CHICAGO – A 50-year old otherwise healthy man was found on routine history and physical to have lymphocytosis and was referred for additional work-up. He denied recent infection, had no lymphadenopathy, organomegaly, or rash or other concerning skin lesions. A complete blood count showed a white cell count of 23 x 10⁹/Land absolute lymphocyte count of 19 x 10⁹/L and normal hemoglobin and platelets.

Based on recently updated International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines, additional work-up for this patient might include peripheral smear and flow cytometry, according to Paul Barr, MD.

“A peripheral smear is still useful in this day and age just to ensure that a patient has a typical look under the microscope. We expect to see small mature lymphocytes, smudge cells, and perhaps a smaller number of prolymphocytes. But to mark CLL based on flow cytometry we need to see greater than 5 x 10⁹/L clonal B lymphocytes in the peripheral blood sustained over time,” Dr. Barr, medical director of the clinical trials office for Wilmot Cancer Institute at the University of Rochester (N.Y.), said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.

A nuance in the iwCLL guidelines is that CLL also can be defined by a cytopenia caused by a typical marrow infiltrate, regardless of the number of circulating B lymphocytes, he noted.

Immunophenotype

As for CLL immunophenotype, the cells are CD5- and CD23-positive, and additional B cell markers like CD20 are “often dim, and – understandably – the cells are light-chain restricted,” he said.

A subtle difference between the World Health Organization classification of CLL and the iwCLL guidelines is that, by the former, patients can have “a somewhat atypical immunophenotype.”


“So our pathologists, I like to think, use a commonsense approach where, if there are very minor differences, they will still call it CLL, but not if there are major differences in the immunophenotype,” Dr. Barr said.

Patients with lymphadenopathy, without the critical threshold of circulating B lymphocytes, are considered to have small lymphocytic lymphoma (SLL).

“In this day and age we treat CLL and SLL relatively similarly, however, monoclonal B lymphocytosis (MBL) is the precursor lesion to CLL where we see less than 5 x 10⁹/L of circulating B lymphocytes and an absence of adenopathy and disease-related cytopenias,” he noted.

Staging

It is still common practice to stage patients given the prognostic value of staging and given that treatment is provided in advanced disease, Dr. Barr said.

“This is simple, easy to apply, applicable worldwide, and only requires laboratory testing and a physical exam,” he said.

The stages include:

• Stage 0: Lymphocytosis, peripheral lymphocyte count greater than 15,000/mcL and greater than 40% lymphocytes in bone marrow (low-risk disease status).
• Stage I: Stage 0 disease plus enlarged lymph nodes (intermediate-risk disease status).
• Stage II: Stage 0-I disease with splenomegaly and/or hepatomegaly (intermediate-risk disease status).
• Stage III: Stage 0-II disease with hemoglobin less than 11g/dL or hematocrit less than 33% (high-risk disease status).
• Stage IV: Stage 0-III disease with platelet count less than 100,000/mcL (high-risk disease status).

Prognostic testing

Once a patient is diagnosed with CLL, as was the case with the 50-year-old patient Dr. Barr described, a number of tests can be considered to assess prognosis.

There’s no “perfect answer” when it comes to which tests are considered a reasonable standard of care, he noted.

“I would typically perform [immunoglobulin variable heavy-chain gene] mutation testing, a [fluorescence in situ hybridization] panel, and TP53 mutation testing,” he said.

Scoring systems such as CLL-IPI, which combine prognostic factors to divide patients into various risk categories, can be useful.

For example, such systems may identify high-risk patients who might be appropriate candidates for clinical trials, or low-risk patients who could be expected to do well over time despite having advanced stage disease, he explained.

“I do think it’s a useful process to go through to understand a patient’s risk over time,” he added.

However, treatment for CLL still is not based on molecular aberrations/prognostic features. In fact, the treatment indications according to the updated iwCLL guidelines remain exactly the same, he said.

Therefore, the case of the 50-year-old man described earlier would be observed as long as he remained asymptomatic.

Dr. Barr is a consultant for Pharmacyclics, AbbVie, Celgene, Gilead, Infinity, Novartis, and Seattle Genetics and has received research funding from Pharmacyclics and AbbVie.

[email protected]

CHICAGO – A 50-year old otherwise healthy man was found on routine history and physical to have lymphocytosis and was referred for additional work-up. He denied recent infection, had no lymphadenopathy, organomegaly, or rash or other concerning skin lesions. A complete blood count showed a white cell count of 23 x 10⁹/Land absolute lymphocyte count of 19 x 10⁹/L and normal hemoglobin and platelets.

Based on recently updated International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines, additional work-up for this patient might include peripheral smear and flow cytometry, according to Paul Barr, MD.

“A peripheral smear is still useful in this day and age just to ensure that a patient has a typical look under the microscope. We expect to see small mature lymphocytes, smudge cells, and perhaps a smaller number of prolymphocytes. But to mark CLL based on flow cytometry we need to see greater than 5 x 10⁹/L clonal B lymphocytes in the peripheral blood sustained over time,” Dr. Barr, medical director of the clinical trials office for Wilmot Cancer Institute at the University of Rochester (N.Y.), said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.

A nuance in the iwCLL guidelines is that CLL also can be defined by a cytopenia caused by a typical marrow infiltrate, regardless of the number of circulating B lymphocytes, he noted.

Immunophenotype

As for CLL immunophenotype, the cells are CD5- and CD23-positive, and additional B cell markers like CD20 are “often dim, and – understandably – the cells are light-chain restricted,” he said.

A subtle difference between the World Health Organization classification of CLL and the iwCLL guidelines is that, by the former, patients can have “a somewhat atypical immunophenotype.”


“So our pathologists, I like to think, use a commonsense approach where, if there are very minor differences, they will still call it CLL, but not if there are major differences in the immunophenotype,” Dr. Barr said.

Patients with lymphadenopathy, without the critical threshold of circulating B lymphocytes, are considered to have small lymphocytic lymphoma (SLL).

“In this day and age we treat CLL and SLL relatively similarly, however, monoclonal B lymphocytosis (MBL) is the precursor lesion to CLL where we see less than 5 x 10⁹/L of circulating B lymphocytes and an absence of adenopathy and disease-related cytopenias,” he noted.

Staging

It is still common practice to stage patients given the prognostic value of staging and given that treatment is provided in advanced disease, Dr. Barr said.

“This is simple, easy to apply, applicable worldwide, and only requires laboratory testing and a physical exam,” he said.

The stages include:

• Stage 0: Lymphocytosis, peripheral lymphocyte count greater than 15,000/mcL and greater than 40% lymphocytes in bone marrow (low-risk disease status).
• Stage I: Stage 0 disease plus enlarged lymph nodes (intermediate-risk disease status).
• Stage II: Stage 0-I disease with splenomegaly and/or hepatomegaly (intermediate-risk disease status).
• Stage III: Stage 0-II disease with hemoglobin less than 11g/dL or hematocrit less than 33% (high-risk disease status).
• Stage IV: Stage 0-III disease with platelet count less than 100,000/mcL (high-risk disease status).

Prognostic testing

Once a patient is diagnosed with CLL, as was the case with the 50-year-old patient Dr. Barr described, a number of tests can be considered to assess prognosis.

There’s no “perfect answer” when it comes to which tests are considered a reasonable standard of care, he noted.

“I would typically perform [immunoglobulin variable heavy-chain gene] mutation testing, a [fluorescence in situ hybridization] panel, and TP53 mutation testing,” he said.

Scoring systems such as CLL-IPI, which combine prognostic factors to divide patients into various risk categories, can be useful.

For example, such systems may identify high-risk patients who might be appropriate candidates for clinical trials, or low-risk patients who could be expected to do well over time despite having advanced stage disease, he explained.

“I do think it’s a useful process to go through to understand a patient’s risk over time,” he added.

However, treatment for CLL still is not based on molecular aberrations/prognostic features. In fact, the treatment indications according to the updated iwCLL guidelines remain exactly the same, he said.

Therefore, the case of the 50-year-old man described earlier would be observed as long as he remained asymptomatic.

Dr. Barr is a consultant for Pharmacyclics, AbbVie, Celgene, Gilead, Infinity, Novartis, and Seattle Genetics and has received research funding from Pharmacyclics and AbbVie.

[email protected]

CHICAGO – A 50-year old otherwise healthy man was found on routine history and physical to have lymphocytosis and was referred for additional work-up. He denied recent infection, had no lymphadenopathy, organomegaly, or rash or other concerning skin lesions. A complete blood count showed a white cell count of 23 x 10⁹/Land absolute lymphocyte count of 19 x 10⁹/L and normal hemoglobin and platelets.

Based on recently updated International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines, additional work-up for this patient might include peripheral smear and flow cytometry, according to Paul Barr, MD.

“A peripheral smear is still useful in this day and age just to ensure that a patient has a typical look under the microscope. We expect to see small mature lymphocytes, smudge cells, and perhaps a smaller number of prolymphocytes. But to mark CLL based on flow cytometry we need to see greater than 5 x 10⁹/L clonal B lymphocytes in the peripheral blood sustained over time,” Dr. Barr, medical director of the clinical trials office for Wilmot Cancer Institute at the University of Rochester (N.Y.), said during a presentation at the American Society of Hematology Meeting on Hematologic Malignancies.

A nuance in the iwCLL guidelines is that CLL also can be defined by a cytopenia caused by a typical marrow infiltrate, regardless of the number of circulating B lymphocytes, he noted.

Immunophenotype

As for CLL immunophenotype, the cells are CD5- and CD23-positive, and additional B cell markers like CD20 are “often dim, and – understandably – the cells are light-chain restricted,” he said.

A subtle difference between the World Health Organization classification of CLL and the iwCLL guidelines is that, by the former, patients can have “a somewhat atypical immunophenotype.”


“So our pathologists, I like to think, use a commonsense approach where, if there are very minor differences, they will still call it CLL, but not if there are major differences in the immunophenotype,” Dr. Barr said.

Patients with lymphadenopathy, without the critical threshold of circulating B lymphocytes, are considered to have small lymphocytic lymphoma (SLL).

“In this day and age we treat CLL and SLL relatively similarly, however, monoclonal B lymphocytosis (MBL) is the precursor lesion to CLL where we see less than 5 x 10⁹/L of circulating B lymphocytes and an absence of adenopathy and disease-related cytopenias,” he noted.

Staging

It is still common practice to stage patients given the prognostic value of staging and given that treatment is provided in advanced disease, Dr. Barr said.

“This is simple, easy to apply, applicable worldwide, and only requires laboratory testing and a physical exam,” he said.

The stages include:

• Stage 0: Lymphocytosis, peripheral lymphocyte count greater than 15,000/mcL and greater than 40% lymphocytes in bone marrow (low-risk disease status).
• Stage I: Stage 0 disease plus enlarged lymph nodes (intermediate-risk disease status).
• Stage II: Stage 0-I disease with splenomegaly and/or hepatomegaly (intermediate-risk disease status).
• Stage III: Stage 0-II disease with hemoglobin less than 11g/dL or hematocrit less than 33% (high-risk disease status).
• Stage IV: Stage 0-III disease with platelet count less than 100,000/mcL (high-risk disease status).

Prognostic testing

Once a patient is diagnosed with CLL, as was the case with the 50-year-old patient Dr. Barr described, a number of tests can be considered to assess prognosis.

There’s no “perfect answer” when it comes to which tests are considered a reasonable standard of care, he noted.

“I would typically perform [immunoglobulin variable heavy-chain gene] mutation testing, a [fluorescence in situ hybridization] panel, and TP53 mutation testing,” he said.

Scoring systems such as CLL-IPI, which combine prognostic factors to divide patients into various risk categories, can be useful.

For example, such systems may identify high-risk patients who might be appropriate candidates for clinical trials, or low-risk patients who could be expected to do well over time despite having advanced stage disease, he explained.

“I do think it’s a useful process to go through to understand a patient’s risk over time,” he added.

However, treatment for CLL still is not based on molecular aberrations/prognostic features. In fact, the treatment indications according to the updated iwCLL guidelines remain exactly the same, he said.

Therefore, the case of the 50-year-old man described earlier would be observed as long as he remained asymptomatic.

Dr. Barr is a consultant for Pharmacyclics, AbbVie, Celgene, Gilead, Infinity, Novartis, and Seattle Genetics and has received research funding from Pharmacyclics and AbbVie.

[email protected]

Acute flaccid myelitis (AFM) has stricken 90 patients in the United States this year and another 252 cases are being investigated, according to new data from the Centers for Disease Control and Prevention.

Sasiistock/iStock/Getty Images Plus

The number of confirmed cases is triple that seen in 2017.

Nearly all of the patients (90%) were children aged 2-8 years, and 99% experienced a fever and /or respiratory illness 7-10 days before the onset of symptoms. But although the prodrome and seasonality of AFM suggest an infective process, only 54% of the patients tested positive for the virus, Nancy Messonnier, MD, said during a briefing held by CDC officials. The most common findings were the enteroviruses EV-A71 (29%) and EV-D68 (37%); other viruses were recovered in the remaining pathogen-positive cases.

It’s not at all clear that these were causative agents, said Dr. Messonnier, director of the National Center for Immunization and Respiratory Diseases.

“At this time of year lots of children have a fever and respiratory infections,” she said. AFM may be caused by one of the identified viruses, a still-undetected pathogen, or a pathogen hiding in untested tissue. “Or, it could be an infection that’s kicking off an immune process,” attacking gray matter in the spinal cord.

The reported increase in cases must be viewed cautiously, Dr. Messonnier said. Physicians are becoming more aware of AFM, so the spike could represent an increase in reporting as well as actual incidence.

It’s not clear why the disease manifests almost exclusively in children, Dr. Messonnier said. Nor do health officials have much of a grasp on AFM’s long-term sequelae.

“We know that patients can recover fully, but at least half don’t, and some of those have serious sequelae. Unfortunately, we have not been following every patient, so this is a gap in our knowledge.”

A newly created national task force will examine AFM’s long-term effects, Dr. Messonnier said. The task force will also look at mortality; health departments across the country will examine mortality records to identify any past deaths preceded by AFM-like symptoms.

