes in smoking patterns. According to 2017 data from the National Health Interview Survey data, more adults in metropolitan areas than nonmetropolitan areas smoked (23% versus 13%) but fewer had tried to quit (50% vs. 56%). Successful quitting attempts also were lower (5% vs. 9%).

Although it is a large contributing factor, smoking is not the only risk factor for lung cancer, the authors wrote. About 10%-15% of lung cancer patients have never smoked tobacco. Nonsmoked tobacco products and second-hand exposure to cigarette smoke are risks, as are indoor radon and asbestos exposure.

Clinicians can help improve this scenario by screening at each office visit, the authors said. The recommendation is based on U.S. Preventive Services Task Force guidance.

“Lung cancer screening is recommended for adults at high risk for developing lung cancer because of their age and cigarette smoking history. Screening efforts can identify lung cancer in its early stages and provide an important opportunity to promote tobacco smoking cessation.”

However, lack of insurance among residents of nonmetropolitan areas may hamper access to these services, they said. In those regions, “a higher percentage of residents aged less than 65 years report being uninsured compared with those in metropolitan areas.”

msullivan@mdedge.com

SOURCE: O’Neil ME et al. MMWR Morb Mortal Wkly Rep. 2019 Nov 8: 68(44);993-8.

The European League Against Rheumatism has released its first recommendations for the management of Sjögren’s syndrome with topical and systemic treatments.

First author Manuel Ramos-Casals, MD, PhD, of Hospital Clinic de Barcelona Institut Clinic de Medicina i Dermatologia and colleagues on the multinational, multispecialty EULAR Sjögren Syndrome Task Force Group said the EULAR recommendations “synthesize current thinking” of management for Sjögren’s syndrome, which is complicated by individualized treatment that does not address the systemic disease and for which therapeutic decisions are often made based on expert opinion and personal experience because of a lack of data.

“Sjögren’s syndrome is generally treated through symptom management,” noted Sara McCoy, MD, who is director of the University of Wisconsin Health Sjögren’s Syndrome Clinic and was not involved in the recommendations, which were published in Annals of the Rheumatic Diseases. “Although we have measures to address these symptoms, we do not have any approved therapy that ameliorates the driving cause.”

There is limited high-quality evidence for many of the therapies discussed in the recommendations: In total, 9 randomized controlled trials, 18 prospective studies, and 5 case-control studies were included as evidence in the recommendations, and many involved a small number of patients.

The first overarching recommendation says that patients with Sjögren’s syndrome should be managed at centers of expertise using a multidisciplinary approach, the authors wrote. Two other overarching recommendations focus on how to manage certain patient cases. In cases of dryness, first-line therapy should include topical therapies for symptomatic relief, while clinicians should consider systemic therapies for patients with active systemic disease. All three overarching recommendations had a high level of agreement among task force members.

The task force also offered 12 specific recommendations on disease management, which take an “algorithmic approach” to Sjögren’s syndrome management that is guided by the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI), Dr. McCoy said in an interview.

“The EULAR recommendations structure a clear approach to treatment of Sjögren’s manifestations, ranging from oral and ocular sicca management, to treatment of uncommon but severe systemic involvement of Sjögren’s,” she said.

Before treating patients for oral dryness symptoms, clinicians should evaluate salivary function at baseline using unstimulated whole salivary flows. First-line therapeutic approaches for oral dryness can include nonpharmacologic stimulation in cases of mild salivary gland dysfunction, pharmacologic stimulation in cases of moderate dysfunction, and substitution of saliva in cases of severe dysfunction, the authors said.

Ocular dryness should be assessed using ocular staining score followed by ocular surface–disease index, and once identified, it can be managed with artificial tears and ocular gels or ointments as first-line therapy. Topical immunosuppressive-containing drops and autologous serum eye drops are options for more severe or refractory ocular dryness.

Patients who have fatigue or pain associated with Sjögren’s syndrome should have their fatigue or pain scored with the EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI), and any concomitant disease should also be evaluated. Clinicians should consider acetaminophen and NSAIDs for treatment of acute musculoskeletal pain and other pain-modifying agents, such as hydroxychloroquine in cases of articular pain, despite a lack of evidence showing its efficacy in trials.

For systemic disease, the task force advised matching treatment to the organ(s) involved and using the ESSDAI to evaluate disease severity., They said that “patients presenting with at least moderate activity in one clinical domain, or with a global moderate disease activity score” of 5 or higher can be considered for systemic therapy.

Although many clinicians use glucocorticoids (GCs) for managing Sjögren’s syndrome, there is no evidence of the treatment’s efficacy in systemic disease. The task force recommended using glucocorticoids such as methylprednisolone at the minimum dose and withdrawing use “as soon as possible” in patients with inactive disease. “Based on the potential development of chronic damage in patients with uncontrolled systemic disease, some patients may require long-term therapy with GCs, especially those with severe organ impairments,” Dr. Ramos-Casals and colleagues wrote. “In these patients, the addition of immunosuppressive agents as GC-sparing agents is justified, always weighing the potential benefits and risks.” Because of a lack of head-to-head studies of different immunosuppressive agents, the task force did not recommend one particular agent over another.

One recommendation that contained a high level of evidence was for the use of B-cell targeted therapies for patients with severe, refractory systemic disease. Efficacy of rituximab was mixed in studies totaling more than 400 patients, but generally showed a positive outcome in at least one of the following areas: global response, organ-specific response, ESSDAI reduction, and prednisone reduction. The task force recommended that rituximab “may be considered” in “patients with severe, refractory systemic disease” and may be best for those with symptoms linked to cryoglobulinemic-associated vasculitis, with the potential of using belimumab (Benlysta) as rescue therapy. While systemic organ-specific therapeutic approaches vary, the general rule should be to treat with GCs first, followed by immunosuppressive agents and biologics as second-line therapy in cases refractory to GCs, either sequentially or in combination, the authors said.

For patients with B-cell lymphoma, clinicians should use individualized treatment based on the World Health Organization 2016 histologic subtype and the stage of the disease. While some clinicians employ a “watchful waiting” approach to treating low-grade hematologic neoplasia, “the decision to treat low-grade lymphomas or not must be discussed in a multidisciplinary committee, taking into account the fact that they are linked to the disease activity and are the ultimate stage of autoimmune B-cell activation,” the authors wrote.

The task force also defined a number of future research agenda goals for Sjögren’s syndrome treatment management, including developing personalized therapeutic approaches, finding predictors of biological response to agents used in treatment, and identifying biomarkers of poor outcomes.

In addition, EULAR acknowledged some research gaps exist in the guidelines for particular symptoms of Sjögren’s syndrome, such as in the case of fatigue. “The EULAR recommendations mention the common association of fatigue with Sjögren’s syndrome, though acknowledge that fatigue is more commonly seen in the same demographic cohort as Sjögren’s,” Dr. McCoy said. “Aside from exercise, there remains little available to address this common and burdensome symptom amongst Sjögren’s patients. Overall, this is a pertinent gap in knowledge in our Sjögren’s patients.”

The Sjögren’s syndrome recommendations were funded by EULAR. Many task force members reported relationships with industry in the form of advisory board and speaker’s bureau memberships, consultancies, and grants. Dr. McCoy reported serving on a data monitoring committee for Bristol-Myers Squibb unrelated to the data in the EULAR recommendations.

