Conference Coverage

Prior to shoulder surgery, application of 3% hydrogen peroxide is a simple and inexpensive strategy to reduce the risk of postoperative cultures of Cutibacterium acnes, according to findings from a prospective randomized trial. The results were reported in an abstract scheduled for release at the annual meeting of the American Academy of Orthopaedic Surgeons. The meeting was canceled because of COVID-19.

“This approach is simple, cheap, and does not rely on patient compliance,” explained Surena Namdari, MD, associate professor of orthopedic surgery at Thomas Jefferson University, Philadelphia.

C. acnes, formerly known as Propionibacterium acnes, is increasingly seen as an important target for prevention of postoperative shoulder infections because of published reports that it is the most commonly isolated bacterium from such infections, Dr. Namdari said in an interview.

In the prospective, randomized trial, male patients scheduled for shoulder arthroscopy were recruited if they did not have active acne, history of psoriatic or eczematous lesions, or recent antibiotic use. Most of the preoperative preparation of the surgical site was the same in the experimental and control arms. This included hair clipping, application of 2% chlorhexidine, and cleansing with saturated 7.5% povidone-iodine solution surgical scrub brushes.

The difference was that 3% hydrogen peroxide–soaked gauzes were applied to perioperative skin of those randomized to the experimental group but not to controls. All patients received routine preoperative oral antibiotics as well as perioperative applications of a formulation containing 2% chlorhexidine gluconate and 70% isopropyl alcohol.

Following surgery, 11 (18.6%) of the 59 patients in the experimental arm versus 23 (34.8%) of the 66 patients randomized to the control group had positive cultures for C. acnes (P = .047), according to the trial results, which have now been published (J Shoulder Elbow Surg. 2020;29:212-6).

There were no cases of skin reactions in either the experimental or control groups.

Topical skin cleansers that contain peroxide, such as benzoyl peroxide, have been shown to have a C. acnes decolonizing effect if applied repeatedly in the days prior to surgery, but Dr. Namdari suggested the problem with this approach is that it depends on patient compliance. A prophylaxis included in the preoperative routine eliminates this potential problem.

C. acnes is an anaerobic bacterium that is part of the resident flora of the skin around several joints, including the knee and the hip, but it is particularly common in the posterior shoulder. Colonization has been found substantially more common in men than in women, according to Dr. Namdari.

The specific threat posed by C. acnes to risk of postoperative infections “is still being defined,” and this trial was not large enough to associate the reduction in postoperative C. acnes cultures with a reduced risk of an adverse clinical outcome, but Dr. Namdari says that the data do show that the nearly 50% reduction in positive cultures was achieved efficiently and inexpensively with no apparent risk.

Several previous studies have also evaluated strategies for reducing C. acnes skin burden on the basis of expected protection against postoperative infection. In one, which associated a 3-day preoperative course of benzoyl peroxide with a reduction in the skin burden of C. acnes, the authors also concluded that this approach deserves consideration in routine skin preparation for shoulder arthroplasty (J Shoulder Elbow Surg. 2018;27:1539-44).

“We believe that a preoperative skin prep protocol that reduces C. acnes load on the skin would likely lead to reduced postoperative infections,” reported the senior author, Mohit N. Gilotra, MD, assistant professor, University of Maryland, Baltimore. Contacted about the rationale for reducing C. acnes skin burden without objective evidence of an impact on postoperative infection risk, Dr. Gilotra indicated these strategies make sense.

“It seems to be true for staph infections and is a reasonable assumption to make here,” he added. “Future work will help determine how much benzoyl peroxide, hydrogen peroxide, or other skin prep can reduce surgical site infection.”

Dr. Namdari reports financial relationships with multiple device and pharmaceutical companies but none relevant to this study.

SOURCE: Namdari S et al. AAOS 2020. Abstract P0808.

Prior to shoulder surgery, application of 3% hydrogen peroxide is a simple and inexpensive strategy to reduce the risk of postoperative cultures of Cutibacterium acnes, according to findings from a prospective randomized trial. The results were reported in an abstract scheduled for release at the annual meeting of the American Academy of Orthopaedic Surgeons. The meeting was canceled because of COVID-19.

“This approach is simple, cheap, and does not rely on patient compliance,” explained Surena Namdari, MD, associate professor of orthopedic surgery at Thomas Jefferson University, Philadelphia.

C. acnes, formerly known as Propionibacterium acnes, is increasingly seen as an important target for prevention of postoperative shoulder infections because of published reports that it is the most commonly isolated bacterium from such infections, Dr. Namdari said in an interview.

In the prospective, randomized trial, male patients scheduled for shoulder arthroscopy were recruited if they did not have active acne, history of psoriatic or eczematous lesions, or recent antibiotic use. Most of the preoperative preparation of the surgical site was the same in the experimental and control arms. This included hair clipping, application of 2% chlorhexidine, and cleansing with saturated 7.5% povidone-iodine solution surgical scrub brushes.

The difference was that 3% hydrogen peroxide–soaked gauzes were applied to perioperative skin of those randomized to the experimental group but not to controls. All patients received routine preoperative oral antibiotics as well as perioperative applications of a formulation containing 2% chlorhexidine gluconate and 70% isopropyl alcohol.

Following surgery, 11 (18.6%) of the 59 patients in the experimental arm versus 23 (34.8%) of the 66 patients randomized to the control group had positive cultures for C. acnes (P = .047), according to the trial results, which have now been published (J Shoulder Elbow Surg. 2020;29:212-6).

There were no cases of skin reactions in either the experimental or control groups.

Topical skin cleansers that contain peroxide, such as benzoyl peroxide, have been shown to have a C. acnes decolonizing effect if applied repeatedly in the days prior to surgery, but Dr. Namdari suggested the problem with this approach is that it depends on patient compliance. A prophylaxis included in the preoperative routine eliminates this potential problem.

C. acnes is an anaerobic bacterium that is part of the resident flora of the skin around several joints, including the knee and the hip, but it is particularly common in the posterior shoulder. Colonization has been found substantially more common in men than in women, according to Dr. Namdari.

The specific threat posed by C. acnes to risk of postoperative infections “is still being defined,” and this trial was not large enough to associate the reduction in postoperative C. acnes cultures with a reduced risk of an adverse clinical outcome, but Dr. Namdari says that the data do show that the nearly 50% reduction in positive cultures was achieved efficiently and inexpensively with no apparent risk.

Several previous studies have also evaluated strategies for reducing C. acnes skin burden on the basis of expected protection against postoperative infection. In one, which associated a 3-day preoperative course of benzoyl peroxide with a reduction in the skin burden of C. acnes, the authors also concluded that this approach deserves consideration in routine skin preparation for shoulder arthroplasty (J Shoulder Elbow Surg. 2018;27:1539-44).

“We believe that a preoperative skin prep protocol that reduces C. acnes load on the skin would likely lead to reduced postoperative infections,” reported the senior author, Mohit N. Gilotra, MD, assistant professor, University of Maryland, Baltimore. Contacted about the rationale for reducing C. acnes skin burden without objective evidence of an impact on postoperative infection risk, Dr. Gilotra indicated these strategies make sense.

“It seems to be true for staph infections and is a reasonable assumption to make here,” he added. “Future work will help determine how much benzoyl peroxide, hydrogen peroxide, or other skin prep can reduce surgical site infection.”

Dr. Namdari reports financial relationships with multiple device and pharmaceutical companies but none relevant to this study.

SOURCE: Namdari S et al. AAOS 2020. Abstract P0808.

Prior to shoulder surgery, application of 3% hydrogen peroxide is a simple and inexpensive strategy to reduce the risk of postoperative cultures of Cutibacterium acnes, according to findings from a prospective randomized trial. The results were reported in an abstract scheduled for release at the annual meeting of the American Academy of Orthopaedic Surgeons. The meeting was canceled because of COVID-19.

“This approach is simple, cheap, and does not rely on patient compliance,” explained Surena Namdari, MD, associate professor of orthopedic surgery at Thomas Jefferson University, Philadelphia.

C. acnes, formerly known as Propionibacterium acnes, is increasingly seen as an important target for prevention of postoperative shoulder infections because of published reports that it is the most commonly isolated bacterium from such infections, Dr. Namdari said in an interview.

In the prospective, randomized trial, male patients scheduled for shoulder arthroscopy were recruited if they did not have active acne, history of psoriatic or eczematous lesions, or recent antibiotic use. Most of the preoperative preparation of the surgical site was the same in the experimental and control arms. This included hair clipping, application of 2% chlorhexidine, and cleansing with saturated 7.5% povidone-iodine solution surgical scrub brushes.

The difference was that 3% hydrogen peroxide–soaked gauzes were applied to perioperative skin of those randomized to the experimental group but not to controls. All patients received routine preoperative oral antibiotics as well as perioperative applications of a formulation containing 2% chlorhexidine gluconate and 70% isopropyl alcohol.

Following surgery, 11 (18.6%) of the 59 patients in the experimental arm versus 23 (34.8%) of the 66 patients randomized to the control group had positive cultures for C. acnes (P = .047), according to the trial results, which have now been published (J Shoulder Elbow Surg. 2020;29:212-6).

There were no cases of skin reactions in either the experimental or control groups.

Topical skin cleansers that contain peroxide, such as benzoyl peroxide, have been shown to have a C. acnes decolonizing effect if applied repeatedly in the days prior to surgery, but Dr. Namdari suggested the problem with this approach is that it depends on patient compliance. A prophylaxis included in the preoperative routine eliminates this potential problem.

C. acnes is an anaerobic bacterium that is part of the resident flora of the skin around several joints, including the knee and the hip, but it is particularly common in the posterior shoulder. Colonization has been found substantially more common in men than in women, according to Dr. Namdari.

The specific threat posed by C. acnes to risk of postoperative infections “is still being defined,” and this trial was not large enough to associate the reduction in postoperative C. acnes cultures with a reduced risk of an adverse clinical outcome, but Dr. Namdari says that the data do show that the nearly 50% reduction in positive cultures was achieved efficiently and inexpensively with no apparent risk.