“One of the reasons we have convened this task force is to think about this hypothesis [of an autoimmune syndrome]. We have not backed off on the idea of an infectious organism causing it, but we are thinking more broadly,” Dr. Messonnier said.

Some anti-immunization groups are blaming vaccines for the disease, noting that several childhood vaccines list encephalomyelitis and transverse myelitis as possible adverse events.

“We are investigating every one of the cases in this and prior years and have a list of hypotheses based on the epidemiology,” Dr. Messonnier said. “I would say toxins are low on that list. Many of the children may have been vaccinated [before developing AFM] and that is something we will look at, but for now we recommend that all children should be vaccinated” according to the recommended schedule.

Additional details were published on 80 of the cases. Patients’ mean age was 4 years; 59% were male. Symptoms suggesting a viral illness occurred in 99%; these included fever (81%), cough, rhinorrhea, and congestion (78%), and vomiting and diarrhea (38%).

AFM symptoms varied; 47% had only upper limb involvement, 9% only lower limb, 15% two or three upper, and 29% all four limbs. All the patients with confirmed AFM were hospitalized, and 59% treated in intensive care units. There were no deaths (MMWR. 2018;ePub:13 November. DOI: http://dx.doi.org/10.15585/mmwr.mm6745e1).

AFM remains extremely rare, Dr. Messonnier said. But physicians should be alert for any signs of sudden limb weakness in children and report those immediately. The workup should include questions about recent fever with or without respiratory or gastrointestinal symptoms. Prompt collection of viral testing samples (cerebrospinal fluid, serum, respiratory, and stool specimens) is critical.

Additional information for health care professionals is available on the CDC AFM web page.

[email protected]

Acute flaccid myelitis (AFM) has stricken 90 patients in the United States this year and another 252 cases are being investigated, according to new data from the Centers for Disease Control and Prevention.

Sasiistock/iStock/Getty Images Plus

The number of confirmed cases is triple that seen in 2017.

Nearly all of the patients (90%) were children aged 2-8 years, and 99% experienced a fever and /or respiratory illness 7-10 days before the onset of symptoms. But although the prodrome and seasonality of AFM suggest an infective process, only 54% of the patients tested positive for the virus, Nancy Messonnier, MD, said during a briefing held by CDC officials. The most common findings were the enteroviruses EV-A71 (29%) and EV-D68 (37%); other viruses were recovered in the remaining pathogen-positive cases.

It’s not at all clear that these were causative agents, said Dr. Messonnier, director of the National Center for Immunization and Respiratory Diseases.

“At this time of year lots of children have a fever and respiratory infections,” she said. AFM may be caused by one of the identified viruses, a still-undetected pathogen, or a pathogen hiding in untested tissue. “Or, it could be an infection that’s kicking off an immune process,” attacking gray matter in the spinal cord.

The reported increase in cases must be viewed cautiously, Dr. Messonnier said. Physicians are becoming more aware of AFM, so the spike could represent an increase in reporting as well as actual incidence.

It’s not clear why the disease manifests almost exclusively in children, Dr. Messonnier said. Nor do health officials have much of a grasp on AFM’s long-term sequelae.

“We know that patients can recover fully, but at least half don’t, and some of those have serious sequelae. Unfortunately, we have not been following every patient, so this is a gap in our knowledge.”

A newly created national task force will examine AFM’s long-term effects, Dr. Messonnier said. The task force will also look at mortality; health departments across the country will examine mortality records to identify any past deaths preceded by AFM-like symptoms.

“One of the reasons we have convened this task force is to think about this hypothesis [of an autoimmune syndrome]. We have not backed off on the idea of an infectious organism causing it, but we are thinking more broadly,” Dr. Messonnier said.

Some anti-immunization groups are blaming vaccines for the disease, noting that several childhood vaccines list encephalomyelitis and transverse myelitis as possible adverse events.

“We are investigating every one of the cases in this and prior years and have a list of hypotheses based on the epidemiology,” Dr. Messonnier said. “I would say toxins are low on that list. Many of the children may have been vaccinated [before developing AFM] and that is something we will look at, but for now we recommend that all children should be vaccinated” according to the recommended schedule.

Additional details were published on 80 of the cases. Patients’ mean age was 4 years; 59% were male. Symptoms suggesting a viral illness occurred in 99%; these included fever (81%), cough, rhinorrhea, and congestion (78%), and vomiting and diarrhea (38%).

AFM symptoms varied; 47% had only upper limb involvement, 9% only lower limb, 15% two or three upper, and 29% all four limbs. All the patients with confirmed AFM were hospitalized, and 59% treated in intensive care units. There were no deaths (MMWR. 2018;ePub:13 November. DOI: http://dx.doi.org/10.15585/mmwr.mm6745e1).

AFM remains extremely rare, Dr. Messonnier said. But physicians should be alert for any signs of sudden limb weakness in children and report those immediately. The workup should include questions about recent fever with or without respiratory or gastrointestinal symptoms. Prompt collection of viral testing samples (cerebrospinal fluid, serum, respiratory, and stool specimens) is critical.

Additional information for health care professionals is available on the CDC AFM web page.

[email protected]

Acute flaccid myelitis (AFM) has stricken 90 patients in the United States this year and another 252 cases are being investigated, according to new data from the Centers for Disease Control and Prevention.

Sasiistock/iStock/Getty Images Plus

The number of confirmed cases is triple that seen in 2017.

Nearly all of the patients (90%) were children aged 2-8 years, and 99% experienced a fever and /or respiratory illness 7-10 days before the onset of symptoms. But although the prodrome and seasonality of AFM suggest an infective process, only 54% of the patients tested positive for the virus, Nancy Messonnier, MD, said during a briefing held by CDC officials. The most common findings were the enteroviruses EV-A71 (29%) and EV-D68 (37%); other viruses were recovered in the remaining pathogen-positive cases.

It’s not at all clear that these were causative agents, said Dr. Messonnier, director of the National Center for Immunization and Respiratory Diseases.

“At this time of year lots of children have a fever and respiratory infections,” she said. AFM may be caused by one of the identified viruses, a still-undetected pathogen, or a pathogen hiding in untested tissue. “Or, it could be an infection that’s kicking off an immune process,” attacking gray matter in the spinal cord.

The reported increase in cases must be viewed cautiously, Dr. Messonnier said. Physicians are becoming more aware of AFM, so the spike could represent an increase in reporting as well as actual incidence.

It’s not clear why the disease manifests almost exclusively in children, Dr. Messonnier said. Nor do health officials have much of a grasp on AFM’s long-term sequelae.

“We know that patients can recover fully, but at least half don’t, and some of those have serious sequelae. Unfortunately, we have not been following every patient, so this is a gap in our knowledge.”

A newly created national task force will examine AFM’s long-term effects, Dr. Messonnier said. The task force will also look at mortality; health departments across the country will examine mortality records to identify any past deaths preceded by AFM-like symptoms.

“One of the reasons we have convened this task force is to think about this hypothesis [of an autoimmune syndrome]. We have not backed off on the idea of an infectious organism causing it, but we are thinking more broadly,” Dr. Messonnier said.

Some anti-immunization groups are blaming vaccines for the disease, noting that several childhood vaccines list encephalomyelitis and transverse myelitis as possible adverse events.

“We are investigating every one of the cases in this and prior years and have a list of hypotheses based on the epidemiology,” Dr. Messonnier said. “I would say toxins are low on that list. Many of the children may have been vaccinated [before developing AFM] and that is something we will look at, but for now we recommend that all children should be vaccinated” according to the recommended schedule.

Additional details were published on 80 of the cases. Patients’ mean age was 4 years; 59% were male. Symptoms suggesting a viral illness occurred in 99%; these included fever (81%), cough, rhinorrhea, and congestion (78%), and vomiting and diarrhea (38%).

AFM symptoms varied; 47% had only upper limb involvement, 9% only lower limb, 15% two or three upper, and 29% all four limbs. All the patients with confirmed AFM were hospitalized, and 59% treated in intensive care units. There were no deaths (MMWR. 2018;ePub:13 November. DOI: http://dx.doi.org/10.15585/mmwr.mm6745e1).

AFM remains extremely rare, Dr. Messonnier said. But physicians should be alert for any signs of sudden limb weakness in children and report those immediately. The workup should include questions about recent fever with or without respiratory or gastrointestinal symptoms. Prompt collection of viral testing samples (cerebrospinal fluid, serum, respiratory, and stool specimens) is critical.

Additional information for health care professionals is available on the CDC AFM web page.

[email protected]

Vidyard Video

Click here to view the articles published in November 2018.

Click here to view the articles published in the Psoriasis Special Issue.

Vidyard Video

Click here to view the articles published in November 2018.

Click here to view the articles published in the Psoriasis Special Issue.

Vidyard Video

Click here to view the articles published in November 2018.

Click here to view the articles published in the Psoriasis Special Issue.

It may not seem intuitive, but to understand some of the new skin care claims, you need to know a bit about the gut microbiome and its role in skin health. The skin and gut host a copious and disparate array of bacteria, fungi, viruses, and mites. New research shows us that these microbes play an important role in skin health. The gut and skin play a balancing act between beneficial, neutral, and harmful flora that are interrelated with the innate and adaptive immune systems.¹ The skin and gut seem to be intertwined and express several comorbidities.² In this column, the focus is on the cutaneous microbiome’s role in skin health. To understand the cosmeceutical claims about pre- and probiotics, you first need to familiarize yourself with skin microbiome science. The skin-gut nexus will be discussed in next month’s column, which will address the role of the skin microbiome in skin diseases.

ChrisChrisW/Getty Images

Why is the microbiome such a hot topic?

Genetic sequencing has spurred advances in the study of the microbiome and has provided intriguing clues that the gut and skin microbiome have influences on each other. Sequencing assays that focus on bacterial 16S ribosomal RNA genes have been used by investigators to distinguish and describe the wide variety of resident and transient microorganisms on the skin and elucidate their roles in skin health and disease.¹ Genomic sequencing has identified species in the skin and gut that were not found previously by cultivating microbial isolates.^3,4 Advances in technologies such as whole-genome shotgun sequencing, metagenomics, and functional metabolomics will further contribute to our understanding of the effects of the skin microbiome on skin health and skin type. Of course, many supplement and cosmeceutical companies have jumped on this bandwagon prematurely and claim that their products increase “good bacteria while diminishing bad bacteria.” While there are interesting data that have emerged, we still cannot say which bacteria are “good” and ‘bad” as far as the skin is concerned – with a few exceptions that we have known all along. For example, Cutibacterium acnes and Staphylococcus aureus still remain in the undesirable category. (P. acnes has been renamed and now is officially referred to as C. acnes.) While it is premature to recommend probiotic– or prebiotic–containing cosmeceuticals, your patients will ask you about them. New studies about rosacea and the microbiome have generated a lot of patient questions in my practice, so I am writing several blogs about how to answer patient questions, which can be found at STSFranchise.com/blog. I’m also educating consumers on Facebook and Instagram @skintypesolutions so that they will not be taken advantage of by the too early “pseudoscience.” So now that you have heard that it is too early to recommend pre- and probiotic skin care to target skin issues, let’s look at the science that does exist.

Terminology

• Microbiome: Microbes that live in a particular environment or biome.
• Microbiota: The collection of living microbes that live in or on an environment. This term includes the microorganisms only and not the characteristics of their environment.
• Prebiotics: A nondigestible food ingredient that promotes the growth of microorganisms in the intestines. These can promote the growth of beneficial or harmful microorganisms. Think of them as a type of “fertilizer” for the microbiome.
• Probiotics: Living microorganisms that can provide beneficial qualities when used orally or topically. What probiotics are not? Microbes naturally found in your body and on your skin; microbes that are no longer alive; fermented foods that contain an unknown amount of bacteria.

Skin surface area

Richard Gallo, MD, a dermatologist from the University of California, San Diego, who is a leader in the microbiome field of study, says that estimates of the cutaneous microbiome’s impact on human health via skin have failed to acknowledge the inner follicular surface, thus drastically undervaluing the potential of the cutaneous microbiome to influence systemic health.⁵ He suggests that the surface area of skin has been miscalculated as measuring 2 m² because it is considered a flat surface. This ignores the plethora of hair follicles and sweat ducts that significantly broaden the epithelial surface to measure closer to 25 m² and underscores that the expansive skin microbiome is much larger than previously recognized.⁵ Taking the hair follicle surface area into account, the skin has vast space to harbor various organisms and microbiome environments. What our patients use on their skin certainly influences these environments. The key is trying to figure out how to manipulate the microbiome to our patient’s advantage.