SOURCE: Ramos-Casals M et al. Ann Rheum Dis. 2019 Oct 31. doi: 10.1136/annrheumdis-2019-216114

The European League Against Rheumatism has released its first recommendations for the management of Sjögren’s syndrome with topical and systemic treatments.

First author Manuel Ramos-Casals, MD, PhD, of Hospital Clinic de Barcelona Institut Clinic de Medicina i Dermatologia and colleagues on the multinational, multispecialty EULAR Sjögren Syndrome Task Force Group said the EULAR recommendations “synthesize current thinking” of management for Sjögren’s syndrome, which is complicated by individualized treatment that does not address the systemic disease and for which therapeutic decisions are often made based on expert opinion and personal experience because of a lack of data.

“Sjögren’s syndrome is generally treated through symptom management,” noted Sara McCoy, MD, who is director of the University of Wisconsin Health Sjögren’s Syndrome Clinic and was not involved in the recommendations, which were published in Annals of the Rheumatic Diseases. “Although we have measures to address these symptoms, we do not have any approved therapy that ameliorates the driving cause.”

There is limited high-quality evidence for many of the therapies discussed in the recommendations: In total, 9 randomized controlled trials, 18 prospective studies, and 5 case-control studies were included as evidence in the recommendations, and many involved a small number of patients.

The first overarching recommendation says that patients with Sjögren’s syndrome should be managed at centers of expertise using a multidisciplinary approach, the authors wrote. Two other overarching recommendations focus on how to manage certain patient cases. In cases of dryness, first-line therapy should include topical therapies for symptomatic relief, while clinicians should consider systemic therapies for patients with active systemic disease. All three overarching recommendations had a high level of agreement among task force members.

The task force also offered 12 specific recommendations on disease management, which take an “algorithmic approach” to Sjögren’s syndrome management that is guided by the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI), Dr. McCoy said in an interview.

“The EULAR recommendations structure a clear approach to treatment of Sjögren’s manifestations, ranging from oral and ocular sicca management, to treatment of uncommon but severe systemic involvement of Sjögren’s,” she said.

Before treating patients for oral dryness symptoms, clinicians should evaluate salivary function at baseline using unstimulated whole salivary flows. First-line therapeutic approaches for oral dryness can include nonpharmacologic stimulation in cases of mild salivary gland dysfunction, pharmacologic stimulation in cases of moderate dysfunction, and substitution of saliva in cases of severe dysfunction, the authors said.

Ocular dryness should be assessed using ocular staining score followed by ocular surface–disease index, and once identified, it can be managed with artificial tears and ocular gels or ointments as first-line therapy. Topical immunosuppressive-containing drops and autologous serum eye drops are options for more severe or refractory ocular dryness.

Patients who have fatigue or pain associated with Sjögren’s syndrome should have their fatigue or pain scored with the EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI), and any concomitant disease should also be evaluated. Clinicians should consider acetaminophen and NSAIDs for treatment of acute musculoskeletal pain and other pain-modifying agents, such as hydroxychloroquine in cases of articular pain, despite a lack of evidence showing its efficacy in trials.

For systemic disease, the task force advised matching treatment to the organ(s) involved and using the ESSDAI to evaluate disease severity., They said that “patients presenting with at least moderate activity in one clinical domain, or with a global moderate disease activity score” of 5 or higher can be considered for systemic therapy.

Although many clinicians use glucocorticoids (GCs) for managing Sjögren’s syndrome, there is no evidence of the treatment’s efficacy in systemic disease. The task force recommended using glucocorticoids such as methylprednisolone at the minimum dose and withdrawing use “as soon as possible” in patients with inactive disease. “Based on the potential development of chronic damage in patients with uncontrolled systemic disease, some patients may require long-term therapy with GCs, especially those with severe organ impairments,” Dr. Ramos-Casals and colleagues wrote. “In these patients, the addition of immunosuppressive agents as GC-sparing agents is justified, always weighing the potential benefits and risks.” Because of a lack of head-to-head studies of different immunosuppressive agents, the task force did not recommend one particular agent over another.

One recommendation that contained a high level of evidence was for the use of B-cell targeted therapies for patients with severe, refractory systemic disease. Efficacy of rituximab was mixed in studies totaling more than 400 patients, but generally showed a positive outcome in at least one of the following areas: global response, organ-specific response, ESSDAI reduction, and prednisone reduction. The task force recommended that rituximab “may be considered” in “patients with severe, refractory systemic disease” and may be best for those with symptoms linked to cryoglobulinemic-associated vasculitis, with the potential of using belimumab (Benlysta) as rescue therapy. While systemic organ-specific therapeutic approaches vary, the general rule should be to treat with GCs first, followed by immunosuppressive agents and biologics as second-line therapy in cases refractory to GCs, either sequentially or in combination, the authors said.

For patients with B-cell lymphoma, clinicians should use individualized treatment based on the World Health Organization 2016 histologic subtype and the stage of the disease. While some clinicians employ a “watchful waiting” approach to treating low-grade hematologic neoplasia, “the decision to treat low-grade lymphomas or not must be discussed in a multidisciplinary committee, taking into account the fact that they are linked to the disease activity and are the ultimate stage of autoimmune B-cell activation,” the authors wrote.

The task force also defined a number of future research agenda goals for Sjögren’s syndrome treatment management, including developing personalized therapeutic approaches, finding predictors of biological response to agents used in treatment, and identifying biomarkers of poor outcomes.

In addition, EULAR acknowledged some research gaps exist in the guidelines for particular symptoms of Sjögren’s syndrome, such as in the case of fatigue. “The EULAR recommendations mention the common association of fatigue with Sjögren’s syndrome, though acknowledge that fatigue is more commonly seen in the same demographic cohort as Sjögren’s,” Dr. McCoy said. “Aside from exercise, there remains little available to address this common and burdensome symptom amongst Sjögren’s patients. Overall, this is a pertinent gap in knowledge in our Sjögren’s patients.”

The Sjögren’s syndrome recommendations were funded by EULAR. Many task force members reported relationships with industry in the form of advisory board and speaker’s bureau memberships, consultancies, and grants. Dr. McCoy reported serving on a data monitoring committee for Bristol-Myers Squibb unrelated to the data in the EULAR recommendations.

SOURCE: Ramos-Casals M et al. Ann Rheum Dis. 2019 Oct 31. doi: 10.1136/annrheumdis-2019-216114

The European League Against Rheumatism has released its first recommendations for the management of Sjögren’s syndrome with topical and systemic treatments.

First author Manuel Ramos-Casals, MD, PhD, of Hospital Clinic de Barcelona Institut Clinic de Medicina i Dermatologia and colleagues on the multinational, multispecialty EULAR Sjögren Syndrome Task Force Group said the EULAR recommendations “synthesize current thinking” of management for Sjögren’s syndrome, which is complicated by individualized treatment that does not address the systemic disease and for which therapeutic decisions are often made based on expert opinion and personal experience because of a lack of data.

“Sjögren’s syndrome is generally treated through symptom management,” noted Sara McCoy, MD, who is director of the University of Wisconsin Health Sjögren’s Syndrome Clinic and was not involved in the recommendations, which were published in Annals of the Rheumatic Diseases. “Although we have measures to address these symptoms, we do not have any approved therapy that ameliorates the driving cause.”