Several previous studies have also evaluated strategies for reducing C. acnes skin burden on the basis of expected protection against postoperative infection. In one, which associated a 3-day preoperative course of benzoyl peroxide with a reduction in the skin burden of C. acnes, the authors also concluded that this approach deserves consideration in routine skin preparation for shoulder arthroplasty (J Shoulder Elbow Surg. 2018;27:1539-44).

“We believe that a preoperative skin prep protocol that reduces C. acnes load on the skin would likely lead to reduced postoperative infections,” reported the senior author, Mohit N. Gilotra, MD, assistant professor, University of Maryland, Baltimore. Contacted about the rationale for reducing C. acnes skin burden without objective evidence of an impact on postoperative infection risk, Dr. Gilotra indicated these strategies make sense.

“It seems to be true for staph infections and is a reasonable assumption to make here,” he added. “Future work will help determine how much benzoyl peroxide, hydrogen peroxide, or other skin prep can reduce surgical site infection.”

Dr. Namdari reports financial relationships with multiple device and pharmaceutical companies but none relevant to this study.

SOURCE: Namdari S et al. AAOS 2020. Abstract P0808.

MAUI, HAWAII – Anti-Ro52 autoantibodies are the latest and most potent of the autoantibody predictors of interstitial lung disease (ILD) discovered in patients with juvenile dermatomyositis, Anne M. Stevens, MD, PhD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

In addition to detailing the autoantibody red flags for ILD in juvenile dermatomyositis (JDM), she called for “hypervigilance” in patients with systemic juvenile idiopathic arthritis (SJIA) who exhibit any of a series of risk factors for ILD.

“Most of the lung disease in kids with systemic JIA is asymptomatic until very late, but it can be reversible if we treat it. So it’s worth finding and monitoring and giving everyone PCP [pneumocystis pneumonia] prophylaxis, because they have a high incidence of PCP if they have any of those risk factors,” observed Dr. Stevens, a pediatric rheumatologist at the University of Washington, Seattle, and senior director for the adaptive immunity research program at Janssen Pharmaceuticals.
 

Autoantibodies predict ILD in JDM

Dr. Stevens highlighted recent work by Sara Sabbagh, DO, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and coinvestigators in the Childhood Myositis Heterogeneity Collaborative Study Group. They reported the presence of anti-Ro52 autoantibodies in 14% of a cohort of 302 patients with JDM as well as in 12% of 25 patients with juvenile polymyositis and in 18% of 44 youths with an overlap of juvenile connective tissue disease and myositis. In addition, 13% of patients were positive for autoantibodies previously identified as being associated with ILD in these forms of juvenile myositis: Namely, 9% of the cohort were positive for antimelanoma differentiation–associated protein 5 (anti-MDA5) autoantibodies, and antiaminoacyl tRNA synthestase (anti-Jo-1) autoantibodies were present in 4%.

A total of 33 of the 371 juvenile myositis patients had ILD based upon CT imaging, chest X-ray, dyspnea on exertion, and/or biopsy. Most patients with anti-Ro52 also had other autoantibodies associated with ILD. Indeed, 31% of patients with anti-MDA5 autoantibodies also had anti-Ro52, as did 64% of those with anti-Jo-1. After controlling for the presence of these other myositis-specific autoantibodies, auto-Ro52 autoantibodies were independently associated with ILD, which was present in 36% of those with and just 4% of those without anti-Ro52 autoantibodies.

Importantly, if a patient with JDM or another form of juvenile myositis had both anti-Ro52 and another myositis-specific autoantibody, the risk for ILD rose dramatically, climbing to 70% in patients with anti-Ro52 and anti-MDA5 autoantibodies, and to 100% in those who were both anti-Ro52- and anti-Jo-1 positive.

Patients with anti-Ro52 autoantibodies had a worse prognosis, with more severe and chronic disease, Dr. Stevens noted.
 

Novel potential treatment for ILD in JDM: JAK inhibitors

Standard treatment of ILD in JDM in all cases includes high-dose pulsed corticosteroids, intravenous immunoglobulin (IVIG), and either methotrexate or mycophenolate mofetil. Consideration should be given to adding cyclosporine, particularly when a macrophage activation syndrome component is present. In addition, several exciting recent lines of evidence suggest a potential role for Janus kinase (JAK) inhibitors in the subset of JDM patients with anti-MDA5 autoantibody-positive disease, according to Dr. Stevens.

For one, Dr. Sabbagh and colleagues have reported impressive success with the use of the JAK 1/3 inhibitor tofacitinib (Xeljanz) in two patients with anti-MDA5 autoantibody-positive refractory JDM with ILD. Both patients experienced moderate clinical improvement in disease activity in their skin, muscles, and other target organs. But particularly striking was what the investigators termed the “remarkable” improvement in ILD, including near-resolution of abnormal findings on high-resolution CT imaging and a more robust performance on pulmonary function testing.

Both of these hitherto treatment-refractory patients were able to wean or discontinue their immunosuppressive medications. The patients’ elevated blood interferon-response gene signature improved significantly in response to tofacitinib, and their problematic upregulation of STAT1 phosphorylation of CD4+ T cells and monocytes stimulated with interferon-gamma was tamed, dropping to levels typically seen in healthy individuals.

Also, French pediatric rheumatologists have identified key phenotypic and cytokine differences between 13 patients with JDM or juvenile overlap myositis who were anti-MDA5 autoantibody positive at presentation and 51 others who were not. The anti-MDA5 autoantibody–positive group had a higher frequency of ILD, arthritis, skin ulcerations, and lupus features, but milder muscle involvement than did the anti-MDA5 autoantibody–negative group. The anti-MDA5 autoantibody–positive patients demonstrated enhanced interferon-alpha signaling based upon their significantly higher serum interferon-alpha levels, compared with the anti-MDA5-negative group, and those levels decreased following treatment with improvement in symptoms.

The French investigators proposed that interferon-alpha may constitute a novel therapeutic target in the subgroup of patients with severe, refractory juvenile myositis and anti-MDA5 autoantibodies – and, as it happens, it’s known that JAK inhibitors modulate the interferon pathway.
 

Risk factors for ILD in SJIA

In the past half-dozen years or so, pediatric rheumatologists have become increasingly aware of and concerned about a new development in SJIA: the occurrence of comorbid ILD. This is a poor-prognosis disease: In a cohort from the United Kingdom, 5-year mortality from the time of diagnosis was 41%, fully 40-fold higher than in patients with SJIA only.

Patient cohorts with SJIA and ILD have unusual clinical and laboratory features that aren’t part of the typical picture in SJIA. These include acute clubbing, lymphopenia, a fixed pruritic rash, unexplained abdominal pain, peripheral eosinophilia, facial swelling, and an increased ferritin level, a hallmark of acute macrophage activation syndrome. Onset of SJIA before 2 years of age is another red flag associated with increased risk for ILD. So is trisomy 21, which is up to 50 times more prevalent in patients with SJIA and ILD than in the general population or in patients with SJIA only. Another clue is an adverse reaction to tocilizumab (Actemra).

Any of these findings warrant hypervigilance: “Be on high alert and monitor these patients for ILD much more closely,” Dr. Stevens advised.

This means ordering a CT scan, prescribing PCP prophylaxis, and regularly measuring pulmonary function, admittedly a challenge in children under 7 years old. In these younger kids, practical solutions include measuring their oxygen saturation before and after running around the room to see if it drops. A 6-minute walk test and sleep oximetry are other options.

The explanation for the abrupt arrival of ILD as part of the picture in SJIA during the past decade remains unclear. The timing coincides with a major advance in the treatment of SJIA: the arrival of biologic agents blocking interleukin-1 and -6. Could this be a serious treatment side effect?

“It’s all association so far, and we’re not really sure why we’re seeing this association. Is it because we’re using a lot [fewer] corticosteroids now, and maybe those were preventing lung disease in the past?” Dr. Stevens speculated.

At this point, she and her fellow pediatric rheumatologists are awaiting further evidence before discussing a curb in their use of IL-1 or -6 inhibitors in patients with SJIA.

“These drugs have turned around the lives of kids with SJIA. They used to suffer through all our ineffective treatments for years, with terrible joint destruction and a pretty high mortality rate. These are great drugs for this disease, and we certainly don’t want to limit them,” she said.

Dr. Stevens reported research collaborations with Kineta and Seattle Genetics in addition to her employment at Janssen Pharmaceuticals.

bjancin@mdedge.com

MAUI, HAWAII – Anti-Ro52 autoantibodies are the latest and most potent of the autoantibody predictors of interstitial lung disease (ILD) discovered in patients with juvenile dermatomyositis, Anne M. Stevens, MD, PhD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

In addition to detailing the autoantibody red flags for ILD in juvenile dermatomyositis (JDM), she called for “hypervigilance” in patients with systemic juvenile idiopathic arthritis (SJIA) who exhibit any of a series of risk factors for ILD.

“Most of the lung disease in kids with systemic JIA is asymptomatic until very late, but it can be reversible if we treat it. So it’s worth finding and monitoring and giving everyone PCP [pneumocystis pneumonia] prophylaxis, because they have a high incidence of PCP if they have any of those risk factors,” observed Dr. Stevens, a pediatric rheumatologist at the University of Washington, Seattle, and senior director for the adaptive immunity research program at Janssen Pharmaceuticals.
 

Autoantibodies predict ILD in JDM

Dr. Stevens highlighted recent work by Sara Sabbagh, DO, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and coinvestigators in the Childhood Myositis Heterogeneity Collaborative Study Group. They reported the presence of anti-Ro52 autoantibodies in 14% of a cohort of 302 patients with JDM as well as in 12% of 25 patients with juvenile polymyositis and in 18% of 44 youths with an overlap of juvenile connective tissue disease and myositis. In addition, 13% of patients were positive for autoantibodies previously identified as being associated with ILD in these forms of juvenile myositis: Namely, 9% of the cohort were positive for antimelanoma differentiation–associated protein 5 (anti-MDA5) autoantibodies, and antiaminoacyl tRNA synthestase (anti-Jo-1) autoantibodies were present in 4%.