Microbes have environmental preferences

Different microbial species thrive on particular regions of the diverse topography of the expansive surface area and choose their preferred environments from among sebaceous or nonsebaceous, hairy or smooth, moist or dry, and creased or noncreased areas.^6,7 Other host factors that affect which microorganisms colonize the skin include hair follicle thickness, age, sex, diet (especially high fat and sugar intake), climate, occupation, and personal hygiene.^7-10 Gene sequencing has revealed that these variations are partially because of factors such as ultraviolet exposure, pH, and temperature.^4,6,11 For example, C. acnes has been found to be more prevalent in highly sebaceous sites on the head and upper torso.⁴ In general, Propionibacteriaceae (Cutibacterium) prefer sebaceous areas, whereas Corynebacteriaceae and Staphylococcaceae prevail in moist regions, such as the navel or axilla. Dry areas host the widest diversity of microbes, including Corynebacterium, Staphylococcus, and Streptococcus species.^1,7,12

Impact of sebum and skin hydration on microbiome

In 2016, Mukherjee et al. measured sebum and hydration from the forehead and cheeks of 30 healthy female volunteers in a study that tested the hypothesis that differences in sebum and hydration levels in specific facial areas account for interindividual variation in facial skin microbiome. They found that the most significant predictor of microbiome composition was cheek sebum level, followed by forehead hydration level, while cheek hydration and forehead sebum levels were not predictive. The prevalence of Actinobacteria/Propionibacterium rose, while microbiome diversity diminished with an increase in cheek sebum, with such trends reversed in relation to forehead hydration. The investigators concluded that site-specific sebum and water levels impact the nature and diversity of the facial skin microbiome.¹³

Lability of the cutaneous microbiome

The skin microbiome changes during various times of life. For example, in puberty, more lipophilic species such as Propionibacteriaceae and Cornebacteriaceae predominate, while prior to puberty there is a preponderance of Firmicutes, Bacteroidetes, and Proteobacteria.^4,14 However, in the absence of lifestyle changes, cutaneous microbial communities have been found through longitudinal studies to be relatively stable over a 2-year period.⁶ A person’s skin microbiome is subject to influence from an adjacent skin microbiome, such as between cohabiting couples or the influence of breastfeeding mothers.¹⁵ It is never too early to consider the role of the microbiome in health and disease. For example, infant microbiomes play a role in eczema and the atopic march.¹⁶ For this reason, those of us who treat children need to be familiar with studies that have demonstrate how the cutaneous microbiome is affected by childbirth delivery method, breastfeeding, the mother’s diet antibiotic use during pregnancy and breastfeeding.^4,17

Microbiome effects on skin function

The skin barrier, a bilayer lipid-laden membrane that surrounds keratinocytes and prevents transepidermal water loss, is affected by resident microbial communities and has been shown by research to be influenced by the volume and diversity of such microbes.¹⁸ Organisms on the skin’s surface play an important role in communicating with and educating the cutaneous arm of the immune system.¹⁹ In 2017, Maguire and Maguire reviewed recent studies of the gut and skin microbiomes and suggested that Nitrobacter, Lactobacillus, and Bifidobacterium can improve skin health and could be useful bacterial adjuvants in a probiotic and prebiotic strategy in homeostatic renormalization when skin health is compromised.²⁰Nitrobacter has displayed antifungal activity against dermatophytes and Staphylococcus; Lactobacillus has exhibited anti-inflammatory effects and was shown to improve adult acne in a small study; Bifidobacterium combined with Lactobacillus lowered the incidence of atopic eczema in early childhood; and Bifidobacterium and the prebiotic galacto-oligosaccharide prevented hydration level losses in the stratum corneum among other beneficial effects in a double-blind, placebo-controlled, randomized trial.²⁰

Microbiome diversity is key

Microbes interact, collaborate, and oppose one another while exerting influence and being affected by the host. Effective communication among the innate and adaptive parts of the immune system, epithelial cells, and cutaneous microbiota is essential for optimal functioning of the skin.^6,7 Studies on subjects with atopic dermatitis showed a strong association between decreased diversity and increased disease severity. This suggests that a diverse microbiome is associated with skin health.²¹ For this reason, use of pre- and probiotics for skin issues is discouraged at this time. If we replace the normal diverse flora with one organism, we do not yet know the consequences. It is much more likely that successful treatments in the future will contain a diverse group of organisms.

Cosmeceutical effects on the skin microbiome

Cleansing and use of emollients certainly affect the skin biome, but we do not yet know to what extent. A study that looked at the effects of emollients on infants with atopic dermatitis showed that the emollient group has a lower skin pH and a more diverse microbiome.²² In a 2016 study on the impact of acute treatment with topical skin cleansers on the cutaneous microbiome, investigators evaluated multiple common skin cleansers in the washing of human forearms. Group A Streptococcus growth was reduced after washing with soaps infused with such antimicrobial compounds as benzalkonium chloride or triclocarban. The researchers stipulated that much more research is necessary to ascertain the effects of chronic washing as well as the that role skin care products may play in skin homeostasis or dysbiosis in some individuals.²³

In a 2017 analysis of the effects of cosmetics on the skin microbiome of facial cheeks with high- and low-hydration levels over 4 weeks, Lee et al. found that bacterial diversity was higher in the low-hydration group, with increases in both observed after the use of cosmetics. The high-hydration group showed a greater supply of Propionibacterium. Cosmetic use was found not to have caused a shift in bacterial communities in the low-hydration group.²⁴

Conclusion

We are in the early stages as we strive to learn more about the microbiome to leverage such knowledge to improve skin health. In the meantime, there is not enough evidence to suggest the use of any oral or topical prebiotics or probiotics to improve skin health. In fact, we may be causing harm by lessening diversity. The New York Times recently published an article called “The Problem with Probiotics” that referenced a JAMA Internal Medicine article entitled “Probiotic Safety – No Guarantees.”²⁵ I recommend that you read those. Next month, I will look more closely at microbiome research pertaining to skin disease.
 

Dr. Baumann is a private practice dermatologist, researcher, author and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC.

References

1. Dréno B et al. J Eur Acad Dermatol Venereol. 2016 Dec;30(12):2038-47.

2. O’Neill CA et al. Bioessays. 2016 Nov;38(11):1167-76.

3. Kong HH. Trends Mol Med. 2011 Jun;17(6):320-8.

4. Kong HH et al. J Invest Dermatol. 2017 May;137(5):e119-22.

5. Gallo RL. J Invest Dermatol. 2017 Jun;137(6):1213-4.

6. Byrd AL et al. Nat Rev Microbiol. 2018 Mar;16(3):143-55.

7. Grice EA et al. Nat Rev Microbiol. 2011 Apr;9(4):244-53.

8. Rodrigues Hoffmann A. Vet Dermatol. 2017 Feb;28(1):60-e15.

9. Moestrup KS et al. J Invest Dermatol. 2018 May;138(5):1225-8.

10. Prescott SL et al. World Allergy Organ J. 2017 Aug 22;10(1):29.

11. Costello EK et al. Science. 2009 Dec 18;326(5960):1694-7.

12. Zeeuwen PL et al. Genome Biol. 2012 Nov 15;13(11):R101.

13. Mukherjee S et al. Sci Rep. 2016 Oct 27;6:36062.

14. Oh J et al. Genome Med. 2012 Oct 10;4(10):77.

15. Ross AA et al. mSystems. 2017 Jul 20;2(4).

16. Blázquez AB et al. Transl Res. 2017 Jan;179:199-203.

17. Rock R et al. Open Forum Infect Dis. 2017 Oct;4(1):S232.

18. Baldwin HE et al. J Drugs Dermatol. 2017 Jan 1;16(1):12-8.

19. Byrd AL et al. Nat Rev Microbiol. 2018 Mar;16(3):143-55.

20. Maguire M et al. Arch Dermatol Res. 2017 Aug;309(6):411-21.

21. Kong HH et al. Genome Res. 2012 May;22(5):850-9.

22. Glatz M et al. PLoS One. 2018 Feb 28;13(2):e0192443.

23. Two AM et al. J Invest Dermatol. 2016 Oct;136(10):1950-4.

24. Lee HJ et al. MicrobiologyOpen. 2018 Apr;7(2):e00557. doi: 10.1002/mbo3.557.

25. Cohen PA. JAMA Intern Med. 2018 Sep 17. doi: 10.1001/jamainternmed.2018.5403.






 

It may not seem intuitive, but to understand some of the new skin care claims, you need to know a bit about the gut microbiome and its role in skin health. The skin and gut host a copious and disparate array of bacteria, fungi, viruses, and mites. New research shows us that these microbes play an important role in skin health. The gut and skin play a balancing act between beneficial, neutral, and harmful flora that are interrelated with the innate and adaptive immune systems.¹ The skin and gut seem to be intertwined and express several comorbidities.² In this column, the focus is on the cutaneous microbiome’s role in skin health. To understand the cosmeceutical claims about pre- and probiotics, you first need to familiarize yourself with skin microbiome science. The skin-gut nexus will be discussed in next month’s column, which will address the role of the skin microbiome in skin diseases.

ChrisChrisW/Getty Images

Why is the microbiome such a hot topic?

Genetic sequencing has spurred advances in the study of the microbiome and has provided intriguing clues that the gut and skin microbiome have influences on each other. Sequencing assays that focus on bacterial 16S ribosomal RNA genes have been used by investigators to distinguish and describe the wide variety of resident and transient microorganisms on the skin and elucidate their roles in skin health and disease.¹ Genomic sequencing has identified species in the skin and gut that were not found previously by cultivating microbial isolates.^3,4 Advances in technologies such as whole-genome shotgun sequencing, metagenomics, and functional metabolomics will further contribute to our understanding of the effects of the skin microbiome on skin health and skin type. Of course, many supplement and cosmeceutical companies have jumped on this bandwagon prematurely and claim that their products increase “good bacteria while diminishing bad bacteria.” While there are interesting data that have emerged, we still cannot say which bacteria are “good” and ‘bad” as far as the skin is concerned – with a few exceptions that we have known all along. For example, Cutibacterium acnes and Staphylococcus aureus still remain in the undesirable category. (P. acnes has been renamed and now is officially referred to as C. acnes.) While it is premature to recommend probiotic– or prebiotic–containing cosmeceuticals, your patients will ask you about them. New studies about rosacea and the microbiome have generated a lot of patient questions in my practice, so I am writing several blogs about how to answer patient questions, which can be found at STSFranchise.com/blog. I’m also educating consumers on Facebook and Instagram @skintypesolutions so that they will not be taken advantage of by the too early “pseudoscience.” So now that you have heard that it is too early to recommend pre- and probiotic skin care to target skin issues, let’s look at the science that does exist.

Terminology

• Microbiome: Microbes that live in a particular environment or biome.
• Microbiota: The collection of living microbes that live in or on an environment. This term includes the microorganisms only and not the characteristics of their environment.
• Prebiotics: A nondigestible food ingredient that promotes the growth of microorganisms in the intestines. These can promote the growth of beneficial or harmful microorganisms. Think of them as a type of “fertilizer” for the microbiome.
• Probiotics: Living microorganisms that can provide beneficial qualities when used orally or topically. What probiotics are not? Microbes naturally found in your body and on your skin; microbes that are no longer alive; fermented foods that contain an unknown amount of bacteria.

Skin surface area

Richard Gallo, MD, a dermatologist from the University of California, San Diego, who is a leader in the microbiome field of study, says that estimates of the cutaneous microbiome’s impact on human health via skin have failed to acknowledge the inner follicular surface, thus drastically undervaluing the potential of the cutaneous microbiome to influence systemic health.⁵ He suggests that the surface area of skin has been miscalculated as measuring 2 m² because it is considered a flat surface. This ignores the plethora of hair follicles and sweat ducts that significantly broaden the epithelial surface to measure closer to 25 m² and underscores that the expansive skin microbiome is much larger than previously recognized.⁵ Taking the hair follicle surface area into account, the skin has vast space to harbor various organisms and microbiome environments. What our patients use on their skin certainly influences these environments. The key is trying to figure out how to manipulate the microbiome to our patient’s advantage.

Microbes have environmental preferences

Different microbial species thrive on particular regions of the diverse topography of the expansive surface area and choose their preferred environments from among sebaceous or nonsebaceous, hairy or smooth, moist or dry, and creased or noncreased areas.^6,7 Other host factors that affect which microorganisms colonize the skin include hair follicle thickness, age, sex, diet (especially high fat and sugar intake), climate, occupation, and personal hygiene.^7-10 Gene sequencing has revealed that these variations are partially because of factors such as ultraviolet exposure, pH, and temperature.^4,6,11 For example, C. acnes has been found to be more prevalent in highly sebaceous sites on the head and upper torso.⁴ In general, Propionibacteriaceae (Cutibacterium) prefer sebaceous areas, whereas Corynebacteriaceae and Staphylococcaceae prevail in moist regions, such as the navel or axilla. Dry areas host the widest diversity of microbes, including Corynebacterium, Staphylococcus, and Streptococcus species.^1,7,12

Impact of sebum and skin hydration on microbiome

In 2016, Mukherjee et al. measured sebum and hydration from the forehead and cheeks of 30 healthy female volunteers in a study that tested the hypothesis that differences in sebum and hydration levels in specific facial areas account for interindividual variation in facial skin microbiome. They found that the most significant predictor of microbiome composition was cheek sebum level, followed by forehead hydration level, while cheek hydration and forehead sebum levels were not predictive. The prevalence of Actinobacteria/Propionibacterium rose, while microbiome diversity diminished with an increase in cheek sebum, with such trends reversed in relation to forehead hydration. The investigators concluded that site-specific sebum and water levels impact the nature and diversity of the facial skin microbiome.¹³

Lability of the cutaneous microbiome

The skin microbiome changes during various times of life. For example, in puberty, more lipophilic species such as Propionibacteriaceae and Cornebacteriaceae predominate, while prior to puberty there is a preponderance of Firmicutes, Bacteroidetes, and Proteobacteria.^4,14 However, in the absence of lifestyle changes, cutaneous microbial communities have been found through longitudinal studies to be relatively stable over a 2-year period.⁶ A person’s skin microbiome is subject to influence from an adjacent skin microbiome, such as between cohabiting couples or the influence of breastfeeding mothers.¹⁵ It is never too early to consider the role of the microbiome in health and disease. For example, infant microbiomes play a role in eczema and the atopic march.¹⁶ For this reason, those of us who treat children need to be familiar with studies that have demonstrate how the cutaneous microbiome is affected by childbirth delivery method, breastfeeding, the mother’s diet antibiotic use during pregnancy and breastfeeding.^4,17

Microbiome effects on skin function

The skin barrier, a bilayer lipid-laden membrane that surrounds keratinocytes and prevents transepidermal water loss, is affected by resident microbial communities and has been shown by research to be influenced by the volume and diversity of such microbes.¹⁸ Organisms on the skin’s surface play an important role in communicating with and educating the cutaneous arm of the immune system.¹⁹ In 2017, Maguire and Maguire reviewed recent studies of the gut and skin microbiomes and suggested that Nitrobacter, Lactobacillus, and Bifidobacterium can improve skin health and could be useful bacterial adjuvants in a probiotic and prebiotic strategy in homeostatic renormalization when skin health is compromised.²⁰Nitrobacter has displayed antifungal activity against dermatophytes and Staphylococcus; Lactobacillus has exhibited anti-inflammatory effects and was shown to improve adult acne in a small study; Bifidobacterium combined with Lactobacillus lowered the incidence of atopic eczema in early childhood; and Bifidobacterium and the prebiotic galacto-oligosaccharide prevented hydration level losses in the stratum corneum among other beneficial effects in a double-blind, placebo-controlled, randomized trial.²⁰

Microbiome diversity is key

Microbes interact, collaborate, and oppose one another while exerting influence and being affected by the host. Effective communication among the innate and adaptive parts of the immune system, epithelial cells, and cutaneous microbiota is essential for optimal functioning of the skin.^6,7 Studies on subjects with atopic dermatitis showed a strong association between decreased diversity and increased disease severity. This suggests that a diverse microbiome is associated with skin health.²¹ For this reason, use of pre- and probiotics for skin issues is discouraged at this time. If we replace the normal diverse flora with one organism, we do not yet know the consequences. It is much more likely that successful treatments in the future will contain a diverse group of organisms.