There is limited high-quality evidence for many of the therapies discussed in the recommendations: In total, 9 randomized controlled trials, 18 prospective studies, and 5 case-control studies were included as evidence in the recommendations, and many involved a small number of patients.

The first overarching recommendation says that patients with Sjögren’s syndrome should be managed at centers of expertise using a multidisciplinary approach, the authors wrote. Two other overarching recommendations focus on how to manage certain patient cases. In cases of dryness, first-line therapy should include topical therapies for symptomatic relief, while clinicians should consider systemic therapies for patients with active systemic disease. All three overarching recommendations had a high level of agreement among task force members.

The task force also offered 12 specific recommendations on disease management, which take an “algorithmic approach” to Sjögren’s syndrome management that is guided by the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI), Dr. McCoy said in an interview.

“The EULAR recommendations structure a clear approach to treatment of Sjögren’s manifestations, ranging from oral and ocular sicca management, to treatment of uncommon but severe systemic involvement of Sjögren’s,” she said.

Before treating patients for oral dryness symptoms, clinicians should evaluate salivary function at baseline using unstimulated whole salivary flows. First-line therapeutic approaches for oral dryness can include nonpharmacologic stimulation in cases of mild salivary gland dysfunction, pharmacologic stimulation in cases of moderate dysfunction, and substitution of saliva in cases of severe dysfunction, the authors said.

Ocular dryness should be assessed using ocular staining score followed by ocular surface–disease index, and once identified, it can be managed with artificial tears and ocular gels or ointments as first-line therapy. Topical immunosuppressive-containing drops and autologous serum eye drops are options for more severe or refractory ocular dryness.

Patients who have fatigue or pain associated with Sjögren’s syndrome should have their fatigue or pain scored with the EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI), and any concomitant disease should also be evaluated. Clinicians should consider acetaminophen and NSAIDs for treatment of acute musculoskeletal pain and other pain-modifying agents, such as hydroxychloroquine in cases of articular pain, despite a lack of evidence showing its efficacy in trials.

For systemic disease, the task force advised matching treatment to the organ(s) involved and using the ESSDAI to evaluate disease severity., They said that “patients presenting with at least moderate activity in one clinical domain, or with a global moderate disease activity score” of 5 or higher can be considered for systemic therapy.

Although many clinicians use glucocorticoids (GCs) for managing Sjögren’s syndrome, there is no evidence of the treatment’s efficacy in systemic disease. The task force recommended using glucocorticoids such as methylprednisolone at the minimum dose and withdrawing use “as soon as possible” in patients with inactive disease. “Based on the potential development of chronic damage in patients with uncontrolled systemic disease, some patients may require long-term therapy with GCs, especially those with severe organ impairments,” Dr. Ramos-Casals and colleagues wrote. “In these patients, the addition of immunosuppressive agents as GC-sparing agents is justified, always weighing the potential benefits and risks.” Because of a lack of head-to-head studies of different immunosuppressive agents, the task force did not recommend one particular agent over another.

One recommendation that contained a high level of evidence was for the use of B-cell targeted therapies for patients with severe, refractory systemic disease. Efficacy of rituximab was mixed in studies totaling more than 400 patients, but generally showed a positive outcome in at least one of the following areas: global response, organ-specific response, ESSDAI reduction, and prednisone reduction. The task force recommended that rituximab “may be considered” in “patients with severe, refractory systemic disease” and may be best for those with symptoms linked to cryoglobulinemic-associated vasculitis, with the potential of using belimumab (Benlysta) as rescue therapy. While systemic organ-specific therapeutic approaches vary, the general rule should be to treat with GCs first, followed by immunosuppressive agents and biologics as second-line therapy in cases refractory to GCs, either sequentially or in combination, the authors said.

For patients with B-cell lymphoma, clinicians should use individualized treatment based on the World Health Organization 2016 histologic subtype and the stage of the disease. While some clinicians employ a “watchful waiting” approach to treating low-grade hematologic neoplasia, “the decision to treat low-grade lymphomas or not must be discussed in a multidisciplinary committee, taking into account the fact that they are linked to the disease activity and are the ultimate stage of autoimmune B-cell activation,” the authors wrote.

The task force also defined a number of future research agenda goals for Sjögren’s syndrome treatment management, including developing personalized therapeutic approaches, finding predictors of biological response to agents used in treatment, and identifying biomarkers of poor outcomes.

In addition, EULAR acknowledged some research gaps exist in the guidelines for particular symptoms of Sjögren’s syndrome, such as in the case of fatigue. “The EULAR recommendations mention the common association of fatigue with Sjögren’s syndrome, though acknowledge that fatigue is more commonly seen in the same demographic cohort as Sjögren’s,” Dr. McCoy said. “Aside from exercise, there remains little available to address this common and burdensome symptom amongst Sjögren’s patients. Overall, this is a pertinent gap in knowledge in our Sjögren’s patients.”

The Sjögren’s syndrome recommendations were funded by EULAR. Many task force members reported relationships with industry in the form of advisory board and speaker’s bureau memberships, consultancies, and grants. Dr. McCoy reported serving on a data monitoring committee for Bristol-Myers Squibb unrelated to the data in the EULAR recommendations.

SOURCE: Ramos-Casals M et al. Ann Rheum Dis. 2019 Oct 31. doi: 10.1136/annrheumdis-2019-216114

Background: Aspirin is beneficial in secondary prevention of stroke and MI. There is no consensus on its role in primary prevention of the same.

Bottom line: Aspirin for primary prevention lowers risk of CV events and increases risk of major bleeding. Health care providers should include this as part of informed decision-making discussions with patients about the use of aspirin for primary prevention.

Citation: Zheng S et al. Association of aspirin use for primary prevention with cardiovascular events and bleeding events: A systematic review and meta-analysis. JAMA. 2019 Jan 22;321(3):277-87.
 

Dr. Radhakrishnan is a hospitalist at Beth Israel Deaconess Medical Center.

Background: Aspirin is beneficial in secondary prevention of stroke and MI. There is no consensus on its role in primary prevention of the same.

Bottom line: Aspirin for primary prevention lowers risk of CV events and increases risk of major bleeding. Health care providers should include this as part of informed decision-making discussions with patients about the use of aspirin for primary prevention.

Citation: Zheng S et al. Association of aspirin use for primary prevention with cardiovascular events and bleeding events: A systematic review and meta-analysis. JAMA. 2019 Jan 22;321(3):277-87.
 

Dr. Radhakrishnan is a hospitalist at Beth Israel Deaconess Medical Center.

Background: Aspirin is beneficial in secondary prevention of stroke and MI. There is no consensus on its role in primary prevention of the same.

Bottom line: Aspirin for primary prevention lowers risk of CV events and increases risk of major bleeding. Health care providers should include this as part of informed decision-making discussions with patients about the use of aspirin for primary prevention.

Citation: Zheng S et al. Association of aspirin use for primary prevention with cardiovascular events and bleeding events: A systematic review and meta-analysis. JAMA. 2019 Jan 22;321(3):277-87.
 

Dr. Radhakrishnan is a hospitalist at Beth Israel Deaconess Medical Center.