A total of 33 of the 371 juvenile myositis patients had ILD based upon CT imaging, chest X-ray, dyspnea on exertion, and/or biopsy. Most patients with anti-Ro52 also had other autoantibodies associated with ILD. Indeed, 31% of patients with anti-MDA5 autoantibodies also had anti-Ro52, as did 64% of those with anti-Jo-1. After controlling for the presence of these other myositis-specific autoantibodies, auto-Ro52 autoantibodies were independently associated with ILD, which was present in 36% of those with and just 4% of those without anti-Ro52 autoantibodies.

Importantly, if a patient with JDM or another form of juvenile myositis had both anti-Ro52 and another myositis-specific autoantibody, the risk for ILD rose dramatically, climbing to 70% in patients with anti-Ro52 and anti-MDA5 autoantibodies, and to 100% in those who were both anti-Ro52- and anti-Jo-1 positive.

Patients with anti-Ro52 autoantibodies had a worse prognosis, with more severe and chronic disease, Dr. Stevens noted.
 

Novel potential treatment for ILD in JDM: JAK inhibitors

Standard treatment of ILD in JDM in all cases includes high-dose pulsed corticosteroids, intravenous immunoglobulin (IVIG), and either methotrexate or mycophenolate mofetil. Consideration should be given to adding cyclosporine, particularly when a macrophage activation syndrome component is present. In addition, several exciting recent lines of evidence suggest a potential role for Janus kinase (JAK) inhibitors in the subset of JDM patients with anti-MDA5 autoantibody-positive disease, according to Dr. Stevens.

For one, Dr. Sabbagh and colleagues have reported impressive success with the use of the JAK 1/3 inhibitor tofacitinib (Xeljanz) in two patients with anti-MDA5 autoantibody-positive refractory JDM with ILD. Both patients experienced moderate clinical improvement in disease activity in their skin, muscles, and other target organs. But particularly striking was what the investigators termed the “remarkable” improvement in ILD, including near-resolution of abnormal findings on high-resolution CT imaging and a more robust performance on pulmonary function testing.

Both of these hitherto treatment-refractory patients were able to wean or discontinue their immunosuppressive medications. The patients’ elevated blood interferon-response gene signature improved significantly in response to tofacitinib, and their problematic upregulation of STAT1 phosphorylation of CD4+ T cells and monocytes stimulated with interferon-gamma was tamed, dropping to levels typically seen in healthy individuals.

Also, French pediatric rheumatologists have identified key phenotypic and cytokine differences between 13 patients with JDM or juvenile overlap myositis who were anti-MDA5 autoantibody positive at presentation and 51 others who were not. The anti-MDA5 autoantibody–positive group had a higher frequency of ILD, arthritis, skin ulcerations, and lupus features, but milder muscle involvement than did the anti-MDA5 autoantibody–negative group. The anti-MDA5 autoantibody–positive patients demonstrated enhanced interferon-alpha signaling based upon their significantly higher serum interferon-alpha levels, compared with the anti-MDA5-negative group, and those levels decreased following treatment with improvement in symptoms.

The French investigators proposed that interferon-alpha may constitute a novel therapeutic target in the subgroup of patients with severe, refractory juvenile myositis and anti-MDA5 autoantibodies – and, as it happens, it’s known that JAK inhibitors modulate the interferon pathway.
 

Risk factors for ILD in SJIA

In the past half-dozen years or so, pediatric rheumatologists have become increasingly aware of and concerned about a new development in SJIA: the occurrence of comorbid ILD. This is a poor-prognosis disease: In a cohort from the United Kingdom, 5-year mortality from the time of diagnosis was 41%, fully 40-fold higher than in patients with SJIA only.

Patient cohorts with SJIA and ILD have unusual clinical and laboratory features that aren’t part of the typical picture in SJIA. These include acute clubbing, lymphopenia, a fixed pruritic rash, unexplained abdominal pain, peripheral eosinophilia, facial swelling, and an increased ferritin level, a hallmark of acute macrophage activation syndrome. Onset of SJIA before 2 years of age is another red flag associated with increased risk for ILD. So is trisomy 21, which is up to 50 times more prevalent in patients with SJIA and ILD than in the general population or in patients with SJIA only. Another clue is an adverse reaction to tocilizumab (Actemra).

Any of these findings warrant hypervigilance: “Be on high alert and monitor these patients for ILD much more closely,” Dr. Stevens advised.

This means ordering a CT scan, prescribing PCP prophylaxis, and regularly measuring pulmonary function, admittedly a challenge in children under 7 years old. In these younger kids, practical solutions include measuring their oxygen saturation before and after running around the room to see if it drops. A 6-minute walk test and sleep oximetry are other options.

The explanation for the abrupt arrival of ILD as part of the picture in SJIA during the past decade remains unclear. The timing coincides with a major advance in the treatment of SJIA: the arrival of biologic agents blocking interleukin-1 and -6. Could this be a serious treatment side effect?

“It’s all association so far, and we’re not really sure why we’re seeing this association. Is it because we’re using a lot [fewer] corticosteroids now, and maybe those were preventing lung disease in the past?” Dr. Stevens speculated.

At this point, she and her fellow pediatric rheumatologists are awaiting further evidence before discussing a curb in their use of IL-1 or -6 inhibitors in patients with SJIA.

“These drugs have turned around the lives of kids with SJIA. They used to suffer through all our ineffective treatments for years, with terrible joint destruction and a pretty high mortality rate. These are great drugs for this disease, and we certainly don’t want to limit them,” she said.

Dr. Stevens reported research collaborations with Kineta and Seattle Genetics in addition to her employment at Janssen Pharmaceuticals.

bjancin@mdedge.com

MAUI, HAWAII – Anti-Ro52 autoantibodies are the latest and most potent of the autoantibody predictors of interstitial lung disease (ILD) discovered in patients with juvenile dermatomyositis, Anne M. Stevens, MD, PhD, said at the 2020 Rheumatology Winter Clinical Symposium.

Bruce Jancin/MDedge News

In addition to detailing the autoantibody red flags for ILD in juvenile dermatomyositis (JDM), she called for “hypervigilance” in patients with systemic juvenile idiopathic arthritis (SJIA) who exhibit any of a series of risk factors for ILD.

“Most of the lung disease in kids with systemic JIA is asymptomatic until very late, but it can be reversible if we treat it. So it’s worth finding and monitoring and giving everyone PCP [pneumocystis pneumonia] prophylaxis, because they have a high incidence of PCP if they have any of those risk factors,” observed Dr. Stevens, a pediatric rheumatologist at the University of Washington, Seattle, and senior director for the adaptive immunity research program at Janssen Pharmaceuticals.
 

Autoantibodies predict ILD in JDM

Dr. Stevens highlighted recent work by Sara Sabbagh, DO, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and coinvestigators in the Childhood Myositis Heterogeneity Collaborative Study Group. They reported the presence of anti-Ro52 autoantibodies in 14% of a cohort of 302 patients with JDM as well as in 12% of 25 patients with juvenile polymyositis and in 18% of 44 youths with an overlap of juvenile connective tissue disease and myositis. In addition, 13% of patients were positive for autoantibodies previously identified as being associated with ILD in these forms of juvenile myositis: Namely, 9% of the cohort were positive for antimelanoma differentiation–associated protein 5 (anti-MDA5) autoantibodies, and antiaminoacyl tRNA synthestase (anti-Jo-1) autoantibodies were present in 4%.

A total of 33 of the 371 juvenile myositis patients had ILD based upon CT imaging, chest X-ray, dyspnea on exertion, and/or biopsy. Most patients with anti-Ro52 also had other autoantibodies associated with ILD. Indeed, 31% of patients with anti-MDA5 autoantibodies also had anti-Ro52, as did 64% of those with anti-Jo-1. After controlling for the presence of these other myositis-specific autoantibodies, auto-Ro52 autoantibodies were independently associated with ILD, which was present in 36% of those with and just 4% of those without anti-Ro52 autoantibodies.

Importantly, if a patient with JDM or another form of juvenile myositis had both anti-Ro52 and another myositis-specific autoantibody, the risk for ILD rose dramatically, climbing to 70% in patients with anti-Ro52 and anti-MDA5 autoantibodies, and to 100% in those who were both anti-Ro52- and anti-Jo-1 positive.

Patients with anti-Ro52 autoantibodies had a worse prognosis, with more severe and chronic disease, Dr. Stevens noted.
 

Novel potential treatment for ILD in JDM: JAK inhibitors

Standard treatment of ILD in JDM in all cases includes high-dose pulsed corticosteroids, intravenous immunoglobulin (IVIG), and either methotrexate or mycophenolate mofetil. Consideration should be given to adding cyclosporine, particularly when a macrophage activation syndrome component is present. In addition, several exciting recent lines of evidence suggest a potential role for Janus kinase (JAK) inhibitors in the subset of JDM patients with anti-MDA5 autoantibody-positive disease, according to Dr. Stevens.

For one, Dr. Sabbagh and colleagues have reported impressive success with the use of the JAK 1/3 inhibitor tofacitinib (Xeljanz) in two patients with anti-MDA5 autoantibody-positive refractory JDM with ILD. Both patients experienced moderate clinical improvement in disease activity in their skin, muscles, and other target organs. But particularly striking was what the investigators termed the “remarkable” improvement in ILD, including near-resolution of abnormal findings on high-resolution CT imaging and a more robust performance on pulmonary function testing.

Both of these hitherto treatment-refractory patients were able to wean or discontinue their immunosuppressive medications. The patients’ elevated blood interferon-response gene signature improved significantly in response to tofacitinib, and their problematic upregulation of STAT1 phosphorylation of CD4+ T cells and monocytes stimulated with interferon-gamma was tamed, dropping to levels typically seen in healthy individuals.