Cosmeceutical effects on the skin microbiome

Cleansing and use of emollients certainly affect the skin biome, but we do not yet know to what extent. A study that looked at the effects of emollients on infants with atopic dermatitis showed that the emollient group has a lower skin pH and a more diverse microbiome.²² In a 2016 study on the impact of acute treatment with topical skin cleansers on the cutaneous microbiome, investigators evaluated multiple common skin cleansers in the washing of human forearms. Group A Streptococcus growth was reduced after washing with soaps infused with such antimicrobial compounds as benzalkonium chloride or triclocarban. The researchers stipulated that much more research is necessary to ascertain the effects of chronic washing as well as the that role skin care products may play in skin homeostasis or dysbiosis in some individuals.²³

In a 2017 analysis of the effects of cosmetics on the skin microbiome of facial cheeks with high- and low-hydration levels over 4 weeks, Lee et al. found that bacterial diversity was higher in the low-hydration group, with increases in both observed after the use of cosmetics. The high-hydration group showed a greater supply of Propionibacterium. Cosmetic use was found not to have caused a shift in bacterial communities in the low-hydration group.²⁴

Conclusion

We are in the early stages as we strive to learn more about the microbiome to leverage such knowledge to improve skin health. In the meantime, there is not enough evidence to suggest the use of any oral or topical prebiotics or probiotics to improve skin health. In fact, we may be causing harm by lessening diversity. The New York Times recently published an article called “The Problem with Probiotics” that referenced a JAMA Internal Medicine article entitled “Probiotic Safety – No Guarantees.”²⁵ I recommend that you read those. Next month, I will look more closely at microbiome research pertaining to skin disease.
 

Dr. Baumann is a private practice dermatologist, researcher, author and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC.

References

1. Dréno B et al. J Eur Acad Dermatol Venereol. 2016 Dec;30(12):2038-47.

2. O’Neill CA et al. Bioessays. 2016 Nov;38(11):1167-76.

3. Kong HH. Trends Mol Med. 2011 Jun;17(6):320-8.

4. Kong HH et al. J Invest Dermatol. 2017 May;137(5):e119-22.

5. Gallo RL. J Invest Dermatol. 2017 Jun;137(6):1213-4.

6. Byrd AL et al. Nat Rev Microbiol. 2018 Mar;16(3):143-55.

7. Grice EA et al. Nat Rev Microbiol. 2011 Apr;9(4):244-53.

8. Rodrigues Hoffmann A. Vet Dermatol. 2017 Feb;28(1):60-e15.

9. Moestrup KS et al. J Invest Dermatol. 2018 May;138(5):1225-8.

10. Prescott SL et al. World Allergy Organ J. 2017 Aug 22;10(1):29.

11. Costello EK et al. Science. 2009 Dec 18;326(5960):1694-7.

12. Zeeuwen PL et al. Genome Biol. 2012 Nov 15;13(11):R101.

13. Mukherjee S et al. Sci Rep. 2016 Oct 27;6:36062.

14. Oh J et al. Genome Med. 2012 Oct 10;4(10):77.

15. Ross AA et al. mSystems. 2017 Jul 20;2(4).

16. Blázquez AB et al. Transl Res. 2017 Jan;179:199-203.

17. Rock R et al. Open Forum Infect Dis. 2017 Oct;4(1):S232.

18. Baldwin HE et al. J Drugs Dermatol. 2017 Jan 1;16(1):12-8.

19. Byrd AL et al. Nat Rev Microbiol. 2018 Mar;16(3):143-55.

20. Maguire M et al. Arch Dermatol Res. 2017 Aug;309(6):411-21.

21. Kong HH et al. Genome Res. 2012 May;22(5):850-9.

22. Glatz M et al. PLoS One. 2018 Feb 28;13(2):e0192443.

23. Two AM et al. J Invest Dermatol. 2016 Oct;136(10):1950-4.

24. Lee HJ et al. MicrobiologyOpen. 2018 Apr;7(2):e00557. doi: 10.1002/mbo3.557.

25. Cohen PA. JAMA Intern Med. 2018 Sep 17. doi: 10.1001/jamainternmed.2018.5403.






 

It may not seem intuitive, but to understand some of the new skin care claims, you need to know a bit about the gut microbiome and its role in skin health. The skin and gut host a copious and disparate array of bacteria, fungi, viruses, and mites. New research shows us that these microbes play an important role in skin health. The gut and skin play a balancing act between beneficial, neutral, and harmful flora that are interrelated with the innate and adaptive immune systems.¹ The skin and gut seem to be intertwined and express several comorbidities.² In this column, the focus is on the cutaneous microbiome’s role in skin health. To understand the cosmeceutical claims about pre- and probiotics, you first need to familiarize yourself with skin microbiome science. The skin-gut nexus will be discussed in next month’s column, which will address the role of the skin microbiome in skin diseases.

ChrisChrisW/Getty Images

Why is the microbiome such a hot topic?

Genetic sequencing has spurred advances in the study of the microbiome and has provided intriguing clues that the gut and skin microbiome have influences on each other. Sequencing assays that focus on bacterial 16S ribosomal RNA genes have been used by investigators to distinguish and describe the wide variety of resident and transient microorganisms on the skin and elucidate their roles in skin health and disease.¹ Genomic sequencing has identified species in the skin and gut that were not found previously by cultivating microbial isolates.^3,4 Advances in technologies such as whole-genome shotgun sequencing, metagenomics, and functional metabolomics will further contribute to our understanding of the effects of the skin microbiome on skin health and skin type. Of course, many supplement and cosmeceutical companies have jumped on this bandwagon prematurely and claim that their products increase “good bacteria while diminishing bad bacteria.” While there are interesting data that have emerged, we still cannot say which bacteria are “good” and ‘bad” as far as the skin is concerned – with a few exceptions that we have known all along. For example, Cutibacterium acnes and Staphylococcus aureus still remain in the undesirable category. (P. acnes has been renamed and now is officially referred to as C. acnes.) While it is premature to recommend probiotic– or prebiotic–containing cosmeceuticals, your patients will ask you about them. New studies about rosacea and the microbiome have generated a lot of patient questions in my practice, so I am writing several blogs about how to answer patient questions, which can be found at STSFranchise.com/blog. I’m also educating consumers on Facebook and Instagram @skintypesolutions so that they will not be taken advantage of by the too early “pseudoscience.” So now that you have heard that it is too early to recommend pre- and probiotic skin care to target skin issues, let’s look at the science that does exist.

Terminology

• Microbiome: Microbes that live in a particular environment or biome.
• Microbiota: The collection of living microbes that live in or on an environment. This term includes the microorganisms only and not the characteristics of their environment.
• Prebiotics: A nondigestible food ingredient that promotes the growth of microorganisms in the intestines. These can promote the growth of beneficial or harmful microorganisms. Think of them as a type of “fertilizer” for the microbiome.
• Probiotics: Living microorganisms that can provide beneficial qualities when used orally or topically. What probiotics are not? Microbes naturally found in your body and on your skin; microbes that are no longer alive; fermented foods that contain an unknown amount of bacteria.

Skin surface area

Richard Gallo, MD, a dermatologist from the University of California, San Diego, who is a leader in the microbiome field of study, says that estimates of the cutaneous microbiome’s impact on human health via skin have failed to acknowledge the inner follicular surface, thus drastically undervaluing the potential of the cutaneous microbiome to influence systemic health.⁵ He suggests that the surface area of skin has been miscalculated as measuring 2 m² because it is considered a flat surface. This ignores the plethora of hair follicles and sweat ducts that significantly broaden the epithelial surface to measure closer to 25 m² and underscores that the expansive skin microbiome is much larger than previously recognized.⁵ Taking the hair follicle surface area into account, the skin has vast space to harbor various organisms and microbiome environments. What our patients use on their skin certainly influences these environments. The key is trying to figure out how to manipulate the microbiome to our patient’s advantage.

Microbes have environmental preferences

Different microbial species thrive on particular regions of the diverse topography of the expansive surface area and choose their preferred environments from among sebaceous or nonsebaceous, hairy or smooth, moist or dry, and creased or noncreased areas.^6,7 Other host factors that affect which microorganisms colonize the skin include hair follicle thickness, age, sex, diet (especially high fat and sugar intake), climate, occupation, and personal hygiene.^7-10 Gene sequencing has revealed that these variations are partially because of factors such as ultraviolet exposure, pH, and temperature.^4,6,11 For example, C. acnes has been found to be more prevalent in highly sebaceous sites on the head and upper torso.⁴ In general, Propionibacteriaceae (Cutibacterium) prefer sebaceous areas, whereas Corynebacteriaceae and Staphylococcaceae prevail in moist regions, such as the navel or axilla. Dry areas host the widest diversity of microbes, including Corynebacterium, Staphylococcus, and Streptococcus species.^1,7,12

Impact of sebum and skin hydration on microbiome

In 2016, Mukherjee et al. measured sebum and hydration from the forehead and cheeks of 30 healthy female volunteers in a study that tested the hypothesis that differences in sebum and hydration levels in specific facial areas account for interindividual variation in facial skin microbiome. They found that the most significant predictor of microbiome composition was cheek sebum level, followed by forehead hydration level, while cheek hydration and forehead sebum levels were not predictive. The prevalence of Actinobacteria/Propionibacterium rose, while microbiome diversity diminished with an increase in cheek sebum, with such trends reversed in relation to forehead hydration. The investigators concluded that site-specific sebum and water levels impact the nature and diversity of the facial skin microbiome.¹³

Lability of the cutaneous microbiome

The skin microbiome changes during various times of life. For example, in puberty, more lipophilic species such as Propionibacteriaceae and Cornebacteriaceae predominate, while prior to puberty there is a preponderance of Firmicutes, Bacteroidetes, and Proteobacteria.^4,14 However, in the absence of lifestyle changes, cutaneous microbial communities have been found through longitudinal studies to be relatively stable over a 2-year period.⁶ A person’s skin microbiome is subject to influence from an adjacent skin microbiome, such as between cohabiting couples or the influence of breastfeeding mothers.¹⁵ It is never too early to consider the role of the microbiome in health and disease. For example, infant microbiomes play a role in eczema and the atopic march.¹⁶ For this reason, those of us who treat children need to be familiar with studies that have demonstrate how the cutaneous microbiome is affected by childbirth delivery method, breastfeeding, the mother’s diet antibiotic use during pregnancy and breastfeeding.^4,17

Microbiome effects on skin function

The skin barrier, a bilayer lipid-laden membrane that surrounds keratinocytes and prevents transepidermal water loss, is affected by resident microbial communities and has been shown by research to be influenced by the volume and diversity of such microbes.¹⁸ Organisms on the skin’s surface play an important role in communicating with and educating the cutaneous arm of the immune system.¹⁹ In 2017, Maguire and Maguire reviewed recent studies of the gut and skin microbiomes and suggested that Nitrobacter, Lactobacillus, and Bifidobacterium can improve skin health and could be useful bacterial adjuvants in a probiotic and prebiotic strategy in homeostatic renormalization when skin health is compromised.²⁰Nitrobacter has displayed antifungal activity against dermatophytes and Staphylococcus; Lactobacillus has exhibited anti-inflammatory effects and was shown to improve adult acne in a small study; Bifidobacterium combined with Lactobacillus lowered the incidence of atopic eczema in early childhood; and Bifidobacterium and the prebiotic galacto-oligosaccharide prevented hydration level losses in the stratum corneum among other beneficial effects in a double-blind, placebo-controlled, randomized trial.²⁰

Microbiome diversity is key

Microbes interact, collaborate, and oppose one another while exerting influence and being affected by the host. Effective communication among the innate and adaptive parts of the immune system, epithelial cells, and cutaneous microbiota is essential for optimal functioning of the skin.^6,7 Studies on subjects with atopic dermatitis showed a strong association between decreased diversity and increased disease severity. This suggests that a diverse microbiome is associated with skin health.²¹ For this reason, use of pre- and probiotics for skin issues is discouraged at this time. If we replace the normal diverse flora with one organism, we do not yet know the consequences. It is much more likely that successful treatments in the future will contain a diverse group of organisms.

Cosmeceutical effects on the skin microbiome

Cleansing and use of emollients certainly affect the skin biome, but we do not yet know to what extent. A study that looked at the effects of emollients on infants with atopic dermatitis showed that the emollient group has a lower skin pH and a more diverse microbiome.²² In a 2016 study on the impact of acute treatment with topical skin cleansers on the cutaneous microbiome, investigators evaluated multiple common skin cleansers in the washing of human forearms. Group A Streptococcus growth was reduced after washing with soaps infused with such antimicrobial compounds as benzalkonium chloride or triclocarban. The researchers stipulated that much more research is necessary to ascertain the effects of chronic washing as well as the that role skin care products may play in skin homeostasis or dysbiosis in some individuals.²³

In a 2017 analysis of the effects of cosmetics on the skin microbiome of facial cheeks with high- and low-hydration levels over 4 weeks, Lee et al. found that bacterial diversity was higher in the low-hydration group, with increases in both observed after the use of cosmetics. The high-hydration group showed a greater supply of Propionibacterium. Cosmetic use was found not to have caused a shift in bacterial communities in the low-hydration group.²⁴

Conclusion

We are in the early stages as we strive to learn more about the microbiome to leverage such knowledge to improve skin health. In the meantime, there is not enough evidence to suggest the use of any oral or topical prebiotics or probiotics to improve skin health. In fact, we may be causing harm by lessening diversity. The New York Times recently published an article called “The Problem with Probiotics” that referenced a JAMA Internal Medicine article entitled “Probiotic Safety – No Guarantees.”²⁵ I recommend that you read those. Next month, I will look more closely at microbiome research pertaining to skin disease.
 