Tumor microenvironment (TME) profiles could help tailor treatment for triple-negative breast cancer (TNBC), with the TME profile of the immunomodulatory subtype of TNBC making it the most susceptible to the effects of the immune checkpoint inhibitors.

“This study allowed us to gain more insight into the complex interactions between tumor cells and their microenvironment, in particular immune cells,” wrote a team of Belgian and Canadian researchers. Their report is in the Journal of the National Cancer Institute.

At least five molecular subtypes of TNBC have been identified but little was previously known about the heterogeneity of their surroundings, noted Yacine Bareche, MSc, of Institut Jules Bordet, Université Libre de Bruxelles, Brussels, and associates. They looked at a series of 1,512 TNBC samples from four large and publicly available transcriptomic and genomic datasets and their TME, which is made up of many cell types – fibroblasts, adipose, and immune-inflammatory cells – and blood and lymphatic vascular networks.

The researchers explained that each of the four TNBC subtypes identified so far have “distinct mutational profiles, genomic alterations, and biological processes” which were matched by differences in their surrounding environments.

For instance, the immunomodulatory subtype of TNBC was associated with high expression of “adaptive immune-related gene signatures and a fully inflamed spatial pattern appearing to be the optimal candidate for immune check-point inhibitors.” By contrast, Mr. Bareche and coauthors said that “most mesenchymal stem-like and luminal androgen receptor TNBC tumors had an immunosuppressive phenotype with high expression levels of stromal gene signatures.”

The findings include “novel evidence” of how TNBC tumors may become resistant to the effects of immune checkpoint inhibitors.

The results demonstrate that each TNBC subtype is associated with specific TME profiles, “setting the ground for a rationale tailoring of immunotherapy in TNBC patients,” the researchers noted. Mr. Bareche and associates cautioned, however, that “prospective validation of our findings is warranted before their clinical implementation.”

The study was supported by a grant from the Breast Cancer Research Foundation. The researchers had no conflicts of interest.
 

SOURCE: Bareche Y et al. J Natl Cancer Inst. 2019 Oct 29. doi: 10.1093/jnci/djz208.

Tumor microenvironment (TME) profiles could help tailor treatment for triple-negative breast cancer (TNBC), with the TME profile of the immunomodulatory subtype of TNBC making it the most susceptible to the effects of the immune checkpoint inhibitors.

“This study allowed us to gain more insight into the complex interactions between tumor cells and their microenvironment, in particular immune cells,” wrote a team of Belgian and Canadian researchers. Their report is in the Journal of the National Cancer Institute.

At least five molecular subtypes of TNBC have been identified but little was previously known about the heterogeneity of their surroundings, noted Yacine Bareche, MSc, of Institut Jules Bordet, Université Libre de Bruxelles, Brussels, and associates. They looked at a series of 1,512 TNBC samples from four large and publicly available transcriptomic and genomic datasets and their TME, which is made up of many cell types – fibroblasts, adipose, and immune-inflammatory cells – and blood and lymphatic vascular networks.

The researchers explained that each of the four TNBC subtypes identified so far have “distinct mutational profiles, genomic alterations, and biological processes” which were matched by differences in their surrounding environments.

For instance, the immunomodulatory subtype of TNBC was associated with high expression of “adaptive immune-related gene signatures and a fully inflamed spatial pattern appearing to be the optimal candidate for immune check-point inhibitors.” By contrast, Mr. Bareche and coauthors said that “most mesenchymal stem-like and luminal androgen receptor TNBC tumors had an immunosuppressive phenotype with high expression levels of stromal gene signatures.”

The findings include “novel evidence” of how TNBC tumors may become resistant to the effects of immune checkpoint inhibitors.

The results demonstrate that each TNBC subtype is associated with specific TME profiles, “setting the ground for a rationale tailoring of immunotherapy in TNBC patients,” the researchers noted. Mr. Bareche and associates cautioned, however, that “prospective validation of our findings is warranted before their clinical implementation.”

The study was supported by a grant from the Breast Cancer Research Foundation. The researchers had no conflicts of interest.
 

SOURCE: Bareche Y et al. J Natl Cancer Inst. 2019 Oct 29. doi: 10.1093/jnci/djz208.

Tumor microenvironment (TME) profiles could help tailor treatment for triple-negative breast cancer (TNBC), with the TME profile of the immunomodulatory subtype of TNBC making it the most susceptible to the effects of the immune checkpoint inhibitors.

“This study allowed us to gain more insight into the complex interactions between tumor cells and their microenvironment, in particular immune cells,” wrote a team of Belgian and Canadian researchers. Their report is in the Journal of the National Cancer Institute.

At least five molecular subtypes of TNBC have been identified but little was previously known about the heterogeneity of their surroundings, noted Yacine Bareche, MSc, of Institut Jules Bordet, Université Libre de Bruxelles, Brussels, and associates. They looked at a series of 1,512 TNBC samples from four large and publicly available transcriptomic and genomic datasets and their TME, which is made up of many cell types – fibroblasts, adipose, and immune-inflammatory cells – and blood and lymphatic vascular networks.

The researchers explained that each of the four TNBC subtypes identified so far have “distinct mutational profiles, genomic alterations, and biological processes” which were matched by differences in their surrounding environments.

For instance, the immunomodulatory subtype of TNBC was associated with high expression of “adaptive immune-related gene signatures and a fully inflamed spatial pattern appearing to be the optimal candidate for immune check-point inhibitors.” By contrast, Mr. Bareche and coauthors said that “most mesenchymal stem-like and luminal androgen receptor TNBC tumors had an immunosuppressive phenotype with high expression levels of stromal gene signatures.”

The findings include “novel evidence” of how TNBC tumors may become resistant to the effects of immune checkpoint inhibitors.

The results demonstrate that each TNBC subtype is associated with specific TME profiles, “setting the ground for a rationale tailoring of immunotherapy in TNBC patients,” the researchers noted. Mr. Bareche and associates cautioned, however, that “prospective validation of our findings is warranted before their clinical implementation.”

The study was supported by a grant from the Breast Cancer Research Foundation. The researchers had no conflicts of interest.
 

SOURCE: Bareche Y et al. J Natl Cancer Inst. 2019 Oct 29. doi: 10.1093/jnci/djz208.

This month’s cover story on artificial intelligence (AI) and machine learning provides a glimpse into the future of medical care. The article’s title, “An FP’s guide to AI-enabled clinical decision support” points to the fact that practical and useful applications of AI and machine learning are making inroads into medicine. However, other industries are far ahead of medicine when it comes to AI.

For example, I met with a financial advisor last week, and our discussion included a display of the likelihood that my wife and I would have sufficient funds in our retirement account based on a Monte Carlo simulation using 500 trials! In other words, our advisor used a huge database of financial information, analyzed that data with a sophisticated statistical technique, and applied the results to our personal situation. (No, we won’t run out of money—with 99% certainty.)

So as physicians, how can we further increase our certainty in the diagnoses we make and the guidance we offer our patients?

Artificial intelligence will be widely deployed in clinical tools that improve our diagnostic accuracy and provide better personalized data to inform shared decision making.