Also, French pediatric rheumatologists have identified key phenotypic and cytokine differences between 13 patients with JDM or juvenile overlap myositis who were anti-MDA5 autoantibody positive at presentation and 51 others who were not. The anti-MDA5 autoantibody–positive group had a higher frequency of ILD, arthritis, skin ulcerations, and lupus features, but milder muscle involvement than did the anti-MDA5 autoantibody–negative group. The anti-MDA5 autoantibody–positive patients demonstrated enhanced interferon-alpha signaling based upon their significantly higher serum interferon-alpha levels, compared with the anti-MDA5-negative group, and those levels decreased following treatment with improvement in symptoms.

The French investigators proposed that interferon-alpha may constitute a novel therapeutic target in the subgroup of patients with severe, refractory juvenile myositis and anti-MDA5 autoantibodies – and, as it happens, it’s known that JAK inhibitors modulate the interferon pathway.
 

Risk factors for ILD in SJIA

In the past half-dozen years or so, pediatric rheumatologists have become increasingly aware of and concerned about a new development in SJIA: the occurrence of comorbid ILD. This is a poor-prognosis disease: In a cohort from the United Kingdom, 5-year mortality from the time of diagnosis was 41%, fully 40-fold higher than in patients with SJIA only.

Patient cohorts with SJIA and ILD have unusual clinical and laboratory features that aren’t part of the typical picture in SJIA. These include acute clubbing, lymphopenia, a fixed pruritic rash, unexplained abdominal pain, peripheral eosinophilia, facial swelling, and an increased ferritin level, a hallmark of acute macrophage activation syndrome. Onset of SJIA before 2 years of age is another red flag associated with increased risk for ILD. So is trisomy 21, which is up to 50 times more prevalent in patients with SJIA and ILD than in the general population or in patients with SJIA only. Another clue is an adverse reaction to tocilizumab (Actemra).

Any of these findings warrant hypervigilance: “Be on high alert and monitor these patients for ILD much more closely,” Dr. Stevens advised.

This means ordering a CT scan, prescribing PCP prophylaxis, and regularly measuring pulmonary function, admittedly a challenge in children under 7 years old. In these younger kids, practical solutions include measuring their oxygen saturation before and after running around the room to see if it drops. A 6-minute walk test and sleep oximetry are other options.

The explanation for the abrupt arrival of ILD as part of the picture in SJIA during the past decade remains unclear. The timing coincides with a major advance in the treatment of SJIA: the arrival of biologic agents blocking interleukin-1 and -6. Could this be a serious treatment side effect?

“It’s all association so far, and we’re not really sure why we’re seeing this association. Is it because we’re using a lot [fewer] corticosteroids now, and maybe those were preventing lung disease in the past?” Dr. Stevens speculated.

At this point, she and her fellow pediatric rheumatologists are awaiting further evidence before discussing a curb in their use of IL-1 or -6 inhibitors in patients with SJIA.

“These drugs have turned around the lives of kids with SJIA. They used to suffer through all our ineffective treatments for years, with terrible joint destruction and a pretty high mortality rate. These are great drugs for this disease, and we certainly don’t want to limit them,” she said.

Dr. Stevens reported research collaborations with Kineta and Seattle Genetics in addition to her employment at Janssen Pharmaceuticals.

bjancin@mdedge.com

For seriously ill patients with multidrug-resistant organisms (MDROs) in their gastrointestinal tract, performing a fecal microbiota transplant (FMT) may result in fewer and less severe infections, as well as shorter hospital stays, according to investigators.

Significant clinical improvements were observed across the group even though 59% of patients did not clear MDROs, which suggests that complete decolonization of resistant organisms may be unnecessary for patients to benefit from FMT, reported lead author Julian Marchesi, PhD, of Cardiff (Wales) University and Imperial College London (England).

“We see the quality of life for these patients is hugely improved even when we don’t get rid of the organism totally,” Dr. Marchesi said in a virtual press conference.

Although previous studies have suggested that FMT may be used to decolonize MDROs, little research has addressed other clinical outcomes, the investigators wrote in an abstract released as part of the annual Digestive Disease Week®, which was canceled because of COVID-19.

The present study involved 20 patients with MDROs, including extended-spectrum beta-lactamase Enterobacteriaceae (ESBL), carbapenemase-producing Enterobacteriaceae (CPE), or vancomycin-resistant enterococci (VRE). Approximately half of the population (n = 11) had chronic hematological disease. The other half (n = 9) had recurrent urinary tract infections with ESBL, including patients who had undergone renal transplant or had recurrent Clostridioides difficile infection.

For each transplant, 200-300 mL of fecal slurry was delivered via nasogastric tube into the small intestine. Fecal donors underwent a strict screening process that included blood, fecal, and behavioral testing.

Multiple clinical outcomes were evaluated in the 6 months leading up to FMT, then compared with outcomes in the 6 months following fecal transplant. Out of 20 patients, 17 completed the 6-month follow-up. Although only 7 of these patients (41%) were decolonized of MDROs, multiple significant clinical improvements were observed across the group, including reductions in MDRO bloodstream infections (P = .047), all bloodstream infections (P = .03), length of stay in hospital (P = .0002), and duration of carbapenem use (P = .0005). Eight out of 11 patients with hematologic disease improved enough to undergo stem cell transplantation within 6 months of FMT, and in the subgroup of patients who had undergone renal transplant, the rate of urinary tract infections was significantly improved (P = .008).

No serious adverse events were encountered during the trial, which led the investigators to conclude that FMT was safe and well tolerated, even in patients with bloodstream infections and those who were highly immunosuppressed.

Beyond clinical implications, Dr. Marchesi suggested that the study findings should influence FMT trial methodology.

“We’ve got to start thinking a little bit differently in terms of how we measure the impact of FMT,” he said. “It’s not all about ... getting rid of these opportunistic pathogens. There are other quality-of-life factors that we need to measure, because they’re also important for the patient.”

Dr. Marchesi said that more research is needed to confirm findings and gain a mechanistic understanding of why patients may improve despite a lack of decolonization.

“We think we’re on a strong foundation here to take this into a clinical trial,” he said.

The research was funded by the National Institute for Health Research and the Medical Research Council. The investigators reported no conflicts of interest.

For seriously ill patients with multidrug-resistant organisms (MDROs) in their gastrointestinal tract, performing a fecal microbiota transplant (FMT) may result in fewer and less severe infections, as well as shorter hospital stays, according to investigators.

Significant clinical improvements were observed across the group even though 59% of patients did not clear MDROs, which suggests that complete decolonization of resistant organisms may be unnecessary for patients to benefit from FMT, reported lead author Julian Marchesi, PhD, of Cardiff (Wales) University and Imperial College London (England).

“We see the quality of life for these patients is hugely improved even when we don’t get rid of the organism totally,” Dr. Marchesi said in a virtual press conference.

Although previous studies have suggested that FMT may be used to decolonize MDROs, little research has addressed other clinical outcomes, the investigators wrote in an abstract released as part of the annual Digestive Disease Week®, which was canceled because of COVID-19.

The present study involved 20 patients with MDROs, including extended-spectrum beta-lactamase Enterobacteriaceae (ESBL), carbapenemase-producing Enterobacteriaceae (CPE), or vancomycin-resistant enterococci (VRE). Approximately half of the population (n = 11) had chronic hematological disease. The other half (n = 9) had recurrent urinary tract infections with ESBL, including patients who had undergone renal transplant or had recurrent Clostridioides difficile infection.

For each transplant, 200-300 mL of fecal slurry was delivered via nasogastric tube into the small intestine. Fecal donors underwent a strict screening process that included blood, fecal, and behavioral testing.

Multiple clinical outcomes were evaluated in the 6 months leading up to FMT, then compared with outcomes in the 6 months following fecal transplant. Out of 20 patients, 17 completed the 6-month follow-up. Although only 7 of these patients (41%) were decolonized of MDROs, multiple significant clinical improvements were observed across the group, including reductions in MDRO bloodstream infections (P = .047), all bloodstream infections (P = .03), length of stay in hospital (P = .0002), and duration of carbapenem use (P = .0005). Eight out of 11 patients with hematologic disease improved enough to undergo stem cell transplantation within 6 months of FMT, and in the subgroup of patients who had undergone renal transplant, the rate of urinary tract infections was significantly improved (P = .008).

No serious adverse events were encountered during the trial, which led the investigators to conclude that FMT was safe and well tolerated, even in patients with bloodstream infections and those who were highly immunosuppressed.

Beyond clinical implications, Dr. Marchesi suggested that the study findings should influence FMT trial methodology.

“We’ve got to start thinking a little bit differently in terms of how we measure the impact of FMT,” he said. “It’s not all about ... getting rid of these opportunistic pathogens. There are other quality-of-life factors that we need to measure, because they’re also important for the patient.”

Dr. Marchesi said that more research is needed to confirm findings and gain a mechanistic understanding of why patients may improve despite a lack of decolonization.

“We think we’re on a strong foundation here to take this into a clinical trial,” he said.

The research was funded by the National Institute for Health Research and the Medical Research Council. The investigators reported no conflicts of interest.

For seriously ill patients with multidrug-resistant organisms (MDROs) in their gastrointestinal tract, performing a fecal microbiota transplant (FMT) may result in fewer and less severe infections, as well as shorter hospital stays, according to investigators.

Significant clinical improvements were observed across the group even though 59% of patients did not clear MDROs, which suggests that complete decolonization of resistant organisms may be unnecessary for patients to benefit from FMT, reported lead author Julian Marchesi, PhD, of Cardiff (Wales) University and Imperial College London (England).

“We see the quality of life for these patients is hugely improved even when we don’t get rid of the organism totally,” Dr. Marchesi said in a virtual press conference.

Although previous studies have suggested that FMT may be used to decolonize MDROs, little research has addressed other clinical outcomes, the investigators wrote in an abstract released as part of the annual Digestive Disease Week®, which was canceled because of COVID-19.