Dr. Baumann is a private practice dermatologist, researcher, author and entrepreneur who practices in Miami. She founded the Cosmetic Dermatology Center at the University of Miami in 1997. Dr. Baumann wrote two textbooks: “Cosmetic Dermatology: Principles and Practice” (New York: McGraw-Hill, 2002), and “Cosmeceuticals and Cosmetic Ingredients,” (New York: McGraw-Hill, 2014), and a New York Times Best Sellers book for consumers, “The Skin Type Solution” (New York: Bantam Dell, 2006). Dr. Baumann has received funding for advisory boards and/or clinical research trials from Allergan, Evolus, Galderma, and Revance. She is the founder and CEO of Skin Type Solutions Franchise Systems LLC.

References

1. Dréno B et al. J Eur Acad Dermatol Venereol. 2016 Dec;30(12):2038-47.

2. O’Neill CA et al. Bioessays. 2016 Nov;38(11):1167-76.

3. Kong HH. Trends Mol Med. 2011 Jun;17(6):320-8.

4. Kong HH et al. J Invest Dermatol. 2017 May;137(5):e119-22.

5. Gallo RL. J Invest Dermatol. 2017 Jun;137(6):1213-4.

6. Byrd AL et al. Nat Rev Microbiol. 2018 Mar;16(3):143-55.

7. Grice EA et al. Nat Rev Microbiol. 2011 Apr;9(4):244-53.

8. Rodrigues Hoffmann A. Vet Dermatol. 2017 Feb;28(1):60-e15.

9. Moestrup KS et al. J Invest Dermatol. 2018 May;138(5):1225-8.

10. Prescott SL et al. World Allergy Organ J. 2017 Aug 22;10(1):29.

11. Costello EK et al. Science. 2009 Dec 18;326(5960):1694-7.

12. Zeeuwen PL et al. Genome Biol. 2012 Nov 15;13(11):R101.

13. Mukherjee S et al. Sci Rep. 2016 Oct 27;6:36062.

14. Oh J et al. Genome Med. 2012 Oct 10;4(10):77.

15. Ross AA et al. mSystems. 2017 Jul 20;2(4).

16. Blázquez AB et al. Transl Res. 2017 Jan;179:199-203.

17. Rock R et al. Open Forum Infect Dis. 2017 Oct;4(1):S232.

18. Baldwin HE et al. J Drugs Dermatol. 2017 Jan 1;16(1):12-8.

19. Byrd AL et al. Nat Rev Microbiol. 2018 Mar;16(3):143-55.

20. Maguire M et al. Arch Dermatol Res. 2017 Aug;309(6):411-21.

21. Kong HH et al. Genome Res. 2012 May;22(5):850-9.

22. Glatz M et al. PLoS One. 2018 Feb 28;13(2):e0192443.

23. Two AM et al. J Invest Dermatol. 2016 Oct;136(10):1950-4.

24. Lee HJ et al. MicrobiologyOpen. 2018 Apr;7(2):e00557. doi: 10.1002/mbo3.557.

25. Cohen PA. JAMA Intern Med. 2018 Sep 17. doi: 10.1001/jamainternmed.2018.5403.






 

CHICAGO – Rituximab demonstrated a high degree of effectiveness with no safety surprises in the first-ever major clinical trial of the potent B-cell inhibitor conducted in pediatric patients with newly diagnosed or relapsing granulomatosis with polyangiitis or microscopic polyangiitis, Jennifer Cooper, MD, PharmD, said at the annual meeting of the American College of Rheumatology.

Bruce Jancin/MDedge News

“This is exciting news. We know that rituximab is very effective in treating adults with GPA and MPA, both in terms of inducing remission and even for maintenance therapy for this rare and severe disease. A lot of pediatric rheumatologists would like to have access to rituximab. Some are even using it for this condition. But until now there were no data in children. I hope this study improves access to rituximab for pediatric patients with ANCA-associated vasculitis,” said Dr. Cooper, a pediatric rheumatologist at the University of Colorado, Denver.

She presented the results of the PePRS (Pediatric Polyangiitis and Rituximab Study), a phase 2a, single-arm, open-label, long-term study of 25 patients in six countries. She anticipates the results will be practice changing, given that pediatric GPA and MPA are recognized as severe systemic autoimmune disorders with a high unmet need for new therapies.

“I don’t believe there are plans for a randomized, controlled trial. Since we now have the pharmacokinetic and safety data in children, we’ll hopefully be able to use extrapolation and our exploratory efficacy endpoints to gain a pediatric indication, or at least a label update for these patients based on this study,” Dr. Cooper continued.


A total of 19 patients had GPA and 6 had MPA, with a median disease duration of 6 months at study entry. All received three pulsed doses of methylprednisolone during the screening period. Then for induction remission they got four once-weekly intravenous infusions of rituximab (Rituxan) at 375 mg/m² as well as oral corticosteroids, which were tapered from 1 mg/kg per day to 0.2 mg/kg per day over the course of the first 6 months. After that, two-thirds of patients received additional rituximab at their provider’s discretion.

The remission rate by 6 months as defined by Pediatric Vasculitis Activity Score (PVAS) criteria was 56%. At 12 months, the rate was 92%, and at 18 months the rate of remission and sustained disease control was 100%. The mean and median durations of remission were 72 and 56 weeks, respectively.

These results in pediatric patients are comparable to those seen in adults in the landmark RAVE (Rituximab in ANCA-Associated Vasculitis) trial (N Engl J Med. 2013 Aug 1;369[5]:417-27), where 64% of patients reached remission at 6 months, Dr. Cooper noted.

All 25 patients were able to tolerate the four rituximab infusions for remission induction. The main side effect was infusion-related reactions. Overall, 32% of patients experienced such reactions in response to their first infusion, 20% with the second, 12% with the third, and only 8% with the fourth.

Eight patients withdrew from the study after 18 months, mostly because of transfer to adult care. The remaining participants were followed for as long as 4.5 years.

F. Hoffmann-La Roche and Genentech sponsored the PePRS study. Dr. Cooper was a Genentech clinical research fellow at the time.

[email protected]

SOURCE: Brogan P at al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L04.

CHICAGO – Rituximab demonstrated a high degree of effectiveness with no safety surprises in the first-ever major clinical trial of the potent B-cell inhibitor conducted in pediatric patients with newly diagnosed or relapsing granulomatosis with polyangiitis or microscopic polyangiitis, Jennifer Cooper, MD, PharmD, said at the annual meeting of the American College of Rheumatology.

Bruce Jancin/MDedge News

“This is exciting news. We know that rituximab is very effective in treating adults with GPA and MPA, both in terms of inducing remission and even for maintenance therapy for this rare and severe disease. A lot of pediatric rheumatologists would like to have access to rituximab. Some are even using it for this condition. But until now there were no data in children. I hope this study improves access to rituximab for pediatric patients with ANCA-associated vasculitis,” said Dr. Cooper, a pediatric rheumatologist at the University of Colorado, Denver.

She presented the results of the PePRS (Pediatric Polyangiitis and Rituximab Study), a phase 2a, single-arm, open-label, long-term study of 25 patients in six countries. She anticipates the results will be practice changing, given that pediatric GPA and MPA are recognized as severe systemic autoimmune disorders with a high unmet need for new therapies.

“I don’t believe there are plans for a randomized, controlled trial. Since we now have the pharmacokinetic and safety data in children, we’ll hopefully be able to use extrapolation and our exploratory efficacy endpoints to gain a pediatric indication, or at least a label update for these patients based on this study,” Dr. Cooper continued.


A total of 19 patients had GPA and 6 had MPA, with a median disease duration of 6 months at study entry. All received three pulsed doses of methylprednisolone during the screening period. Then for induction remission they got four once-weekly intravenous infusions of rituximab (Rituxan) at 375 mg/m² as well as oral corticosteroids, which were tapered from 1 mg/kg per day to 0.2 mg/kg per day over the course of the first 6 months. After that, two-thirds of patients received additional rituximab at their provider’s discretion.

The remission rate by 6 months as defined by Pediatric Vasculitis Activity Score (PVAS) criteria was 56%. At 12 months, the rate was 92%, and at 18 months the rate of remission and sustained disease control was 100%. The mean and median durations of remission were 72 and 56 weeks, respectively.

These results in pediatric patients are comparable to those seen in adults in the landmark RAVE (Rituximab in ANCA-Associated Vasculitis) trial (N Engl J Med. 2013 Aug 1;369[5]:417-27), where 64% of patients reached remission at 6 months, Dr. Cooper noted.

All 25 patients were able to tolerate the four rituximab infusions for remission induction. The main side effect was infusion-related reactions. Overall, 32% of patients experienced such reactions in response to their first infusion, 20% with the second, 12% with the third, and only 8% with the fourth.

Eight patients withdrew from the study after 18 months, mostly because of transfer to adult care. The remaining participants were followed for as long as 4.5 years.

F. Hoffmann-La Roche and Genentech sponsored the PePRS study. Dr. Cooper was a Genentech clinical research fellow at the time.

[email protected]

SOURCE: Brogan P at al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L04.

CHICAGO – Rituximab demonstrated a high degree of effectiveness with no safety surprises in the first-ever major clinical trial of the potent B-cell inhibitor conducted in pediatric patients with newly diagnosed or relapsing granulomatosis with polyangiitis or microscopic polyangiitis, Jennifer Cooper, MD, PharmD, said at the annual meeting of the American College of Rheumatology.

Bruce Jancin/MDedge News

“This is exciting news. We know that rituximab is very effective in treating adults with GPA and MPA, both in terms of inducing remission and even for maintenance therapy for this rare and severe disease. A lot of pediatric rheumatologists would like to have access to rituximab. Some are even using it for this condition. But until now there were no data in children. I hope this study improves access to rituximab for pediatric patients with ANCA-associated vasculitis,” said Dr. Cooper, a pediatric rheumatologist at the University of Colorado, Denver.

She presented the results of the PePRS (Pediatric Polyangiitis and Rituximab Study), a phase 2a, single-arm, open-label, long-term study of 25 patients in six countries. She anticipates the results will be practice changing, given that pediatric GPA and MPA are recognized as severe systemic autoimmune disorders with a high unmet need for new therapies.

“I don’t believe there are plans for a randomized, controlled trial. Since we now have the pharmacokinetic and safety data in children, we’ll hopefully be able to use extrapolation and our exploratory efficacy endpoints to gain a pediatric indication, or at least a label update for these patients based on this study,” Dr. Cooper continued.


A total of 19 patients had GPA and 6 had MPA, with a median disease duration of 6 months at study entry. All received three pulsed doses of methylprednisolone during the screening period. Then for induction remission they got four once-weekly intravenous infusions of rituximab (Rituxan) at 375 mg/m² as well as oral corticosteroids, which were tapered from 1 mg/kg per day to 0.2 mg/kg per day over the course of the first 6 months. After that, two-thirds of patients received additional rituximab at their provider’s discretion.

The remission rate by 6 months as defined by Pediatric Vasculitis Activity Score (PVAS) criteria was 56%. At 12 months, the rate was 92%, and at 18 months the rate of remission and sustained disease control was 100%. The mean and median durations of remission were 72 and 56 weeks, respectively.

These results in pediatric patients are comparable to those seen in adults in the landmark RAVE (Rituximab in ANCA-Associated Vasculitis) trial (N Engl J Med. 2013 Aug 1;369[5]:417-27), where 64% of patients reached remission at 6 months, Dr. Cooper noted.

All 25 patients were able to tolerate the four rituximab infusions for remission induction. The main side effect was infusion-related reactions. Overall, 32% of patients experienced such reactions in response to their first infusion, 20% with the second, 12% with the third, and only 8% with the fourth.

Eight patients withdrew from the study after 18 months, mostly because of transfer to adult care. The remaining participants were followed for as long as 4.5 years.

F. Hoffmann-La Roche and Genentech sponsored the PePRS study. Dr. Cooper was a Genentech clinical research fellow at the time.

[email protected]

SOURCE: Brogan P at al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract L04.

SAN FRANCISCO – In a phase 2 clinical trial of nonalcoholic steatohepatitis (NASH), the thyroid hormone receptor (THR)–beta agonist MCL-3196 improved various measures of liver function and led to significant levels of NASH resolution.

Jim Kling/MDedge News

“I think this is an ideal candidate to take into a registration trial for patients with NASH that have stage 2-3 fibrosis,” Stephen Harrison, MD, a visiting professor of hepatology at the University of Oxford (England), said in an interview. He presented the results at the annual meeting of the American Association for the Study of Liver Diseases.

THR-beta acts primarily through nuclear receptors, where it alters gene expression in target cells. THR-beta agonism can lead to a wide range of physiological effects, including reduction of LDL cholesterol, triglycerides, and liver fat. The latter activity has the potential to reduce lipotoxicity and improve NASH. According to a press release from drug sponsor Madrigal Pharmaceuticals, MCL-3196 is more selective for THR-beta than previous drug candidates and is also targeted to the liver, a combination the company hopes will avoid toxicities and nontarget effects that hampered previous THR-beta agonist development.

The study did not include patients with cirrhosis, and the researchers aren’t yet ready to test that population. “Everyone wants to jump into cirrhosis, but cirrhotic patients are a tougher nut to crack,” Dr. Harrison said. “There are a lot nuances – there is well-compensated cirrhosis, and cirrhosis with portal hypertension, and then there’s decompensation. We need to carefully, methodically, study the milder cirrhotics, and then those with portal hypertension that is clinically significant, and then decompensation as a last resort. But if you don’t show that in early phase development, then in my opinion we shouldn’t go to phase 3 in a cirrhotic population.”

The phase 2 study included 18 sites in the United States. The researchers randomly assigned 84 patients to MGL-3196 and 41 to placebo. The treatment group received 80 mg oral MGL-3196 once per day, with an option to adjust the dose 20 mg higher or lower at week 4. All patients underwent liver biopsy at baseline and again at 36 weeks.