Halamka and Cerrato provide some insights. They discuss 2 clinical applications of AI and machine learning that are ready to use in primary care: screening for diabetic retinopathy and risk assessment for colon cancer. The first is an example of using AI for diagnosis and the second for risk assessment; both are core functions of primary care clinicians. These tools were developed with very sophisticated computer programs, but they are not unlike a plethora of clinical decision aids already widely used in primary care for diagnosis and risk assessment, such as the Ottawa Ankle Rules, the Gail Model for breast cancer risk, the FRAX tool for osteoporosis-related fracture risk, the ASCVD Risk Calculator for cardiovascular risk, and the CHA₂DS₂-VASC score for prediction of thrombosis and bleeding risk from anticoagulation therapy.

Some express concern that sophisticated AI could eventually replace primary care clinicians, similar to how automation reduces the need for routine labor in manufacturing. I think this is highly unlikely, but I do think AI will be widely deployed in clinical tools that improve our diagnostic accuracy and provide better personalized data to inform shared decision making. For example, the colon cancer risk calculator may actually help some patients decide NOT to be screened because their personal risk is so low.

It’s incumbent upon us, then, to familiarize ourselves with the potential that these AI tools offer. It’s time to get to know AI.

This month’s cover story on artificial intelligence (AI) and machine learning provides a glimpse into the future of medical care. The article’s title, “An FP’s guide to AI-enabled clinical decision support” points to the fact that practical and useful applications of AI and machine learning are making inroads into medicine. However, other industries are far ahead of medicine when it comes to AI.

For example, I met with a financial advisor last week, and our discussion included a display of the likelihood that my wife and I would have sufficient funds in our retirement account based on a Monte Carlo simulation using 500 trials! In other words, our advisor used a huge database of financial information, analyzed that data with a sophisticated statistical technique, and applied the results to our personal situation. (No, we won’t run out of money—with 99% certainty.)

So as physicians, how can we further increase our certainty in the diagnoses we make and the guidance we offer our patients?

Artificial intelligence will be widely deployed in clinical tools that improve our diagnostic accuracy and provide better personalized data to inform shared decision making.

Halamka and Cerrato provide some insights. They discuss 2 clinical applications of AI and machine learning that are ready to use in primary care: screening for diabetic retinopathy and risk assessment for colon cancer. The first is an example of using AI for diagnosis and the second for risk assessment; both are core functions of primary care clinicians. These tools were developed with very sophisticated computer programs, but they are not unlike a plethora of clinical decision aids already widely used in primary care for diagnosis and risk assessment, such as the Ottawa Ankle Rules, the Gail Model for breast cancer risk, the FRAX tool for osteoporosis-related fracture risk, the ASCVD Risk Calculator for cardiovascular risk, and the CHA₂DS₂-VASC score for prediction of thrombosis and bleeding risk from anticoagulation therapy.

Some express concern that sophisticated AI could eventually replace primary care clinicians, similar to how automation reduces the need for routine labor in manufacturing. I think this is highly unlikely, but I do think AI will be widely deployed in clinical tools that improve our diagnostic accuracy and provide better personalized data to inform shared decision making. For example, the colon cancer risk calculator may actually help some patients decide NOT to be screened because their personal risk is so low.

It’s incumbent upon us, then, to familiarize ourselves with the potential that these AI tools offer. It’s time to get to know AI.

This month’s cover story on artificial intelligence (AI) and machine learning provides a glimpse into the future of medical care. The article’s title, “An FP’s guide to AI-enabled clinical decision support” points to the fact that practical and useful applications of AI and machine learning are making inroads into medicine. However, other industries are far ahead of medicine when it comes to AI.

For example, I met with a financial advisor last week, and our discussion included a display of the likelihood that my wife and I would have sufficient funds in our retirement account based on a Monte Carlo simulation using 500 trials! In other words, our advisor used a huge database of financial information, analyzed that data with a sophisticated statistical technique, and applied the results to our personal situation. (No, we won’t run out of money—with 99% certainty.)

So as physicians, how can we further increase our certainty in the diagnoses we make and the guidance we offer our patients?

Artificial intelligence will be widely deployed in clinical tools that improve our diagnostic accuracy and provide better personalized data to inform shared decision making.

Halamka and Cerrato provide some insights. They discuss 2 clinical applications of AI and machine learning that are ready to use in primary care: screening for diabetic retinopathy and risk assessment for colon cancer. The first is an example of using AI for diagnosis and the second for risk assessment; both are core functions of primary care clinicians. These tools were developed with very sophisticated computer programs, but they are not unlike a plethora of clinical decision aids already widely used in primary care for diagnosis and risk assessment, such as the Ottawa Ankle Rules, the Gail Model for breast cancer risk, the FRAX tool for osteoporosis-related fracture risk, the ASCVD Risk Calculator for cardiovascular risk, and the CHA₂DS₂-VASC score for prediction of thrombosis and bleeding risk from anticoagulation therapy.

Some express concern that sophisticated AI could eventually replace primary care clinicians, similar to how automation reduces the need for routine labor in manufacturing. I think this is highly unlikely, but I do think AI will be widely deployed in clinical tools that improve our diagnostic accuracy and provide better personalized data to inform shared decision making. For example, the colon cancer risk calculator may actually help some patients decide NOT to be screened because their personal risk is so low.

It’s incumbent upon us, then, to familiarize ourselves with the potential that these AI tools offer. It’s time to get to know AI.

BOSTON – A new bispecific antibody, BFKB8488A, may be able to reduce hepatic fat fraction and improve liver health in patients with nonalcoholic fatty liver disease (NAFLD), according to investigators.

In a phase 1b trial, treatment with tolerable doses of the antibody reduced hepatic fat fraction by a mean of 38%, reported lead author Rebecca Kunder, MD, PhD, medical director at Genentech in San Francisco, and colleagues.

According to the investigators, BFKB8488A, which is also being tested in patients with type 2 diabetes mellitus, binds two adipocyte proteins: fibroblast growth factor receptor type 1c and Klotho beta, thereby mimicking metabolic hormone FGF21.

The present trial involved 63 patients with NAFLD who had at least 10% hepatic fat fraction based on MRI. Patients were randomized and for 12 weeks received placebo, one of four doses ranging from 50 to 130 mg given every 2 weeks, a dose of 250 mg given every 4 weeks, or an escalating dose regimen (the results of which were not reported). Treatments were blinded and delivered subcutaneously.

BFKB8488A was generally safe; the trial finished without life-threatening adverse events or deaths. Still, gastrointestinal issues became more common with higher doses, leading the investigators to identify well-tolerated doses as those of 100 mg or less, given every 2 weeks.

The investigators reported efficacy results for patients who received these lower doses, with outcomes presented as mean percentage changes in biomarkers from baseline to 12 weeks.

Adipose-specific pharmacodynamic effect was demonstrated by a mean increase in adiponectin of up to 17%. Positive cardiometabolic effects were also reported, with HDL cholesterol increasing 14% and triglyceride decreasing 24%. In addition, several other markers of liver health improved. Patients with baseline elevations of ALT had decreases in this marker of 10%-30%; plasma type 3 collagen propeptide, which is a measure of fibrosis, fell by 37%; and hepatic fat fraction, as previously stated, decreased by 38%, with a standard deviation of 25%. In contrast, treatment with placebo was associated with a mean 0% change in fat fraction, with a standard deviation of 28%.