The present study involved 20 patients with MDROs, including extended-spectrum beta-lactamase Enterobacteriaceae (ESBL), carbapenemase-producing Enterobacteriaceae (CPE), or vancomycin-resistant enterococci (VRE). Approximately half of the population (n = 11) had chronic hematological disease. The other half (n = 9) had recurrent urinary tract infections with ESBL, including patients who had undergone renal transplant or had recurrent Clostridioides difficile infection.

For each transplant, 200-300 mL of fecal slurry was delivered via nasogastric tube into the small intestine. Fecal donors underwent a strict screening process that included blood, fecal, and behavioral testing.

Multiple clinical outcomes were evaluated in the 6 months leading up to FMT, then compared with outcomes in the 6 months following fecal transplant. Out of 20 patients, 17 completed the 6-month follow-up. Although only 7 of these patients (41%) were decolonized of MDROs, multiple significant clinical improvements were observed across the group, including reductions in MDRO bloodstream infections (P = .047), all bloodstream infections (P = .03), length of stay in hospital (P = .0002), and duration of carbapenem use (P = .0005). Eight out of 11 patients with hematologic disease improved enough to undergo stem cell transplantation within 6 months of FMT, and in the subgroup of patients who had undergone renal transplant, the rate of urinary tract infections was significantly improved (P = .008).

No serious adverse events were encountered during the trial, which led the investigators to conclude that FMT was safe and well tolerated, even in patients with bloodstream infections and those who were highly immunosuppressed.

Beyond clinical implications, Dr. Marchesi suggested that the study findings should influence FMT trial methodology.

“We’ve got to start thinking a little bit differently in terms of how we measure the impact of FMT,” he said. “It’s not all about ... getting rid of these opportunistic pathogens. There are other quality-of-life factors that we need to measure, because they’re also important for the patient.”

Dr. Marchesi said that more research is needed to confirm findings and gain a mechanistic understanding of why patients may improve despite a lack of decolonization.

“We think we’re on a strong foundation here to take this into a clinical trial,” he said.

The research was funded by the National Institute for Health Research and the Medical Research Council. The investigators reported no conflicts of interest.

LONDON – Advances in cell- and gene-based research are paving the way towards the possibility of a cure for the rare inherited skin disorder, recessive dystrophic epidermolysis bullosa (RDEB), several experts said at the first EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA).

Sara Freeman/MDedge News

“I think there is a palpable sense that we are close to some breakthroughs for EB,” which may include “a cure for this intractable disease,” said Jouni Uitto, MD, PhD, in welcoming delegates to the meeting, held in January 2020.

Dr. Uitto, professor of dermatology and cutaneous biology, and biochemistry and molecular biology, at Sidney Kimmel Medical College, Philadelphia, said that the “breadth of academia-based basic science has been tremendous over the past 3 decades. We can now identify 21 different genes harboring mutations associated with different EB phenotypes, and we have a pretty good understanding how those mutations actually explain the phenotypic spectrum of different forms of EB.”

Importantly, “there are now perhaps as many as a dozen different clinical trials that are in the early stages of trying to find a permanent cure for this disease,” Dr. Uitto said, with some that are looking at fixing the underlying defect once and for all, or at the very least, counteracting subsequent complications. “The spectrum varies from attempting to enhance wound healing to gene repair, gene replacement, protein replacement therapies, cell-based therapies. There is a whole spectrum of often complementary approaches that we believe will lead to a cure and treatment for this disease. We look forward to developing therapies which will be helpful to the benefit of all the patients with EB,” said Dr. Uitto, who is also chair of the department of dermatology and cutaneous biology at Sidney Kimmel Medical College.
 

EB research is gathering ‘momentum’

John McGrath, MD, professor of molecular dermatology, King’s College, London, chaired a session on the latest in cell manipulation research and made the following comment: “A few years ago, we were making progress, but we were chatting about a lot of the same things; but now, suddenly there seems to be momentum, re-energy, rediscovery, real progress.”

Dr. McGrath noted that gene and cell research, and preclinical development, were culminating in clinical trials and potentially products that could change the way clinicians thought about managing patients with EB. “That prospect of getting closer and closer to real treatments, and maybe even a cure” is becoming more of a reality, he said.

Dr. McGrath is also head of the genetic skin disease group at King’s College London, and an honorary consultant dermatologist at St. John’s Institute of Dermatology, part of the Guy’s and St. Thomas’ NHS Foundation Trust in London. He has been a principal investigator for clinical trials of fibroblast cell therapy and allogeneic intravenous mesenchymal stromal cells (MSCs) therapy.

“It has been a joy for me to see the benefits of those clinical trials. There is nothing like it as an investigator when you see an intervention make a difference to a patient,” Dr. McGrath said. “For me, it was just a real eye opener when I saw the skin changes in a child that received intravenous allogeneic MSCs. The skin changed dramatically, it went from red and inflamed to calm and pink, [giving a] first glimpse into something that might be reversible, treatable, not just papering over the cracks.”
 

Correcting the genetic defect

The most severe form of RDEB is caused by mutations in COL7A1, the gene for collagen type 7 (COL7), the major connective component of the skin, anchoring the epidermis to the dermis. Its absence results in skin that can be so fragile it has been likened to the wings of a butterfly and results in severe blistering after very little trauma.

There is a lot of research on how to correct the underlying genetic defect, either by replacing COL7A1 entirely, repairing the gene, or editing the gene so that COL 7 can be produced in situ and prevent the formation of wounds and heal those that might already be present.

“The excitement is obvious,” said Jakub Tolar, MD, PhD, professor in the department of pediatrics, blood and marrow transplantation, and dean of the University of Minnesota Medical School, Minneapolis, who chaired a session on gene and gene manipulation therapies. “If one can go and correct that information, it follows that everything else is going to be okay,” he said. “Only it’s not. I think that it’s pretty clear that more than gene correction is needed.”

Some of the approaches to replace the faulty gene discussed at the meeting involved taking skin biopsy samples from a healthy area of skin from a patient with RDEB, isolating specific skin cells (fibroblasts, keratinocytes, or both), transferring a healthy copy of the COL7A1 gene into those cells – then expanding the population to form sheets of cells that can be grafted onto the wounds of the same patient.

Clinical trials of gene therapy for RDEB

Clinical trials with these novel gene-corrected, tissue-engineered grafts have already started, including EBGraft, a phase 1/2 open, nonrandomized, proof-of-concept trial using genetically corrected sheets of fibroblasts and keratinocytes, conducted by Alain Hovnanian, MD, PhD, Necker-Enfants Malades Hospital in Paris, and associates.

Then there is the phase 3 VIITAL trial being conducted at Stanford (Calif.) University by Jean Tang, MD, PhD, and colleagues. Recruitment in this open trial, which will enroll 10-15 patients with RDEB, has just started. The aim of the study is to investigate the efficacy and safety of EB-101, an autologous cell therapy that corrects COL7A1 in keratinocytes.

Positive findings from a phase 1/2 study with EB-101 were presented in a poster at the meeting by Emily Gorell, DO, a postdoctoral medical fellow in dermatology, at Stanford University and her associates. The trial included seven patients with RDEB who were treated and followed for 3 to 6 years. Data from that study showed that there were no serious adverse events and 95% of patients’ wounds that were treated (36/38) were healed by at least 50%, based on an Investigator Global Assessment at 6 months. In comparison, none of the untreated wounds had healed by that time point. “There was evidence of C7 [collagen 7] restoration at 2 years in two participants,” and wound healing was associated with both reduced pain and itch, the investigators wrote in the poster.

Another approach to this so-called ‘ex-vivo’ gene therapy is to take the patient’s cells via a small skin biopsy, genetically modify them, expand the population of these modified cells, and then inject them back into the patient. This approach was described by Peter Marinkovich, MD, of the department of dermatology at Stanford University, during an oral presentation and in a poster at the meeting.

Dr. Marinkovich discussed the results of an ongoing phase 1/2 study in which six subjects with RDEB – five adults and one child ­­– were treated intradermally with genetically modified fibroblasts in a preparation currently known as FCX-007.

“Before we had to graft the cells, take the patients into the OR [operating room], with the risks of general anesthesia, but here we don’t have to take the patients to the OR, we just take them into the hospital for a day, inject their wounds and then send them on their way,” Dr. Marinkovich said. Interim findings show that the patients have tolerated the therapy very well up to 52 weeks, he noted.

A greater percentage of wounds were healed by more than 50% following treatment with FCX-007 than those left untreated at weeks 4 (80% versus 20%), 12 (90% versus 44%), 25 (75% versus 50%), and 52 (83% versus 33%).

These results have been used to inform the design of the upcoming phase 3 study, DEFI-RDEB. The multicenter intrapatient randomized, controlled, open-label study is evaluating FCX-007 in the treatment of persistent nonhealing wounds in about 20 people with RDEB.
 

The promise of ‘off-the-shelf’ topical gene therapy

Another study Dr. Marinkovich is involved with is a phase 1/2 study of beremagene geperpavec (B-VEC), an “in-vivo” gene therapy. B-VEC is a topically administered therapy containing a replication-deficient, nonintegrating viral vector that contains two functional COL7A1 genes. The concept is that, when applied directly onto the skin, the virus gets into the skin and carries with it the healthy gene copies; these get taken up by the skin cells, which then produce COL7.

Initially, two patients with generalized severe RDEB were studied. B-VEC was applied to one of two wounds and a placebo to the other wound in each patient. Another four patients were then enrolled and studied for 3 months. Nine of 10 wounds closed completely after initial administration of B-VEC, with an average time to 100% wound closure of 17.4 days. The average duration of wound closure has been 113 days so far.
 

“One chronic wound that was originally open for over 4 years closed completely following B-VEC readministration. The wound has remained closed for 100 days,” Dr. Marinkovich and associates reported in a poster at the meeting. A postimaging study showed that COL7 was being produced from 48 hours to up to 90 days later.