At 12 weeks, there was a 36% relative reduction in fat across all patients taking MGL-3196, compared with a 10% reduction in the placebo group (P less than .0001). The difference at 36 weeks was 37% versus 8% (P less than .0001). In a predefined group who received high exposure to MCL-3196, the fat reduction was 42% at 12 weeks and 49% at 36 weeks.

At 36 weeks, 68% of all comers on the drug had lost at least 30% of liver fat, compared with 18% in the placebo group (P less than .0001). A total of 77% in the high-exposure group had a similar outcome (P less than .0001), as did 68% of patients with fibrosis stage 2 or 3 (P = .009).

The researchers also found a reduction at 36 weeks in liver enzyme levels among patients in the treatment group who had elevated levels at baseline, including a 40% reduction in ALT, compared with placebo (P = .01). There were smaller, but still significant, reductions in AST and gamma-glutamyltransferase at week 36 in the treatment group, compared with placebo (P = .002 for both).

A 2-point reduction in Nonalcoholic Fatty Liver Disease Activity Score occurred at week 36 in 32% of placebo subjects, compared with 51% (P = .09) of all patients in the treatment group and 61% of the high-exposure group (P = .02). Among patients judged to have been responders based on MRI, 65% had a 2-point reduction (P = .006). NASH resolution occurred in 6% of the placebo group, 27% of the treatment group (P = .02), and 39% of MRI responders (P = .003).

Adverse events were mild and similar between the treatment group and placebo, with the exception of loose stools, which were single events restricted to the initiation of therapy.

The study was funded by Madrigal Pharmaceuticals. Dr. Harrison is a consultant for Madrigal.

SAN FRANCISCO – In a phase 2 clinical trial of nonalcoholic steatohepatitis (NASH), the thyroid hormone receptor (THR)–beta agonist MCL-3196 improved various measures of liver function and led to significant levels of NASH resolution.

Jim Kling/MDedge News

“I think this is an ideal candidate to take into a registration trial for patients with NASH that have stage 2-3 fibrosis,” Stephen Harrison, MD, a visiting professor of hepatology at the University of Oxford (England), said in an interview. He presented the results at the annual meeting of the American Association for the Study of Liver Diseases.

THR-beta acts primarily through nuclear receptors, where it alters gene expression in target cells. THR-beta agonism can lead to a wide range of physiological effects, including reduction of LDL cholesterol, triglycerides, and liver fat. The latter activity has the potential to reduce lipotoxicity and improve NASH. According to a press release from drug sponsor Madrigal Pharmaceuticals, MCL-3196 is more selective for THR-beta than previous drug candidates and is also targeted to the liver, a combination the company hopes will avoid toxicities and nontarget effects that hampered previous THR-beta agonist development.

The study did not include patients with cirrhosis, and the researchers aren’t yet ready to test that population. “Everyone wants to jump into cirrhosis, but cirrhotic patients are a tougher nut to crack,” Dr. Harrison said. “There are a lot nuances – there is well-compensated cirrhosis, and cirrhosis with portal hypertension, and then there’s decompensation. We need to carefully, methodically, study the milder cirrhotics, and then those with portal hypertension that is clinically significant, and then decompensation as a last resort. But if you don’t show that in early phase development, then in my opinion we shouldn’t go to phase 3 in a cirrhotic population.”

The phase 2 study included 18 sites in the United States. The researchers randomly assigned 84 patients to MGL-3196 and 41 to placebo. The treatment group received 80 mg oral MGL-3196 once per day, with an option to adjust the dose 20 mg higher or lower at week 4. All patients underwent liver biopsy at baseline and again at 36 weeks.

At 12 weeks, there was a 36% relative reduction in fat across all patients taking MGL-3196, compared with a 10% reduction in the placebo group (P less than .0001). The difference at 36 weeks was 37% versus 8% (P less than .0001). In a predefined group who received high exposure to MCL-3196, the fat reduction was 42% at 12 weeks and 49% at 36 weeks.

At 36 weeks, 68% of all comers on the drug had lost at least 30% of liver fat, compared with 18% in the placebo group (P less than .0001). A total of 77% in the high-exposure group had a similar outcome (P less than .0001), as did 68% of patients with fibrosis stage 2 or 3 (P = .009).

The researchers also found a reduction at 36 weeks in liver enzyme levels among patients in the treatment group who had elevated levels at baseline, including a 40% reduction in ALT, compared with placebo (P = .01). There were smaller, but still significant, reductions in AST and gamma-glutamyltransferase at week 36 in the treatment group, compared with placebo (P = .002 for both).

A 2-point reduction in Nonalcoholic Fatty Liver Disease Activity Score occurred at week 36 in 32% of placebo subjects, compared with 51% (P = .09) of all patients in the treatment group and 61% of the high-exposure group (P = .02). Among patients judged to have been responders based on MRI, 65% had a 2-point reduction (P = .006). NASH resolution occurred in 6% of the placebo group, 27% of the treatment group (P = .02), and 39% of MRI responders (P = .003).

Adverse events were mild and similar between the treatment group and placebo, with the exception of loose stools, which were single events restricted to the initiation of therapy.

The study was funded by Madrigal Pharmaceuticals. Dr. Harrison is a consultant for Madrigal.

SAN FRANCISCO – In a phase 2 clinical trial of nonalcoholic steatohepatitis (NASH), the thyroid hormone receptor (THR)–beta agonist MCL-3196 improved various measures of liver function and led to significant levels of NASH resolution.

Jim Kling/MDedge News

“I think this is an ideal candidate to take into a registration trial for patients with NASH that have stage 2-3 fibrosis,” Stephen Harrison, MD, a visiting professor of hepatology at the University of Oxford (England), said in an interview. He presented the results at the annual meeting of the American Association for the Study of Liver Diseases.

THR-beta acts primarily through nuclear receptors, where it alters gene expression in target cells. THR-beta agonism can lead to a wide range of physiological effects, including reduction of LDL cholesterol, triglycerides, and liver fat. The latter activity has the potential to reduce lipotoxicity and improve NASH. According to a press release from drug sponsor Madrigal Pharmaceuticals, MCL-3196 is more selective for THR-beta than previous drug candidates and is also targeted to the liver, a combination the company hopes will avoid toxicities and nontarget effects that hampered previous THR-beta agonist development.

The study did not include patients with cirrhosis, and the researchers aren’t yet ready to test that population. “Everyone wants to jump into cirrhosis, but cirrhotic patients are a tougher nut to crack,” Dr. Harrison said. “There are a lot nuances – there is well-compensated cirrhosis, and cirrhosis with portal hypertension, and then there’s decompensation. We need to carefully, methodically, study the milder cirrhotics, and then those with portal hypertension that is clinically significant, and then decompensation as a last resort. But if you don’t show that in early phase development, then in my opinion we shouldn’t go to phase 3 in a cirrhotic population.”

The phase 2 study included 18 sites in the United States. The researchers randomly assigned 84 patients to MGL-3196 and 41 to placebo. The treatment group received 80 mg oral MGL-3196 once per day, with an option to adjust the dose 20 mg higher or lower at week 4. All patients underwent liver biopsy at baseline and again at 36 weeks.

At 12 weeks, there was a 36% relative reduction in fat across all patients taking MGL-3196, compared with a 10% reduction in the placebo group (P less than .0001). The difference at 36 weeks was 37% versus 8% (P less than .0001). In a predefined group who received high exposure to MCL-3196, the fat reduction was 42% at 12 weeks and 49% at 36 weeks.

At 36 weeks, 68% of all comers on the drug had lost at least 30% of liver fat, compared with 18% in the placebo group (P less than .0001). A total of 77% in the high-exposure group had a similar outcome (P less than .0001), as did 68% of patients with fibrosis stage 2 or 3 (P = .009).

The researchers also found a reduction at 36 weeks in liver enzyme levels among patients in the treatment group who had elevated levels at baseline, including a 40% reduction in ALT, compared with placebo (P = .01). There were smaller, but still significant, reductions in AST and gamma-glutamyltransferase at week 36 in the treatment group, compared with placebo (P = .002 for both).

A 2-point reduction in Nonalcoholic Fatty Liver Disease Activity Score occurred at week 36 in 32% of placebo subjects, compared with 51% (P = .09) of all patients in the treatment group and 61% of the high-exposure group (P = .02). Among patients judged to have been responders based on MRI, 65% had a 2-point reduction (P = .006). NASH resolution occurred in 6% of the placebo group, 27% of the treatment group (P = .02), and 39% of MRI responders (P = .003).

Adverse events were mild and similar between the treatment group and placebo, with the exception of loose stools, which were single events restricted to the initiation of therapy.

The study was funded by Madrigal Pharmaceuticals. Dr. Harrison is a consultant for Madrigal.

The Food and Drug Administration has granted marketing clearance for the immunohematology instrument NEO Iris.

NEO Iris is a fully automated blood bank instrument designed for the mid- to high-volume laboratory, according to Immucor, the company marketing the device. Immucor says NEO Iris provides the highest type and screen throughput on the market – up to 60 types and screens per hour.

NEO Iris performs ABO/Rh D typing, weak D testing, donor confirmation, cytomegalovirus screening, immunoglobulin G direct antiglobulin test and crossmatch, and antibody identification and screening.

The workflow management tool on Neo Iris has STAT priority and allows operators to run tests in any order at any time, according to Immucor.

The company says NEO Iris can hold up to 224 samples, and “modules can pipette, incubate, centrifuge, and read simultaneously.” NEO Iris integrates with Immucor’s data management software, ImmuLINK, to aggregate test results and produce reports with complete testing history.

[email protected]

The Food and Drug Administration has granted marketing clearance for the immunohematology instrument NEO Iris.

NEO Iris is a fully automated blood bank instrument designed for the mid- to high-volume laboratory, according to Immucor, the company marketing the device. Immucor says NEO Iris provides the highest type and screen throughput on the market – up to 60 types and screens per hour.

NEO Iris performs ABO/Rh D typing, weak D testing, donor confirmation, cytomegalovirus screening, immunoglobulin G direct antiglobulin test and crossmatch, and antibody identification and screening.

The workflow management tool on Neo Iris has STAT priority and allows operators to run tests in any order at any time, according to Immucor.

The company says NEO Iris can hold up to 224 samples, and “modules can pipette, incubate, centrifuge, and read simultaneously.” NEO Iris integrates with Immucor’s data management software, ImmuLINK, to aggregate test results and produce reports with complete testing history.

[email protected]

The Food and Drug Administration has granted marketing clearance for the immunohematology instrument NEO Iris.

NEO Iris is a fully automated blood bank instrument designed for the mid- to high-volume laboratory, according to Immucor, the company marketing the device. Immucor says NEO Iris provides the highest type and screen throughput on the market – up to 60 types and screens per hour.

NEO Iris performs ABO/Rh D typing, weak D testing, donor confirmation, cytomegalovirus screening, immunoglobulin G direct antiglobulin test and crossmatch, and antibody identification and screening.

The workflow management tool on Neo Iris has STAT priority and allows operators to run tests in any order at any time, according to Immucor.

The company says NEO Iris can hold up to 224 samples, and “modules can pipette, incubate, centrifuge, and read simultaneously.” NEO Iris integrates with Immucor’s data management software, ImmuLINK, to aggregate test results and produce reports with complete testing history.

[email protected]

Focus on ability to perform functional tasks when designing interventions aimed at improving health-related quality of life for patients with symptomatic peripheral arterial disease (PAD), advise the authors of a study published in the Journal of Vascular Surgery.

Pavel Losevsky/iStockphoto

Clinical markers of disease severity and comorbidities are often the primary targets of interventions in PAD patients, but health-related quality of life (HRQoL) based on their functional capabilities matters more to patients, according to Andrew W. Gardner, PhD, of Penn State University, Hershey, and his colleagues.

“Interventions designed to improve HRQoL should focus on improving the quality of executing functional tasks, such as walking more steadily without stumbling; completing ADLs [activities of daily living] that are not specific to walking, such as bathing and transferring; and improving patient-based ability to walk various distances and speeds and to climb stairs,” the researchers wrote.

They studied 216 PAD patients (mean age, 65 years) with ambulatory leg pain confirmed by treadmill exercise and ankle brachial index less than or equal to 0.90 at rest or less than or equal to 0.73 after exercise. Patient HRQoL was measured using the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). All patients performed a maximal treadmill test, a 6-minute walk test, and gait speed from a 4-meter walk test was measured. Their ambulatory activity was monitored for 7 days using a step monitor. In addition, patients self-assessed their ability to perform four lower-level ADLs, consisting of walking across a small room, bathing, transferring from a bed to a chair, and using the toilet. They also evaluated their ability to perform two higher-level ADLs consisting of walking up and down stairs to the second floor without help and walking a half-mile without help.

Approximately 10%-17% of the patients reported either having some difficulty with or being unable to perform basic ADLs, whereas the majority reported either having some difficulty with or being unable to perform higher-level ADLs consisting of walking up and down stairs (74%) and walking a half-mile without help (85%).

The primary novel finding, according to Dr. Gardner and his colleagues, was that patient-based measurements of physical function were the strongest predictors of both physical and mental subscales of HRQoL.

The significant predictors were Walking Impairment Questionnaire speed score (P less than .001), history of stumbling while walking (P less than .001), stair climbing score (P = .001), bathing (P = .001), 6-minute walking distance (P =.004), and daily walking cadence (P = .043). The significant predictors of the role limitations caused by emotional problems subscale of the SF-36 included a history of stumbling while walking (P less than .001), transferring from a bed to a chair (P less than .001), and the walking distance score (P = .022).

Noticeably, a history of stumbling while walking was considered particularly important to the patients. In contrast, objective measurements of physical function (6-minute walking distance and daily walking cadence) were predictive only of the physical function subscale. Comorbid conditions and objective measures of PAD severity, such as ankle brachial index, claudication onset time, and peak walking time, were not at all predictive of HRQoL, the researchers stated.

The authors reported that they had no conflicts of interest.

[email protected]

SOURCE: Gardner AW et al. J Vasc Surg. 2018;68:1126-34.