“In patients with NAFLD, well-tolerated doses of BFKB8488A were highly effective at decreasing hepatic fat fraction and improving liver health,” the investigators concluded in an abstract that will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

According to the investigators, clinical efficacy of the antibody will be assessed in a phase 2 trial involving patients with nonalcoholic steatohepatitis.

The investigators reported financial relationships with Genentech and Gilead.

Share AGA’s patient education content on NAFLD to help your patients understand the condition. Visit https://www.gastro.org/practice-guidance/gi-patient-center/topic/nonalcoholic-steatohepatitis-nash to learn more.

SOURCE: Kunder R et al. The Liver Meeting 2019, Abstract LP8.

BOSTON – A new bispecific antibody, BFKB8488A, may be able to reduce hepatic fat fraction and improve liver health in patients with nonalcoholic fatty liver disease (NAFLD), according to investigators.

In a phase 1b trial, treatment with tolerable doses of the antibody reduced hepatic fat fraction by a mean of 38%, reported lead author Rebecca Kunder, MD, PhD, medical director at Genentech in San Francisco, and colleagues.

According to the investigators, BFKB8488A, which is also being tested in patients with type 2 diabetes mellitus, binds two adipocyte proteins: fibroblast growth factor receptor type 1c and Klotho beta, thereby mimicking metabolic hormone FGF21.

The present trial involved 63 patients with NAFLD who had at least 10% hepatic fat fraction based on MRI. Patients were randomized and for 12 weeks received placebo, one of four doses ranging from 50 to 130 mg given every 2 weeks, a dose of 250 mg given every 4 weeks, or an escalating dose regimen (the results of which were not reported). Treatments were blinded and delivered subcutaneously.

BFKB8488A was generally safe; the trial finished without life-threatening adverse events or deaths. Still, gastrointestinal issues became more common with higher doses, leading the investigators to identify well-tolerated doses as those of 100 mg or less, given every 2 weeks.

The investigators reported efficacy results for patients who received these lower doses, with outcomes presented as mean percentage changes in biomarkers from baseline to 12 weeks.

Adipose-specific pharmacodynamic effect was demonstrated by a mean increase in adiponectin of up to 17%. Positive cardiometabolic effects were also reported, with HDL cholesterol increasing 14% and triglyceride decreasing 24%. In addition, several other markers of liver health improved. Patients with baseline elevations of ALT had decreases in this marker of 10%-30%; plasma type 3 collagen propeptide, which is a measure of fibrosis, fell by 37%; and hepatic fat fraction, as previously stated, decreased by 38%, with a standard deviation of 25%. In contrast, treatment with placebo was associated with a mean 0% change in fat fraction, with a standard deviation of 28%.

“In patients with NAFLD, well-tolerated doses of BFKB8488A were highly effective at decreasing hepatic fat fraction and improving liver health,” the investigators concluded in an abstract that will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

According to the investigators, clinical efficacy of the antibody will be assessed in a phase 2 trial involving patients with nonalcoholic steatohepatitis.

The investigators reported financial relationships with Genentech and Gilead.

Share AGA’s patient education content on NAFLD to help your patients understand the condition. Visit https://www.gastro.org/practice-guidance/gi-patient-center/topic/nonalcoholic-steatohepatitis-nash to learn more.

SOURCE: Kunder R et al. The Liver Meeting 2019, Abstract LP8.

BOSTON – A new bispecific antibody, BFKB8488A, may be able to reduce hepatic fat fraction and improve liver health in patients with nonalcoholic fatty liver disease (NAFLD), according to investigators.

In a phase 1b trial, treatment with tolerable doses of the antibody reduced hepatic fat fraction by a mean of 38%, reported lead author Rebecca Kunder, MD, PhD, medical director at Genentech in San Francisco, and colleagues.

According to the investigators, BFKB8488A, which is also being tested in patients with type 2 diabetes mellitus, binds two adipocyte proteins: fibroblast growth factor receptor type 1c and Klotho beta, thereby mimicking metabolic hormone FGF21.

The present trial involved 63 patients with NAFLD who had at least 10% hepatic fat fraction based on MRI. Patients were randomized and for 12 weeks received placebo, one of four doses ranging from 50 to 130 mg given every 2 weeks, a dose of 250 mg given every 4 weeks, or an escalating dose regimen (the results of which were not reported). Treatments were blinded and delivered subcutaneously.

BFKB8488A was generally safe; the trial finished without life-threatening adverse events or deaths. Still, gastrointestinal issues became more common with higher doses, leading the investigators to identify well-tolerated doses as those of 100 mg or less, given every 2 weeks.

The investigators reported efficacy results for patients who received these lower doses, with outcomes presented as mean percentage changes in biomarkers from baseline to 12 weeks.

Adipose-specific pharmacodynamic effect was demonstrated by a mean increase in adiponectin of up to 17%. Positive cardiometabolic effects were also reported, with HDL cholesterol increasing 14% and triglyceride decreasing 24%. In addition, several other markers of liver health improved. Patients with baseline elevations of ALT had decreases in this marker of 10%-30%; plasma type 3 collagen propeptide, which is a measure of fibrosis, fell by 37%; and hepatic fat fraction, as previously stated, decreased by 38%, with a standard deviation of 25%. In contrast, treatment with placebo was associated with a mean 0% change in fat fraction, with a standard deviation of 28%.

“In patients with NAFLD, well-tolerated doses of BFKB8488A were highly effective at decreasing hepatic fat fraction and improving liver health,” the investigators concluded in an abstract that will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

According to the investigators, clinical efficacy of the antibody will be assessed in a phase 2 trial involving patients with nonalcoholic steatohepatitis.

The investigators reported financial relationships with Genentech and Gilead.

Share AGA’s patient education content on NAFLD to help your patients understand the condition. Visit https://www.gastro.org/practice-guidance/gi-patient-center/topic/nonalcoholic-steatohepatitis-nash to learn more.

SOURCE: Kunder R et al. The Liver Meeting 2019, Abstract LP8.

BOSTON – For most patients with chronic hepatitis D virus (HDV) infection, combination therapy with lonafarnib, ritonavir, and peginterferon may significantly decrease viral loads, based on interim results from the phase IIa LIFT trial.

After 6 months of therapy, more than one-third of evaluable patients (37%) achieved undetectable levels of HDV RNA in serum, according to lead author Christopher Koh, MD, of the National Institute of Diabetes, Digestive and Kidney Diseases at the National Institutes of Health and colleagues.

The open-label LIFT trial, which is ongoing, initially recruited 26 patients with HDV RNA who had serum levels of at least 40 IU/mL (lower limit of quantification). After starting tenofovir or entecavir, patients began a combination regimen of twice-daily oral lonafarnib (50 mg) and ritonavir (100 mg) plus weekly subcutaneous injections of Peginterferon Lambda-1a (180 mcg).

The median patient age was 40 years, with a slightly higher proportion of male participants (60%). Approximately half of the patients were of Asian descent (52%), followed by patients who were white (32%), or African (16%). The investigators reported median baseline measurements of modified histology activity index (9) and Ishak fibrosis stage (3), as well as serum levels of alanine aminotransferase (64 IU/mL), aspartate aminotransferase (47 IU/mL), hepatitis B virus DNA (less than 21 IU/mL), and log HDV RNA (4.74 IU/mL), with this latter measurement serving as a key determinant of efficacy.