“I’m really excited about this type of therapy,” Dr. Marinkovich said during an oral presentation. Unlike the ex-vivo gene therapy approach, where each patient’s cells have to be taken by a biopsy, altered, engineered, and expanded, which takes specialized facilities that can vary by country and location, this in-vivo gene therapy can be considered an “off-the shelf” treatment that can be shipped all over the world and could reach many patients. “It’s another weapon in our armamentarium against this deadly disease that we are all fighting against together,” Dr. Marinkovich added.

EBGRAFT is supported by Cure EB. The VIITAL trial is sponsored by Abeona Therapeutics. The phase 1/2 trials of EB-101 were funded by grants from the National Institutes of Health, EB Research Partnership, EM Medical Research Foundation, and Abeona Therapeutics. The FCX-007 phase 1/2 study was supported by Fibrocell Technologies. The upcoming phase 3 will be funded by Fibrocell Technologies in collaboration with Castle Creek Pharmaceuticals. The B-VEC study is supported by Krystal Biotech.

Dr. Uitto and Dr. McGrath had no potential conflicts of interest to report. Dr. Tolar has received funding from the National Institutes of Health, various EB charities and the Richard M. Schulze Family Foundation (RMSFF). He disclosed receiving honoraria or consultation fees from Ticeba/RHEACELL GmbH and Taiga Biosciences. Dr. Marinkovich disclosed being an investigator working on RDEB-related research projects in collaboration with Krystal Biotech, Fibrocell Technologies, Abeona Therapeutics, and Wings (formerly ProQR).

SOURCES: Gorell E et al. EB 2020, Poster 124; Marinkovich MP et al. EB 2020, Poster 123; Marinkovich MP et al. EB 2020, Poster 52.

LONDON – Advances in cell- and gene-based research are paving the way towards the possibility of a cure for the rare inherited skin disorder, recessive dystrophic epidermolysis bullosa (RDEB), several experts said at the first EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA).

Sara Freeman/MDedge News

“I think there is a palpable sense that we are close to some breakthroughs for EB,” which may include “a cure for this intractable disease,” said Jouni Uitto, MD, PhD, in welcoming delegates to the meeting, held in January 2020.

Dr. Uitto, professor of dermatology and cutaneous biology, and biochemistry and molecular biology, at Sidney Kimmel Medical College, Philadelphia, said that the “breadth of academia-based basic science has been tremendous over the past 3 decades. We can now identify 21 different genes harboring mutations associated with different EB phenotypes, and we have a pretty good understanding how those mutations actually explain the phenotypic spectrum of different forms of EB.”

Importantly, “there are now perhaps as many as a dozen different clinical trials that are in the early stages of trying to find a permanent cure for this disease,” Dr. Uitto said, with some that are looking at fixing the underlying defect once and for all, or at the very least, counteracting subsequent complications. “The spectrum varies from attempting to enhance wound healing to gene repair, gene replacement, protein replacement therapies, cell-based therapies. There is a whole spectrum of often complementary approaches that we believe will lead to a cure and treatment for this disease. We look forward to developing therapies which will be helpful to the benefit of all the patients with EB,” said Dr. Uitto, who is also chair of the department of dermatology and cutaneous biology at Sidney Kimmel Medical College.
 

EB research is gathering ‘momentum’

John McGrath, MD, professor of molecular dermatology, King’s College, London, chaired a session on the latest in cell manipulation research and made the following comment: “A few years ago, we were making progress, but we were chatting about a lot of the same things; but now, suddenly there seems to be momentum, re-energy, rediscovery, real progress.”

Dr. McGrath noted that gene and cell research, and preclinical development, were culminating in clinical trials and potentially products that could change the way clinicians thought about managing patients with EB. “That prospect of getting closer and closer to real treatments, and maybe even a cure” is becoming more of a reality, he said.

Dr. McGrath is also head of the genetic skin disease group at King’s College London, and an honorary consultant dermatologist at St. John’s Institute of Dermatology, part of the Guy’s and St. Thomas’ NHS Foundation Trust in London. He has been a principal investigator for clinical trials of fibroblast cell therapy and allogeneic intravenous mesenchymal stromal cells (MSCs) therapy.

“It has been a joy for me to see the benefits of those clinical trials. There is nothing like it as an investigator when you see an intervention make a difference to a patient,” Dr. McGrath said. “For me, it was just a real eye opener when I saw the skin changes in a child that received intravenous allogeneic MSCs. The skin changed dramatically, it went from red and inflamed to calm and pink, [giving a] first glimpse into something that might be reversible, treatable, not just papering over the cracks.”
 

Correcting the genetic defect

The most severe form of RDEB is caused by mutations in COL7A1, the gene for collagen type 7 (COL7), the major connective component of the skin, anchoring the epidermis to the dermis. Its absence results in skin that can be so fragile it has been likened to the wings of a butterfly and results in severe blistering after very little trauma.

There is a lot of research on how to correct the underlying genetic defect, either by replacing COL7A1 entirely, repairing the gene, or editing the gene so that COL 7 can be produced in situ and prevent the formation of wounds and heal those that might already be present.

“The excitement is obvious,” said Jakub Tolar, MD, PhD, professor in the department of pediatrics, blood and marrow transplantation, and dean of the University of Minnesota Medical School, Minneapolis, who chaired a session on gene and gene manipulation therapies. “If one can go and correct that information, it follows that everything else is going to be okay,” he said. “Only it’s not. I think that it’s pretty clear that more than gene correction is needed.”

Some of the approaches to replace the faulty gene discussed at the meeting involved taking skin biopsy samples from a healthy area of skin from a patient with RDEB, isolating specific skin cells (fibroblasts, keratinocytes, or both), transferring a healthy copy of the COL7A1 gene into those cells – then expanding the population to form sheets of cells that can be grafted onto the wounds of the same patient.

Clinical trials of gene therapy for RDEB

Clinical trials with these novel gene-corrected, tissue-engineered grafts have already started, including EBGraft, a phase 1/2 open, nonrandomized, proof-of-concept trial using genetically corrected sheets of fibroblasts and keratinocytes, conducted by Alain Hovnanian, MD, PhD, Necker-Enfants Malades Hospital in Paris, and associates.

Then there is the phase 3 VIITAL trial being conducted at Stanford (Calif.) University by Jean Tang, MD, PhD, and colleagues. Recruitment in this open trial, which will enroll 10-15 patients with RDEB, has just started. The aim of the study is to investigate the efficacy and safety of EB-101, an autologous cell therapy that corrects COL7A1 in keratinocytes.

Positive findings from a phase 1/2 study with EB-101 were presented in a poster at the meeting by Emily Gorell, DO, a postdoctoral medical fellow in dermatology, at Stanford University and her associates. The trial included seven patients with RDEB who were treated and followed for 3 to 6 years. Data from that study showed that there were no serious adverse events and 95% of patients’ wounds that were treated (36/38) were healed by at least 50%, based on an Investigator Global Assessment at 6 months. In comparison, none of the untreated wounds had healed by that time point. “There was evidence of C7 [collagen 7] restoration at 2 years in two participants,” and wound healing was associated with both reduced pain and itch, the investigators wrote in the poster.

Another approach to this so-called ‘ex-vivo’ gene therapy is to take the patient’s cells via a small skin biopsy, genetically modify them, expand the population of these modified cells, and then inject them back into the patient. This approach was described by Peter Marinkovich, MD, of the department of dermatology at Stanford University, during an oral presentation and in a poster at the meeting.

Dr. Marinkovich discussed the results of an ongoing phase 1/2 study in which six subjects with RDEB – five adults and one child ­­– were treated intradermally with genetically modified fibroblasts in a preparation currently known as FCX-007.

“Before we had to graft the cells, take the patients into the OR [operating room], with the risks of general anesthesia, but here we don’t have to take the patients to the OR, we just take them into the hospital for a day, inject their wounds and then send them on their way,” Dr. Marinkovich said. Interim findings show that the patients have tolerated the therapy very well up to 52 weeks, he noted.

A greater percentage of wounds were healed by more than 50% following treatment with FCX-007 than those left untreated at weeks 4 (80% versus 20%), 12 (90% versus 44%), 25 (75% versus 50%), and 52 (83% versus 33%).

These results have been used to inform the design of the upcoming phase 3 study, DEFI-RDEB. The multicenter intrapatient randomized, controlled, open-label study is evaluating FCX-007 in the treatment of persistent nonhealing wounds in about 20 people with RDEB.
 

The promise of ‘off-the-shelf’ topical gene therapy

Another study Dr. Marinkovich is involved with is a phase 1/2 study of beremagene geperpavec (B-VEC), an “in-vivo” gene therapy. B-VEC is a topically administered therapy containing a replication-deficient, nonintegrating viral vector that contains two functional COL7A1 genes. The concept is that, when applied directly onto the skin, the virus gets into the skin and carries with it the healthy gene copies; these get taken up by the skin cells, which then produce COL7.

Initially, two patients with generalized severe RDEB were studied. B-VEC was applied to one of two wounds and a placebo to the other wound in each patient. Another four patients were then enrolled and studied for 3 months. Nine of 10 wounds closed completely after initial administration of B-VEC, with an average time to 100% wound closure of 17.4 days. The average duration of wound closure has been 113 days so far.
 

“One chronic wound that was originally open for over 4 years closed completely following B-VEC readministration. The wound has remained closed for 100 days,” Dr. Marinkovich and associates reported in a poster at the meeting. A postimaging study showed that COL7 was being produced from 48 hours to up to 90 days later.

“I’m really excited about this type of therapy,” Dr. Marinkovich said during an oral presentation. Unlike the ex-vivo gene therapy approach, where each patient’s cells have to be taken by a biopsy, altered, engineered, and expanded, which takes specialized facilities that can vary by country and location, this in-vivo gene therapy can be considered an “off-the shelf” treatment that can be shipped all over the world and could reach many patients. “It’s another weapon in our armamentarium against this deadly disease that we are all fighting against together,” Dr. Marinkovich added.