Focus on ability to perform functional tasks when designing interventions aimed at improving health-related quality of life for patients with symptomatic peripheral arterial disease (PAD), advise the authors of a study published in the Journal of Vascular Surgery.

Pavel Losevsky/iStockphoto

Clinical markers of disease severity and comorbidities are often the primary targets of interventions in PAD patients, but health-related quality of life (HRQoL) based on their functional capabilities matters more to patients, according to Andrew W. Gardner, PhD, of Penn State University, Hershey, and his colleagues.

“Interventions designed to improve HRQoL should focus on improving the quality of executing functional tasks, such as walking more steadily without stumbling; completing ADLs [activities of daily living] that are not specific to walking, such as bathing and transferring; and improving patient-based ability to walk various distances and speeds and to climb stairs,” the researchers wrote.

They studied 216 PAD patients (mean age, 65 years) with ambulatory leg pain confirmed by treadmill exercise and ankle brachial index less than or equal to 0.90 at rest or less than or equal to 0.73 after exercise. Patient HRQoL was measured using the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). All patients performed a maximal treadmill test, a 6-minute walk test, and gait speed from a 4-meter walk test was measured. Their ambulatory activity was monitored for 7 days using a step monitor. In addition, patients self-assessed their ability to perform four lower-level ADLs, consisting of walking across a small room, bathing, transferring from a bed to a chair, and using the toilet. They also evaluated their ability to perform two higher-level ADLs consisting of walking up and down stairs to the second floor without help and walking a half-mile without help.

Approximately 10%-17% of the patients reported either having some difficulty with or being unable to perform basic ADLs, whereas the majority reported either having some difficulty with or being unable to perform higher-level ADLs consisting of walking up and down stairs (74%) and walking a half-mile without help (85%).

The primary novel finding, according to Dr. Gardner and his colleagues, was that patient-based measurements of physical function were the strongest predictors of both physical and mental subscales of HRQoL.

The significant predictors were Walking Impairment Questionnaire speed score (P less than .001), history of stumbling while walking (P less than .001), stair climbing score (P = .001), bathing (P = .001), 6-minute walking distance (P =.004), and daily walking cadence (P = .043). The significant predictors of the role limitations caused by emotional problems subscale of the SF-36 included a history of stumbling while walking (P less than .001), transferring from a bed to a chair (P less than .001), and the walking distance score (P = .022).

Noticeably, a history of stumbling while walking was considered particularly important to the patients. In contrast, objective measurements of physical function (6-minute walking distance and daily walking cadence) were predictive only of the physical function subscale. Comorbid conditions and objective measures of PAD severity, such as ankle brachial index, claudication onset time, and peak walking time, were not at all predictive of HRQoL, the researchers stated.

The authors reported that they had no conflicts of interest.

[email protected]

SOURCE: Gardner AW et al. J Vasc Surg. 2018;68:1126-34.

Focus on ability to perform functional tasks when designing interventions aimed at improving health-related quality of life for patients with symptomatic peripheral arterial disease (PAD), advise the authors of a study published in the Journal of Vascular Surgery.

Pavel Losevsky/iStockphoto

Clinical markers of disease severity and comorbidities are often the primary targets of interventions in PAD patients, but health-related quality of life (HRQoL) based on their functional capabilities matters more to patients, according to Andrew W. Gardner, PhD, of Penn State University, Hershey, and his colleagues.

“Interventions designed to improve HRQoL should focus on improving the quality of executing functional tasks, such as walking more steadily without stumbling; completing ADLs [activities of daily living] that are not specific to walking, such as bathing and transferring; and improving patient-based ability to walk various distances and speeds and to climb stairs,” the researchers wrote.

They studied 216 PAD patients (mean age, 65 years) with ambulatory leg pain confirmed by treadmill exercise and ankle brachial index less than or equal to 0.90 at rest or less than or equal to 0.73 after exercise. Patient HRQoL was measured using the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36). All patients performed a maximal treadmill test, a 6-minute walk test, and gait speed from a 4-meter walk test was measured. Their ambulatory activity was monitored for 7 days using a step monitor. In addition, patients self-assessed their ability to perform four lower-level ADLs, consisting of walking across a small room, bathing, transferring from a bed to a chair, and using the toilet. They also evaluated their ability to perform two higher-level ADLs consisting of walking up and down stairs to the second floor without help and walking a half-mile without help.

Approximately 10%-17% of the patients reported either having some difficulty with or being unable to perform basic ADLs, whereas the majority reported either having some difficulty with or being unable to perform higher-level ADLs consisting of walking up and down stairs (74%) and walking a half-mile without help (85%).

The primary novel finding, according to Dr. Gardner and his colleagues, was that patient-based measurements of physical function were the strongest predictors of both physical and mental subscales of HRQoL.

The significant predictors were Walking Impairment Questionnaire speed score (P less than .001), history of stumbling while walking (P less than .001), stair climbing score (P = .001), bathing (P = .001), 6-minute walking distance (P =.004), and daily walking cadence (P = .043). The significant predictors of the role limitations caused by emotional problems subscale of the SF-36 included a history of stumbling while walking (P less than .001), transferring from a bed to a chair (P less than .001), and the walking distance score (P = .022).

Noticeably, a history of stumbling while walking was considered particularly important to the patients. In contrast, objective measurements of physical function (6-minute walking distance and daily walking cadence) were predictive only of the physical function subscale. Comorbid conditions and objective measures of PAD severity, such as ankle brachial index, claudication onset time, and peak walking time, were not at all predictive of HRQoL, the researchers stated.

The authors reported that they had no conflicts of interest.

[email protected]

SOURCE: Gardner AW et al. J Vasc Surg. 2018;68:1126-34.

MUNICH – Men with metastatic hormone-naive prostate cancer may benefit from treatment with the combination of abiraterone (Zytiga), prednisolone, and androgen deprivation regardless of risk group or disease volume, STAMPEDE trialists contend.

Results of the STAMPEDE and LATITUDE trials, published in 2017 in the New England Journal of Medicine, showed significant improvements in overall survival with abiraterone, androgen deprivation therapy (ADT) and either prednisone (in LATITUDE) or prednisolone (in STAMPEDE) compared with ADT alone.

Data from the LATITUDE trial were used to support approval by both the Food and Drug Administration and European Medicines Agency of abiraterone in combination with ADT and a glucocorticoid for the new indication of treatment of men with metastatic high-risk castration-sensitive prostate cancer.

“So where we stand, at the minute, in terms of guidance: the EAU [European Urology Association] and the NCCN [National Comprehensive Cancer Network] have suggested that we consider treatment for men with hormone-naive metastatic prostatic cancer, but in 2018 the FDA and EMA licensed the drug for high-risk disease, so there’s therefore an evolving uncertainty about what we should be doing in low-risk disease,” Alex Hoyle, MBChB, of Christie NHS Foundation Trust, Manchester, England, said on behalf of colleagues in the STAMPEDE trial group.

The problem is that there is no international consensus on what constitutes low-risk disease, Dr. Hoyle said at the European Society for Medical Oncology Congress.

For example, in the CHAARTED trial, risk was defined by volume, with high-risk patients defined as those with visceral metastases and/or four or more bone metastases with one or more outside the vertebral column or pelvis. In contrast, the LATITUDE investigators defined high-risk patients as those with two or more high-risk features, including three or more bone metastases, visceral metastases, and/or a Gleason score of 8 or more.

To determine whether men with low-risk disease could also benefit from the combination, Dr. Hoyle and colleagues performed a retrospective analysis of the STAMPEDE trial, using staging scans to stratify patients with M1 disease into either high- or low-risk categories according to the LATITUDE risk criteria. The reviewers were blinded to the treatment arm for each patient. They also performed a secondary differential analysis by tumor volume according to the CHAARTED criteria.

The investigators then retrospectively reviewed outcomes for 901 evaluable patients, median age 67 years, with a median PSA of 96 ng/mL, followed for a median of 42 months. The sample included 428 patients determined to have low-risk disease, and 473 determined to have high-risk disease.

Overall survival (OS), the primary endpoint, was significantly better for patients treated with the combination vs. ADT alone in both high- and low-risk groups. The 3-year OS in high-risk patients treated with the abiraterone/prednisolone/ADT was 64.7% compared with 45% for patients treated with AD alone, an absolute difference of 19.7% that translated into a hazard ratio (HR) for death of 0.54 (P less than .001).

For patients in the low-risk group, 3-year OS was 82.4% with the combination vs. 78% with ADT alone, an absolute difference of 4.4%, translating into an HR of 0.66 (P = .041).

Three-year prostate cancer-specific survival, a secondary endpoint, was better with abiraterone in the high-risk (67% vs. 47.9%, HR 0.57, P less than .001) and low-risk (88.7% vs. 81.6%, HR 0.51, P = .008) populations.

The results were even more pronounced in favor of the abiraterone combination for the secondary endpoint of failure-free survival (FFS) in both groups, with 45.1% of high-risk patients on abiraterone having no biochemical failure at 3 years vs. 12.2% for those treated with ADT alone (HR 0.48, P less than .001). The respective FFS rates in the low-risk group were 80.8% vs. 56.4% (HR 0.66, P = .041).

ADT was superior in analyses of skeletal related event-free survival (HR 0.48 for high risk and 0.31 for low risk, P less than .001 for both comparisons), and metastasis progression-free survival (HR 0.54, P less than .001 for high risk, HR 0.66, P = .041 for low risk).

An exploratory analysis using the CHAARTED risk criteria showed similar results, with the combination significantly better in every category except prostate cancer–specific survival in patients with low-volume disease, although here, too, there was a clear trend favoring abiraterone.

“Abiraterone plus prednisolone in addition to ADT improves survival endpoints in metastatic hormone-naive prostate cancer,” Dr. Hoyle said.

Invited discussant Karim Fizazi, MD, PhD, of Gustave Roussy Cancer Institute at the University of Paris-Sud, France, said that the study, despite some limitations, was very important.

“For patients with high-risk de novo disease, until today we’ve had two standards of care: castration plus abiraterone or castration plus docetaxel. For patients with low risk, that was strongly debated – either castration alone or castration plus docetaxel. After this publication, I think it’s fair to say that for patients with high-risk disease the role of abiraterone is being strengthened, while for patients with low-risk disease, ADT plus abiraterone probably is going to become the new standard,” he said.

The STAMPEDE trial is supported by the Medical Research Council of the United Kingdom, the Salford Royal and the Christie NHS Foundation trusts, and Manchester Cancer Research Centre. Dr. Hoyle reported having no conflicts of interest. Dr. Fizazi reported advisory board participation and/or honoraria from Amgen, Astellas, AstraZeneca, Bayer, Clovis, CureVac, Essa, Genentech, Janssen, MSD, Orion, and Sanofi.

SOURCE: Hoyle AP et al. ESMO 2018. Abstract LBA4.

MUNICH – Men with metastatic hormone-naive prostate cancer may benefit from treatment with the combination of abiraterone (Zytiga), prednisolone, and androgen deprivation regardless of risk group or disease volume, STAMPEDE trialists contend.

Results of the STAMPEDE and LATITUDE trials, published in 2017 in the New England Journal of Medicine, showed significant improvements in overall survival with abiraterone, androgen deprivation therapy (ADT) and either prednisone (in LATITUDE) or prednisolone (in STAMPEDE) compared with ADT alone.

Data from the LATITUDE trial were used to support approval by both the Food and Drug Administration and European Medicines Agency of abiraterone in combination with ADT and a glucocorticoid for the new indication of treatment of men with metastatic high-risk castration-sensitive prostate cancer.

“So where we stand, at the minute, in terms of guidance: the EAU [European Urology Association] and the NCCN [National Comprehensive Cancer Network] have suggested that we consider treatment for men with hormone-naive metastatic prostatic cancer, but in 2018 the FDA and EMA licensed the drug for high-risk disease, so there’s therefore an evolving uncertainty about what we should be doing in low-risk disease,” Alex Hoyle, MBChB, of Christie NHS Foundation Trust, Manchester, England, said on behalf of colleagues in the STAMPEDE trial group.

The problem is that there is no international consensus on what constitutes low-risk disease, Dr. Hoyle said at the European Society for Medical Oncology Congress.

For example, in the CHAARTED trial, risk was defined by volume, with high-risk patients defined as those with visceral metastases and/or four or more bone metastases with one or more outside the vertebral column or pelvis. In contrast, the LATITUDE investigators defined high-risk patients as those with two or more high-risk features, including three or more bone metastases, visceral metastases, and/or a Gleason score of 8 or more.

To determine whether men with low-risk disease could also benefit from the combination, Dr. Hoyle and colleagues performed a retrospective analysis of the STAMPEDE trial, using staging scans to stratify patients with M1 disease into either high- or low-risk categories according to the LATITUDE risk criteria. The reviewers were blinded to the treatment arm for each patient. They also performed a secondary differential analysis by tumor volume according to the CHAARTED criteria.

The investigators then retrospectively reviewed outcomes for 901 evaluable patients, median age 67 years, with a median PSA of 96 ng/mL, followed for a median of 42 months. The sample included 428 patients determined to have low-risk disease, and 473 determined to have high-risk disease.

Overall survival (OS), the primary endpoint, was significantly better for patients treated with the combination vs. ADT alone in both high- and low-risk groups. The 3-year OS in high-risk patients treated with the abiraterone/prednisolone/ADT was 64.7% compared with 45% for patients treated with AD alone, an absolute difference of 19.7% that translated into a hazard ratio (HR) for death of 0.54 (P less than .001).

For patients in the low-risk group, 3-year OS was 82.4% with the combination vs. 78% with ADT alone, an absolute difference of 4.4%, translating into an HR of 0.66 (P = .041).

Three-year prostate cancer-specific survival, a secondary endpoint, was better with abiraterone in the high-risk (67% vs. 47.9%, HR 0.57, P less than .001) and low-risk (88.7% vs. 81.6%, HR 0.51, P = .008) populations.