After 12 weeks of therapy, the median decrease in HDV RNA among 21 evaluable patients was 3.6 log IU/mL with an interquartile range from 2.6 to 4.2 (P less than .0001). Of these patients, 5 (24%) achieved undetectable levels of HDV RNA, while another 5 tested below the lower limit of quantification.

Following an additional 12 weeks of therapy, 19 patients remained evaluable, among whom the median decrease in HDV RNA was 3.4 log IU/mL with an interquartile range from 2.9 to 4.5 (P less than .0001). Seven of these patients (37%) achieved undetectable HDV RNA, whereas 3 others fell below the lower limit of quantification. Furthermore, 18 out of 19 of these patients (95%) experienced a decline in HDV RNA of more than 2 log IU/mL.

According to the investigators, the trial regimen was safe and well tolerated. Adverse events were mild to moderate; most common were anemia, hyperbilirubinemia, weight loss, and gastrointestinal issues. Doses were reduced in three patients while four others discontinued therapy prematurely.

“These interim results support continued exploration of this therapeutic combination in HDV,” the investigators concluded.

The above findings will be presented in an oral abstract session at the annual meeting of the American Association for the Study of Liver Diseases.

The investigators disclosed relationships with I-Cubed Therapeutics, Eiger BioPharmaceuticals, Riboscience, and others.

SOURCE: Koh C et al. The Liver Meeting 2019. Abstract LO8.

BOSTON – For most patients with chronic hepatitis D virus (HDV) infection, combination therapy with lonafarnib, ritonavir, and peginterferon may significantly decrease viral loads, based on interim results from the phase IIa LIFT trial.

After 6 months of therapy, more than one-third of evaluable patients (37%) achieved undetectable levels of HDV RNA in serum, according to lead author Christopher Koh, MD, of the National Institute of Diabetes, Digestive and Kidney Diseases at the National Institutes of Health and colleagues.

The open-label LIFT trial, which is ongoing, initially recruited 26 patients with HDV RNA who had serum levels of at least 40 IU/mL (lower limit of quantification). After starting tenofovir or entecavir, patients began a combination regimen of twice-daily oral lonafarnib (50 mg) and ritonavir (100 mg) plus weekly subcutaneous injections of Peginterferon Lambda-1a (180 mcg).

The median patient age was 40 years, with a slightly higher proportion of male participants (60%). Approximately half of the patients were of Asian descent (52%), followed by patients who were white (32%), or African (16%). The investigators reported median baseline measurements of modified histology activity index (9) and Ishak fibrosis stage (3), as well as serum levels of alanine aminotransferase (64 IU/mL), aspartate aminotransferase (47 IU/mL), hepatitis B virus DNA (less than 21 IU/mL), and log HDV RNA (4.74 IU/mL), with this latter measurement serving as a key determinant of efficacy.

After 12 weeks of therapy, the median decrease in HDV RNA among 21 evaluable patients was 3.6 log IU/mL with an interquartile range from 2.6 to 4.2 (P less than .0001). Of these patients, 5 (24%) achieved undetectable levels of HDV RNA, while another 5 tested below the lower limit of quantification.

Following an additional 12 weeks of therapy, 19 patients remained evaluable, among whom the median decrease in HDV RNA was 3.4 log IU/mL with an interquartile range from 2.9 to 4.5 (P less than .0001). Seven of these patients (37%) achieved undetectable HDV RNA, whereas 3 others fell below the lower limit of quantification. Furthermore, 18 out of 19 of these patients (95%) experienced a decline in HDV RNA of more than 2 log IU/mL.

According to the investigators, the trial regimen was safe and well tolerated. Adverse events were mild to moderate; most common were anemia, hyperbilirubinemia, weight loss, and gastrointestinal issues. Doses were reduced in three patients while four others discontinued therapy prematurely.

“These interim results support continued exploration of this therapeutic combination in HDV,” the investigators concluded.

The above findings will be presented in an oral abstract session at the annual meeting of the American Association for the Study of Liver Diseases.

The investigators disclosed relationships with I-Cubed Therapeutics, Eiger BioPharmaceuticals, Riboscience, and others.

SOURCE: Koh C et al. The Liver Meeting 2019. Abstract LO8.

BOSTON – For most patients with chronic hepatitis D virus (HDV) infection, combination therapy with lonafarnib, ritonavir, and peginterferon may significantly decrease viral loads, based on interim results from the phase IIa LIFT trial.

After 6 months of therapy, more than one-third of evaluable patients (37%) achieved undetectable levels of HDV RNA in serum, according to lead author Christopher Koh, MD, of the National Institute of Diabetes, Digestive and Kidney Diseases at the National Institutes of Health and colleagues.

The open-label LIFT trial, which is ongoing, initially recruited 26 patients with HDV RNA who had serum levels of at least 40 IU/mL (lower limit of quantification). After starting tenofovir or entecavir, patients began a combination regimen of twice-daily oral lonafarnib (50 mg) and ritonavir (100 mg) plus weekly subcutaneous injections of Peginterferon Lambda-1a (180 mcg).

The median patient age was 40 years, with a slightly higher proportion of male participants (60%). Approximately half of the patients were of Asian descent (52%), followed by patients who were white (32%), or African (16%). The investigators reported median baseline measurements of modified histology activity index (9) and Ishak fibrosis stage (3), as well as serum levels of alanine aminotransferase (64 IU/mL), aspartate aminotransferase (47 IU/mL), hepatitis B virus DNA (less than 21 IU/mL), and log HDV RNA (4.74 IU/mL), with this latter measurement serving as a key determinant of efficacy.

After 12 weeks of therapy, the median decrease in HDV RNA among 21 evaluable patients was 3.6 log IU/mL with an interquartile range from 2.6 to 4.2 (P less than .0001). Of these patients, 5 (24%) achieved undetectable levels of HDV RNA, while another 5 tested below the lower limit of quantification.

Following an additional 12 weeks of therapy, 19 patients remained evaluable, among whom the median decrease in HDV RNA was 3.4 log IU/mL with an interquartile range from 2.9 to 4.5 (P less than .0001). Seven of these patients (37%) achieved undetectable HDV RNA, whereas 3 others fell below the lower limit of quantification. Furthermore, 18 out of 19 of these patients (95%) experienced a decline in HDV RNA of more than 2 log IU/mL.

According to the investigators, the trial regimen was safe and well tolerated. Adverse events were mild to moderate; most common were anemia, hyperbilirubinemia, weight loss, and gastrointestinal issues. Doses were reduced in three patients while four others discontinued therapy prematurely.

“These interim results support continued exploration of this therapeutic combination in HDV,” the investigators concluded.

The above findings will be presented in an oral abstract session at the annual meeting of the American Association for the Study of Liver Diseases.

The investigators disclosed relationships with I-Cubed Therapeutics, Eiger BioPharmaceuticals, Riboscience, and others.

SOURCE: Koh C et al. The Liver Meeting 2019. Abstract LO8.

BOSTON – A new bispecific antibody, BFKB8488A, may be able to reduce hepatic fat fraction and improve liver health in patients with nonalcoholic fatty liver disease (NAFLD), according to investigators.