EBGRAFT is supported by Cure EB. The VIITAL trial is sponsored by Abeona Therapeutics. The phase 1/2 trials of EB-101 were funded by grants from the National Institutes of Health, EB Research Partnership, EM Medical Research Foundation, and Abeona Therapeutics. The FCX-007 phase 1/2 study was supported by Fibrocell Technologies. The upcoming phase 3 will be funded by Fibrocell Technologies in collaboration with Castle Creek Pharmaceuticals. The B-VEC study is supported by Krystal Biotech.

Dr. Uitto and Dr. McGrath had no potential conflicts of interest to report. Dr. Tolar has received funding from the National Institutes of Health, various EB charities and the Richard M. Schulze Family Foundation (RMSFF). He disclosed receiving honoraria or consultation fees from Ticeba/RHEACELL GmbH and Taiga Biosciences. Dr. Marinkovich disclosed being an investigator working on RDEB-related research projects in collaboration with Krystal Biotech, Fibrocell Technologies, Abeona Therapeutics, and Wings (formerly ProQR).

SOURCES: Gorell E et al. EB 2020, Poster 124; Marinkovich MP et al. EB 2020, Poster 123; Marinkovich MP et al. EB 2020, Poster 52.

LONDON – Advances in cell- and gene-based research are paving the way towards the possibility of a cure for the rare inherited skin disorder, recessive dystrophic epidermolysis bullosa (RDEB), several experts said at the first EB World Congress, organized by the Dystrophic Epidermolysis Bullosa Association (DEBRA).

Sara Freeman/MDedge News

“I think there is a palpable sense that we are close to some breakthroughs for EB,” which may include “a cure for this intractable disease,” said Jouni Uitto, MD, PhD, in welcoming delegates to the meeting, held in January 2020.

Dr. Uitto, professor of dermatology and cutaneous biology, and biochemistry and molecular biology, at Sidney Kimmel Medical College, Philadelphia, said that the “breadth of academia-based basic science has been tremendous over the past 3 decades. We can now identify 21 different genes harboring mutations associated with different EB phenotypes, and we have a pretty good understanding how those mutations actually explain the phenotypic spectrum of different forms of EB.”

Importantly, “there are now perhaps as many as a dozen different clinical trials that are in the early stages of trying to find a permanent cure for this disease,” Dr. Uitto said, with some that are looking at fixing the underlying defect once and for all, or at the very least, counteracting subsequent complications. “The spectrum varies from attempting to enhance wound healing to gene repair, gene replacement, protein replacement therapies, cell-based therapies. There is a whole spectrum of often complementary approaches that we believe will lead to a cure and treatment for this disease. We look forward to developing therapies which will be helpful to the benefit of all the patients with EB,” said Dr. Uitto, who is also chair of the department of dermatology and cutaneous biology at Sidney Kimmel Medical College.
 

EB research is gathering ‘momentum’

John McGrath, MD, professor of molecular dermatology, King’s College, London, chaired a session on the latest in cell manipulation research and made the following comment: “A few years ago, we were making progress, but we were chatting about a lot of the same things; but now, suddenly there seems to be momentum, re-energy, rediscovery, real progress.”

Dr. McGrath noted that gene and cell research, and preclinical development, were culminating in clinical trials and potentially products that could change the way clinicians thought about managing patients with EB. “That prospect of getting closer and closer to real treatments, and maybe even a cure” is becoming more of a reality, he said.

Dr. McGrath is also head of the genetic skin disease group at King’s College London, and an honorary consultant dermatologist at St. John’s Institute of Dermatology, part of the Guy’s and St. Thomas’ NHS Foundation Trust in London. He has been a principal investigator for clinical trials of fibroblast cell therapy and allogeneic intravenous mesenchymal stromal cells (MSCs) therapy.

“It has been a joy for me to see the benefits of those clinical trials. There is nothing like it as an investigator when you see an intervention make a difference to a patient,” Dr. McGrath said. “For me, it was just a real eye opener when I saw the skin changes in a child that received intravenous allogeneic MSCs. The skin changed dramatically, it went from red and inflamed to calm and pink, [giving a] first glimpse into something that might be reversible, treatable, not just papering over the cracks.”
 

Correcting the genetic defect

The most severe form of RDEB is caused by mutations in COL7A1, the gene for collagen type 7 (COL7), the major connective component of the skin, anchoring the epidermis to the dermis. Its absence results in skin that can be so fragile it has been likened to the wings of a butterfly and results in severe blistering after very little trauma.

There is a lot of research on how to correct the underlying genetic defect, either by replacing COL7A1 entirely, repairing the gene, or editing the gene so that COL 7 can be produced in situ and prevent the formation of wounds and heal those that might already be present.

“The excitement is obvious,” said Jakub Tolar, MD, PhD, professor in the department of pediatrics, blood and marrow transplantation, and dean of the University of Minnesota Medical School, Minneapolis, who chaired a session on gene and gene manipulation therapies. “If one can go and correct that information, it follows that everything else is going to be okay,” he said. “Only it’s not. I think that it’s pretty clear that more than gene correction is needed.”

Some of the approaches to replace the faulty gene discussed at the meeting involved taking skin biopsy samples from a healthy area of skin from a patient with RDEB, isolating specific skin cells (fibroblasts, keratinocytes, or both), transferring a healthy copy of the COL7A1 gene into those cells – then expanding the population to form sheets of cells that can be grafted onto the wounds of the same patient.

Clinical trials of gene therapy for RDEB

Clinical trials with these novel gene-corrected, tissue-engineered grafts have already started, including EBGraft, a phase 1/2 open, nonrandomized, proof-of-concept trial using genetically corrected sheets of fibroblasts and keratinocytes, conducted by Alain Hovnanian, MD, PhD, Necker-Enfants Malades Hospital in Paris, and associates.

Then there is the phase 3 VIITAL trial being conducted at Stanford (Calif.) University by Jean Tang, MD, PhD, and colleagues. Recruitment in this open trial, which will enroll 10-15 patients with RDEB, has just started. The aim of the study is to investigate the efficacy and safety of EB-101, an autologous cell therapy that corrects COL7A1 in keratinocytes.

Positive findings from a phase 1/2 study with EB-101 were presented in a poster at the meeting by Emily Gorell, DO, a postdoctoral medical fellow in dermatology, at Stanford University and her associates. The trial included seven patients with RDEB who were treated and followed for 3 to 6 years. Data from that study showed that there were no serious adverse events and 95% of patients’ wounds that were treated (36/38) were healed by at least 50%, based on an Investigator Global Assessment at 6 months. In comparison, none of the untreated wounds had healed by that time point. “There was evidence of C7 [collagen 7] restoration at 2 years in two participants,” and wound healing was associated with both reduced pain and itch, the investigators wrote in the poster.

Another approach to this so-called ‘ex-vivo’ gene therapy is to take the patient’s cells via a small skin biopsy, genetically modify them, expand the population of these modified cells, and then inject them back into the patient. This approach was described by Peter Marinkovich, MD, of the department of dermatology at Stanford University, during an oral presentation and in a poster at the meeting.

Dr. Marinkovich discussed the results of an ongoing phase 1/2 study in which six subjects with RDEB – five adults and one child ­­– were treated intradermally with genetically modified fibroblasts in a preparation currently known as FCX-007.

“Before we had to graft the cells, take the patients into the OR [operating room], with the risks of general anesthesia, but here we don’t have to take the patients to the OR, we just take them into the hospital for a day, inject their wounds and then send them on their way,” Dr. Marinkovich said. Interim findings show that the patients have tolerated the therapy very well up to 52 weeks, he noted.

A greater percentage of wounds were healed by more than 50% following treatment with FCX-007 than those left untreated at weeks 4 (80% versus 20%), 12 (90% versus 44%), 25 (75% versus 50%), and 52 (83% versus 33%).

These results have been used to inform the design of the upcoming phase 3 study, DEFI-RDEB. The multicenter intrapatient randomized, controlled, open-label study is evaluating FCX-007 in the treatment of persistent nonhealing wounds in about 20 people with RDEB.
 

The promise of ‘off-the-shelf’ topical gene therapy

Another study Dr. Marinkovich is involved with is a phase 1/2 study of beremagene geperpavec (B-VEC), an “in-vivo” gene therapy. B-VEC is a topically administered therapy containing a replication-deficient, nonintegrating viral vector that contains two functional COL7A1 genes. The concept is that, when applied directly onto the skin, the virus gets into the skin and carries with it the healthy gene copies; these get taken up by the skin cells, which then produce COL7.

Initially, two patients with generalized severe RDEB were studied. B-VEC was applied to one of two wounds and a placebo to the other wound in each patient. Another four patients were then enrolled and studied for 3 months. Nine of 10 wounds closed completely after initial administration of B-VEC, with an average time to 100% wound closure of 17.4 days. The average duration of wound closure has been 113 days so far.
 

“One chronic wound that was originally open for over 4 years closed completely following B-VEC readministration. The wound has remained closed for 100 days,” Dr. Marinkovich and associates reported in a poster at the meeting. A postimaging study showed that COL7 was being produced from 48 hours to up to 90 days later.

“I’m really excited about this type of therapy,” Dr. Marinkovich said during an oral presentation. Unlike the ex-vivo gene therapy approach, where each patient’s cells have to be taken by a biopsy, altered, engineered, and expanded, which takes specialized facilities that can vary by country and location, this in-vivo gene therapy can be considered an “off-the shelf” treatment that can be shipped all over the world and could reach many patients. “It’s another weapon in our armamentarium against this deadly disease that we are all fighting against together,” Dr. Marinkovich added.

EBGRAFT is supported by Cure EB. The VIITAL trial is sponsored by Abeona Therapeutics. The phase 1/2 trials of EB-101 were funded by grants from the National Institutes of Health, EB Research Partnership, EM Medical Research Foundation, and Abeona Therapeutics. The FCX-007 phase 1/2 study was supported by Fibrocell Technologies. The upcoming phase 3 will be funded by Fibrocell Technologies in collaboration with Castle Creek Pharmaceuticals. The B-VEC study is supported by Krystal Biotech.