The results were even more pronounced in favor of the abiraterone combination for the secondary endpoint of failure-free survival (FFS) in both groups, with 45.1% of high-risk patients on abiraterone having no biochemical failure at 3 years vs. 12.2% for those treated with ADT alone (HR 0.48, P less than .001). The respective FFS rates in the low-risk group were 80.8% vs. 56.4% (HR 0.66, P = .041).

ADT was superior in analyses of skeletal related event-free survival (HR 0.48 for high risk and 0.31 for low risk, P less than .001 for both comparisons), and metastasis progression-free survival (HR 0.54, P less than .001 for high risk, HR 0.66, P = .041 for low risk).

An exploratory analysis using the CHAARTED risk criteria showed similar results, with the combination significantly better in every category except prostate cancer–specific survival in patients with low-volume disease, although here, too, there was a clear trend favoring abiraterone.

“Abiraterone plus prednisolone in addition to ADT improves survival endpoints in metastatic hormone-naive prostate cancer,” Dr. Hoyle said.

Invited discussant Karim Fizazi, MD, PhD, of Gustave Roussy Cancer Institute at the University of Paris-Sud, France, said that the study, despite some limitations, was very important.

“For patients with high-risk de novo disease, until today we’ve had two standards of care: castration plus abiraterone or castration plus docetaxel. For patients with low risk, that was strongly debated – either castration alone or castration plus docetaxel. After this publication, I think it’s fair to say that for patients with high-risk disease the role of abiraterone is being strengthened, while for patients with low-risk disease, ADT plus abiraterone probably is going to become the new standard,” he said.

The STAMPEDE trial is supported by the Medical Research Council of the United Kingdom, the Salford Royal and the Christie NHS Foundation trusts, and Manchester Cancer Research Centre. Dr. Hoyle reported having no conflicts of interest. Dr. Fizazi reported advisory board participation and/or honoraria from Amgen, Astellas, AstraZeneca, Bayer, Clovis, CureVac, Essa, Genentech, Janssen, MSD, Orion, and Sanofi.

SOURCE: Hoyle AP et al. ESMO 2018. Abstract LBA4.

MUNICH – Men with metastatic hormone-naive prostate cancer may benefit from treatment with the combination of abiraterone (Zytiga), prednisolone, and androgen deprivation regardless of risk group or disease volume, STAMPEDE trialists contend.

Results of the STAMPEDE and LATITUDE trials, published in 2017 in the New England Journal of Medicine, showed significant improvements in overall survival with abiraterone, androgen deprivation therapy (ADT) and either prednisone (in LATITUDE) or prednisolone (in STAMPEDE) compared with ADT alone.

Data from the LATITUDE trial were used to support approval by both the Food and Drug Administration and European Medicines Agency of abiraterone in combination with ADT and a glucocorticoid for the new indication of treatment of men with metastatic high-risk castration-sensitive prostate cancer.

“So where we stand, at the minute, in terms of guidance: the EAU [European Urology Association] and the NCCN [National Comprehensive Cancer Network] have suggested that we consider treatment for men with hormone-naive metastatic prostatic cancer, but in 2018 the FDA and EMA licensed the drug for high-risk disease, so there’s therefore an evolving uncertainty about what we should be doing in low-risk disease,” Alex Hoyle, MBChB, of Christie NHS Foundation Trust, Manchester, England, said on behalf of colleagues in the STAMPEDE trial group.

The problem is that there is no international consensus on what constitutes low-risk disease, Dr. Hoyle said at the European Society for Medical Oncology Congress.

For example, in the CHAARTED trial, risk was defined by volume, with high-risk patients defined as those with visceral metastases and/or four or more bone metastases with one or more outside the vertebral column or pelvis. In contrast, the LATITUDE investigators defined high-risk patients as those with two or more high-risk features, including three or more bone metastases, visceral metastases, and/or a Gleason score of 8 or more.

To determine whether men with low-risk disease could also benefit from the combination, Dr. Hoyle and colleagues performed a retrospective analysis of the STAMPEDE trial, using staging scans to stratify patients with M1 disease into either high- or low-risk categories according to the LATITUDE risk criteria. The reviewers were blinded to the treatment arm for each patient. They also performed a secondary differential analysis by tumor volume according to the CHAARTED criteria.

The investigators then retrospectively reviewed outcomes for 901 evaluable patients, median age 67 years, with a median PSA of 96 ng/mL, followed for a median of 42 months. The sample included 428 patients determined to have low-risk disease, and 473 determined to have high-risk disease.

Overall survival (OS), the primary endpoint, was significantly better for patients treated with the combination vs. ADT alone in both high- and low-risk groups. The 3-year OS in high-risk patients treated with the abiraterone/prednisolone/ADT was 64.7% compared with 45% for patients treated with AD alone, an absolute difference of 19.7% that translated into a hazard ratio (HR) for death of 0.54 (P less than .001).

For patients in the low-risk group, 3-year OS was 82.4% with the combination vs. 78% with ADT alone, an absolute difference of 4.4%, translating into an HR of 0.66 (P = .041).

Three-year prostate cancer-specific survival, a secondary endpoint, was better with abiraterone in the high-risk (67% vs. 47.9%, HR 0.57, P less than .001) and low-risk (88.7% vs. 81.6%, HR 0.51, P = .008) populations.

The results were even more pronounced in favor of the abiraterone combination for the secondary endpoint of failure-free survival (FFS) in both groups, with 45.1% of high-risk patients on abiraterone having no biochemical failure at 3 years vs. 12.2% for those treated with ADT alone (HR 0.48, P less than .001). The respective FFS rates in the low-risk group were 80.8% vs. 56.4% (HR 0.66, P = .041).

ADT was superior in analyses of skeletal related event-free survival (HR 0.48 for high risk and 0.31 for low risk, P less than .001 for both comparisons), and metastasis progression-free survival (HR 0.54, P less than .001 for high risk, HR 0.66, P = .041 for low risk).

An exploratory analysis using the CHAARTED risk criteria showed similar results, with the combination significantly better in every category except prostate cancer–specific survival in patients with low-volume disease, although here, too, there was a clear trend favoring abiraterone.

“Abiraterone plus prednisolone in addition to ADT improves survival endpoints in metastatic hormone-naive prostate cancer,” Dr. Hoyle said.

Invited discussant Karim Fizazi, MD, PhD, of Gustave Roussy Cancer Institute at the University of Paris-Sud, France, said that the study, despite some limitations, was very important.

“For patients with high-risk de novo disease, until today we’ve had two standards of care: castration plus abiraterone or castration plus docetaxel. For patients with low risk, that was strongly debated – either castration alone or castration plus docetaxel. After this publication, I think it’s fair to say that for patients with high-risk disease the role of abiraterone is being strengthened, while for patients with low-risk disease, ADT plus abiraterone probably is going to become the new standard,” he said.

The STAMPEDE trial is supported by the Medical Research Council of the United Kingdom, the Salford Royal and the Christie NHS Foundation trusts, and Manchester Cancer Research Centre. Dr. Hoyle reported having no conflicts of interest. Dr. Fizazi reported advisory board participation and/or honoraria from Amgen, Astellas, AstraZeneca, Bayer, Clovis, CureVac, Essa, Genentech, Janssen, MSD, Orion, and Sanofi.

SOURCE: Hoyle AP et al. ESMO 2018. Abstract LBA4.

All adults aged 18 years and older, including pregnant women, should be screened in primary care settings for unhealthy alcohol use and offered behavioral counseling if needed, according to recommendations from the U.S. Preventive Services Task Force.

Vonschonertagen/Thinkstock

Adults who meet the criteria for unhealthy alcohol use should be offered brief behavioral counseling interventions, the task force concluded with a B recommendation.

However, the task force also concluded that evidence is insufficient to recommend screening for alcohol use in adolescents aged 12-17 years in primary care settings (an I statement), wrote Susan J. Curry, PhD, of the University of Iowa, Iowa City, and colleagues. The recommendations were published in JAMA as an update of the USPSTF 2013 recommendation on screening for unhealthy alcohol use in primary care settings.

Approximately 88,000 deaths occurred each year in the United States between 2006 and 2010, the task force noted. Those deaths include death by acute causes, such as alcohol-related injuries, and chronic causes, such as alcoholic liver disease. In addition, alcohol use during pregnancy is a major preventable cause of birth defects and developmental disabilities, the task force wrote.

After reviewing the evidence, the USPSTF concluded that brief behavioral counseling offered moderate net benefits for adults 18 years and older, including pregnant women, who met criteria for unhealthy alcohol use.

Unhealthy alcohol used was defined as exceeding the National Institute on Alcohol Abuse and Alcoholism (NIAAA) recommended limits of 4 drinks per day, or 14 drinks per week, for men aged 21-64 years, and 3 drinks per day, or 7 drinks per week, for women aged 21-64 years.

In the evidence review accompanying the recommendations, Elizabeth A. O’Connor, PhD, of Kaiser Permanente in Portland, Ore., and colleagues analyzed data from 113 studies, including 314,466 individuals; 10 studies included adolescents.

In 68 studies including 36,528 individuals, brief counseling was associated with fewer drinks per week, fewer individuals exceeding recommended limits for alcohol consumption, fewer drinkers reporting a heavy drinking episode, and a greater proportion of pregnant women reporting alcohol abstinence after 6-12 months.

None of the studies assessed benefits or harms, but no evidence suggested that the interventions could be harmful.

The USPSTF is supported by the Agency for Healthcare Research and Quality. The researchers had no financial conflicts to disclose.

SOURCES: Curry S et al. JAMA. 2018;320(18):1899-1909; O’Connor E et al. JAMA. 2018;320(18):1910-28.

All adults aged 18 years and older, including pregnant women, should be screened in primary care settings for unhealthy alcohol use and offered behavioral counseling if needed, according to recommendations from the U.S. Preventive Services Task Force.

Vonschonertagen/Thinkstock

Adults who meet the criteria for unhealthy alcohol use should be offered brief behavioral counseling interventions, the task force concluded with a B recommendation.

However, the task force also concluded that evidence is insufficient to recommend screening for alcohol use in adolescents aged 12-17 years in primary care settings (an I statement), wrote Susan J. Curry, PhD, of the University of Iowa, Iowa City, and colleagues. The recommendations were published in JAMA as an update of the USPSTF 2013 recommendation on screening for unhealthy alcohol use in primary care settings.

Approximately 88,000 deaths occurred each year in the United States between 2006 and 2010, the task force noted. Those deaths include death by acute causes, such as alcohol-related injuries, and chronic causes, such as alcoholic liver disease. In addition, alcohol use during pregnancy is a major preventable cause of birth defects and developmental disabilities, the task force wrote.

After reviewing the evidence, the USPSTF concluded that brief behavioral counseling offered moderate net benefits for adults 18 years and older, including pregnant women, who met criteria for unhealthy alcohol use.

Unhealthy alcohol used was defined as exceeding the National Institute on Alcohol Abuse and Alcoholism (NIAAA) recommended limits of 4 drinks per day, or 14 drinks per week, for men aged 21-64 years, and 3 drinks per day, or 7 drinks per week, for women aged 21-64 years.

In the evidence review accompanying the recommendations, Elizabeth A. O’Connor, PhD, of Kaiser Permanente in Portland, Ore., and colleagues analyzed data from 113 studies, including 314,466 individuals; 10 studies included adolescents.

In 68 studies including 36,528 individuals, brief counseling was associated with fewer drinks per week, fewer individuals exceeding recommended limits for alcohol consumption, fewer drinkers reporting a heavy drinking episode, and a greater proportion of pregnant women reporting alcohol abstinence after 6-12 months.

None of the studies assessed benefits or harms, but no evidence suggested that the interventions could be harmful.

The USPSTF is supported by the Agency for Healthcare Research and Quality. The researchers had no financial conflicts to disclose.

SOURCES: Curry S et al. JAMA. 2018;320(18):1899-1909; O’Connor E et al. JAMA. 2018;320(18):1910-28.

All adults aged 18 years and older, including pregnant women, should be screened in primary care settings for unhealthy alcohol use and offered behavioral counseling if needed, according to recommendations from the U.S. Preventive Services Task Force.

Vonschonertagen/Thinkstock

Adults who meet the criteria for unhealthy alcohol use should be offered brief behavioral counseling interventions, the task force concluded with a B recommendation.

However, the task force also concluded that evidence is insufficient to recommend screening for alcohol use in adolescents aged 12-17 years in primary care settings (an I statement), wrote Susan J. Curry, PhD, of the University of Iowa, Iowa City, and colleagues. The recommendations were published in JAMA as an update of the USPSTF 2013 recommendation on screening for unhealthy alcohol use in primary care settings.

Approximately 88,000 deaths occurred each year in the United States between 2006 and 2010, the task force noted. Those deaths include death by acute causes, such as alcohol-related injuries, and chronic causes, such as alcoholic liver disease. In addition, alcohol use during pregnancy is a major preventable cause of birth defects and developmental disabilities, the task force wrote.

After reviewing the evidence, the USPSTF concluded that brief behavioral counseling offered moderate net benefits for adults 18 years and older, including pregnant women, who met criteria for unhealthy alcohol use.

Unhealthy alcohol used was defined as exceeding the National Institute on Alcohol Abuse and Alcoholism (NIAAA) recommended limits of 4 drinks per day, or 14 drinks per week, for men aged 21-64 years, and 3 drinks per day, or 7 drinks per week, for women aged 21-64 years.

In the evidence review accompanying the recommendations, Elizabeth A. O’Connor, PhD, of Kaiser Permanente in Portland, Ore., and colleagues analyzed data from 113 studies, including 314,466 individuals; 10 studies included adolescents.

In 68 studies including 36,528 individuals, brief counseling was associated with fewer drinks per week, fewer individuals exceeding recommended limits for alcohol consumption, fewer drinkers reporting a heavy drinking episode, and a greater proportion of pregnant women reporting alcohol abstinence after 6-12 months.

None of the studies assessed benefits or harms, but no evidence suggested that the interventions could be harmful.

The USPSTF is supported by the Agency for Healthcare Research and Quality. The researchers had no financial conflicts to disclose.

SOURCES: Curry S et al. JAMA. 2018;320(18):1899-1909; O’Connor E et al. JAMA. 2018;320(18):1910-28.