In a phase 1b trial, treatment with tolerable doses of the antibody reduced hepatic fat fraction by a mean of 38%, reported lead author Rebecca Kunder, MD, PhD, medical director at Genentech in San Francisco, and colleagues.

According to the investigators, BFKB8488A, which is also being tested in patients with type 2 diabetes mellitus, binds two adipocyte proteins: fibroblast growth factor receptor type 1c and Klotho beta, thereby mimicking metabolic hormone FGF21.

The present trial involved 63 patients with NAFLD who had at least 10% hepatic fat fraction based on MRI. Patients were randomized and for 12 weeks received placebo, one of four doses ranging from 50 to 130 mg given every 2 weeks, a dose of 250 mg given every 4 weeks, or an escalating dose regimen (the results of which were not reported). Treatments were blinded and delivered subcutaneously.

BFKB8488A was generally safe; the trial finished without life-threatening adverse events or deaths. Still, gastrointestinal issues became more common with higher doses, leading the investigators to identify well-tolerated doses as those of 100 mg or less, given every 2 weeks.

The investigators reported efficacy results for patients who received these lower doses, with outcomes presented as mean percentage changes in biomarkers from baseline to 12 weeks.

Adipose-specific pharmacodynamic effect was demonstrated by a mean increase in adiponectin of up to 17%. Positive cardiometabolic effects were also reported, with HDL cholesterol increasing 14% and triglyceride decreasing 24%. In addition, several other markers of liver health improved. Patients with baseline elevations of ALT had decreases in this marker of 10%-30%; plasma type 3 collagen propeptide, which is a measure of fibrosis, fell by 37%; and hepatic fat fraction, as previously stated, decreased by 38%, with a standard deviation of 25%. In contrast, treatment with placebo was associated with a mean 0% change in fat fraction, with a standard deviation of 28%.

“In patients with NAFLD, well-tolerated doses of BFKB8488A were highly effective at decreasing hepatic fat fraction and improving liver health,” the investigators concluded in an abstract that will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

According to the investigators, clinical efficacy of the antibody will be assessed in a phase 2 trial involving patients with nonalcoholic steatohepatitis.

The investigators reported financial relationships with Genentech and Gilead.

SOURCE: Kunder R et al. The Liver Meeting 2019, Abstract LP8.

BOSTON – A new bispecific antibody, BFKB8488A, may be able to reduce hepatic fat fraction and improve liver health in patients with nonalcoholic fatty liver disease (NAFLD), according to investigators.

In a phase 1b trial, treatment with tolerable doses of the antibody reduced hepatic fat fraction by a mean of 38%, reported lead author Rebecca Kunder, MD, PhD, medical director at Genentech in San Francisco, and colleagues.

According to the investigators, BFKB8488A, which is also being tested in patients with type 2 diabetes mellitus, binds two adipocyte proteins: fibroblast growth factor receptor type 1c and Klotho beta, thereby mimicking metabolic hormone FGF21.

The present trial involved 63 patients with NAFLD who had at least 10% hepatic fat fraction based on MRI. Patients were randomized and for 12 weeks received placebo, one of four doses ranging from 50 to 130 mg given every 2 weeks, a dose of 250 mg given every 4 weeks, or an escalating dose regimen (the results of which were not reported). Treatments were blinded and delivered subcutaneously.

BFKB8488A was generally safe; the trial finished without life-threatening adverse events or deaths. Still, gastrointestinal issues became more common with higher doses, leading the investigators to identify well-tolerated doses as those of 100 mg or less, given every 2 weeks.

The investigators reported efficacy results for patients who received these lower doses, with outcomes presented as mean percentage changes in biomarkers from baseline to 12 weeks.

Adipose-specific pharmacodynamic effect was demonstrated by a mean increase in adiponectin of up to 17%. Positive cardiometabolic effects were also reported, with HDL cholesterol increasing 14% and triglyceride decreasing 24%. In addition, several other markers of liver health improved. Patients with baseline elevations of ALT had decreases in this marker of 10%-30%; plasma type 3 collagen propeptide, which is a measure of fibrosis, fell by 37%; and hepatic fat fraction, as previously stated, decreased by 38%, with a standard deviation of 25%. In contrast, treatment with placebo was associated with a mean 0% change in fat fraction, with a standard deviation of 28%.

“In patients with NAFLD, well-tolerated doses of BFKB8488A were highly effective at decreasing hepatic fat fraction and improving liver health,” the investigators concluded in an abstract that will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

According to the investigators, clinical efficacy of the antibody will be assessed in a phase 2 trial involving patients with nonalcoholic steatohepatitis.

The investigators reported financial relationships with Genentech and Gilead.

SOURCE: Kunder R et al. The Liver Meeting 2019, Abstract LP8.

BOSTON – A new bispecific antibody, BFKB8488A, may be able to reduce hepatic fat fraction and improve liver health in patients with nonalcoholic fatty liver disease (NAFLD), according to investigators.

In a phase 1b trial, treatment with tolerable doses of the antibody reduced hepatic fat fraction by a mean of 38%, reported lead author Rebecca Kunder, MD, PhD, medical director at Genentech in San Francisco, and colleagues.

According to the investigators, BFKB8488A, which is also being tested in patients with type 2 diabetes mellitus, binds two adipocyte proteins: fibroblast growth factor receptor type 1c and Klotho beta, thereby mimicking metabolic hormone FGF21.

The present trial involved 63 patients with NAFLD who had at least 10% hepatic fat fraction based on MRI. Patients were randomized and for 12 weeks received placebo, one of four doses ranging from 50 to 130 mg given every 2 weeks, a dose of 250 mg given every 4 weeks, or an escalating dose regimen (the results of which were not reported). Treatments were blinded and delivered subcutaneously.

BFKB8488A was generally safe; the trial finished without life-threatening adverse events or deaths. Still, gastrointestinal issues became more common with higher doses, leading the investigators to identify well-tolerated doses as those of 100 mg or less, given every 2 weeks.

The investigators reported efficacy results for patients who received these lower doses, with outcomes presented as mean percentage changes in biomarkers from baseline to 12 weeks.

Adipose-specific pharmacodynamic effect was demonstrated by a mean increase in adiponectin of up to 17%. Positive cardiometabolic effects were also reported, with HDL cholesterol increasing 14% and triglyceride decreasing 24%. In addition, several other markers of liver health improved. Patients with baseline elevations of ALT had decreases in this marker of 10%-30%; plasma type 3 collagen propeptide, which is a measure of fibrosis, fell by 37%; and hepatic fat fraction, as previously stated, decreased by 38%, with a standard deviation of 25%. In contrast, treatment with placebo was associated with a mean 0% change in fat fraction, with a standard deviation of 28%.

“In patients with NAFLD, well-tolerated doses of BFKB8488A were highly effective at decreasing hepatic fat fraction and improving liver health,” the investigators concluded in an abstract that will be presented at the annual meeting of the American Association for the Study of Liver Diseases.

According to the investigators, clinical efficacy of the antibody will be assessed in a phase 2 trial involving patients with nonalcoholic steatohepatitis.

The investigators reported financial relationships with Genentech and Gilead.

SOURCE: Kunder R et al. The Liver Meeting 2019, Abstract LP8.