Dr. Uitto and Dr. McGrath had no potential conflicts of interest to report. Dr. Tolar has received funding from the National Institutes of Health, various EB charities and the Richard M. Schulze Family Foundation (RMSFF). He disclosed receiving honoraria or consultation fees from Ticeba/RHEACELL GmbH and Taiga Biosciences. Dr. Marinkovich disclosed being an investigator working on RDEB-related research projects in collaboration with Krystal Biotech, Fibrocell Technologies, Abeona Therapeutics, and Wings (formerly ProQR).

SOURCES: Gorell E et al. EB 2020, Poster 124; Marinkovich MP et al. EB 2020, Poster 123; Marinkovich MP et al. EB 2020, Poster 52.

Starting treatment for relapsing-remitting multiple sclerosis (MS) with high-efficacy therapy (HET) is associated with lower long-term disability compared with a step-wise increase to reach more aggressive treatment later, new research suggests. However, there is a trade-off: In this study of nearly 300 patients, those treated with initial HET experienced more disease activity in the first 2 years than other participants.

The HET benefit emerged between 2 and 10 years into the study. For example, the mean Expanded Disability Status Scale (EDSS) scores were significantly lower at 6 years in the early, aggressive treatment group than in the later HET group (2.4 vs 3.3, respectively).

“Treatment decisions made around the time of diagnosis will affect long-term outcomes,” said lead author Anna He, MBBS, currently with the Department of Clinical Neuroscience, Karolinska Institute, Stockholm, and the UCL Queen Square Institute of Neurology in London.

Using the most efficacious disease-modifying therapies from the start minimizes disability, “whereas those patients escalating to high-efficacy disease-modifying therapies later do not seem to catch up to those who commenced earlier,” Dr. He said.

“Patients and clinicians should be aware of this when choosing treatment in early MS,” she added.

This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
 

Patient-centered outcome

Instead of measures of brain volume, lesion count, serum neurofilament, or other biomarkers that are mainly of interest to clinicians and scientists, “the main outcome of interest to our patients is their disability,” Dr. He said. “The first question they ask at diagnosis is usually along the lines of: ‘What will my disability be in 10 years?’ ”

“This is what matters to patients and is fundamentally what motivated this study,” Dr. He added.

The investigators searched international MS registries for patients with relapsing-remitting MS starting HET, which included rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab.

They compared 117 participants who started HET within the first 2 years of clinical disease onset (the early group) with 181 participants who started HET after more than 4 years (the late group). All were followed for a median of 7.4 years (range, 6.4 to 8.6 years).

Difference in EDSS scores from baseline was the primary outcome. Both cohorts began the study with a mean EDSS score of 2.4, but between-group differences were significant at 10 years.

The secondary outcome of cumulative hazard of disability progression was higher in the early-treatment group from baseline to 2 years. Between the period of 2 and 10 years, the inverse was true.

In patients with highly active MS, “early exposure to high efficacy therapies is recommended,” Dr. He noted.

“We can already affect our patients’ lives enormously by utilizing our current toolbox in the most optimal way. It is our task to optimize this in a data-driven manner.”

Going forward, Dr. He plans to look at other outcomes, including patient-reported quality of life and health economic measures, and to take a different approach to future research.

Rather than assess MS outcomes from a disease-biology perspective, “I will be looking at MS outcomes from the perspective of its key stakeholders—the individual and society,” and the factors that influence them, Dr. He said.
 

Confirmatory evidence?

Commenting on the findings, Robert Gross, MD, a neurologist at the Rocky Mountain MS Center at the University of Colorado Denver in Aurora, said it is “hard to believe we are still having this debate” about earlier versus later HET.

There are now “numerous studies, including head-to-head trials and large cohort studies, showing superiority of highly efficacious agents to older disease-modifying therapies of more limited efficacy, as well as better outcomes with early versus delayed use of high-efficacy therapy,” said Dr. Gross, who was not involved with the current research.

“This study further adds to the evidence that we should be preferentially starting folks with relapsing-remitting MS right away on high-efficacy therapy, rather than waiting for relapses and disease progression to occur,” he added.

Drs. He and Gross have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Starting treatment for relapsing-remitting multiple sclerosis (MS) with high-efficacy therapy (HET) is associated with lower long-term disability compared with a step-wise increase to reach more aggressive treatment later, new research suggests. However, there is a trade-off: In this study of nearly 300 patients, those treated with initial HET experienced more disease activity in the first 2 years than other participants.

The HET benefit emerged between 2 and 10 years into the study. For example, the mean Expanded Disability Status Scale (EDSS) scores were significantly lower at 6 years in the early, aggressive treatment group than in the later HET group (2.4 vs 3.3, respectively).

“Treatment decisions made around the time of diagnosis will affect long-term outcomes,” said lead author Anna He, MBBS, currently with the Department of Clinical Neuroscience, Karolinska Institute, Stockholm, and the UCL Queen Square Institute of Neurology in London.

Using the most efficacious disease-modifying therapies from the start minimizes disability, “whereas those patients escalating to high-efficacy disease-modifying therapies later do not seem to catch up to those who commenced earlier,” Dr. He said.

“Patients and clinicians should be aware of this when choosing treatment in early MS,” she added.

This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
 

Patient-centered outcome

Instead of measures of brain volume, lesion count, serum neurofilament, or other biomarkers that are mainly of interest to clinicians and scientists, “the main outcome of interest to our patients is their disability,” Dr. He said. “The first question they ask at diagnosis is usually along the lines of: ‘What will my disability be in 10 years?’ ”

“This is what matters to patients and is fundamentally what motivated this study,” Dr. He added.

The investigators searched international MS registries for patients with relapsing-remitting MS starting HET, which included rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab.

They compared 117 participants who started HET within the first 2 years of clinical disease onset (the early group) with 181 participants who started HET after more than 4 years (the late group). All were followed for a median of 7.4 years (range, 6.4 to 8.6 years).

Difference in EDSS scores from baseline was the primary outcome. Both cohorts began the study with a mean EDSS score of 2.4, but between-group differences were significant at 10 years.

The secondary outcome of cumulative hazard of disability progression was higher in the early-treatment group from baseline to 2 years. Between the period of 2 and 10 years, the inverse was true.

In patients with highly active MS, “early exposure to high efficacy therapies is recommended,” Dr. He noted.

“We can already affect our patients’ lives enormously by utilizing our current toolbox in the most optimal way. It is our task to optimize this in a data-driven manner.”

Going forward, Dr. He plans to look at other outcomes, including patient-reported quality of life and health economic measures, and to take a different approach to future research.

Rather than assess MS outcomes from a disease-biology perspective, “I will be looking at MS outcomes from the perspective of its key stakeholders—the individual and society,” and the factors that influence them, Dr. He said.
 

Confirmatory evidence?

Commenting on the findings, Robert Gross, MD, a neurologist at the Rocky Mountain MS Center at the University of Colorado Denver in Aurora, said it is “hard to believe we are still having this debate” about earlier versus later HET.

There are now “numerous studies, including head-to-head trials and large cohort studies, showing superiority of highly efficacious agents to older disease-modifying therapies of more limited efficacy, as well as better outcomes with early versus delayed use of high-efficacy therapy,” said Dr. Gross, who was not involved with the current research.

“This study further adds to the evidence that we should be preferentially starting folks with relapsing-remitting MS right away on high-efficacy therapy, rather than waiting for relapses and disease progression to occur,” he added.

Drs. He and Gross have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Starting treatment for relapsing-remitting multiple sclerosis (MS) with high-efficacy therapy (HET) is associated with lower long-term disability compared with a step-wise increase to reach more aggressive treatment later, new research suggests. However, there is a trade-off: In this study of nearly 300 patients, those treated with initial HET experienced more disease activity in the first 2 years than other participants.

The HET benefit emerged between 2 and 10 years into the study. For example, the mean Expanded Disability Status Scale (EDSS) scores were significantly lower at 6 years in the early, aggressive treatment group than in the later HET group (2.4 vs 3.3, respectively).

“Treatment decisions made around the time of diagnosis will affect long-term outcomes,” said lead author Anna He, MBBS, currently with the Department of Clinical Neuroscience, Karolinska Institute, Stockholm, and the UCL Queen Square Institute of Neurology in London.

Using the most efficacious disease-modifying therapies from the start minimizes disability, “whereas those patients escalating to high-efficacy disease-modifying therapies later do not seem to catch up to those who commenced earlier,” Dr. He said.

“Patients and clinicians should be aware of this when choosing treatment in early MS,” she added.

This research was presented online as part of the 2020 American Academy of Neurology Science Highlights.
 

Patient-centered outcome

Instead of measures of brain volume, lesion count, serum neurofilament, or other biomarkers that are mainly of interest to clinicians and scientists, “the main outcome of interest to our patients is their disability,” Dr. He said. “The first question they ask at diagnosis is usually along the lines of: ‘What will my disability be in 10 years?’ ”

“This is what matters to patients and is fundamentally what motivated this study,” Dr. He added.

The investigators searched international MS registries for patients with relapsing-remitting MS starting HET, which included rituximab, ocrelizumab, mitoxantrone, alemtuzumab, or natalizumab.

They compared 117 participants who started HET within the first 2 years of clinical disease onset (the early group) with 181 participants who started HET after more than 4 years (the late group). All were followed for a median of 7.4 years (range, 6.4 to 8.6 years).

Difference in EDSS scores from baseline was the primary outcome. Both cohorts began the study with a mean EDSS score of 2.4, but between-group differences were significant at 10 years.

The secondary outcome of cumulative hazard of disability progression was higher in the early-treatment group from baseline to 2 years. Between the period of 2 and 10 years, the inverse was true.

In patients with highly active MS, “early exposure to high efficacy therapies is recommended,” Dr. He noted.

“We can already affect our patients’ lives enormously by utilizing our current toolbox in the most optimal way. It is our task to optimize this in a data-driven manner.”

Going forward, Dr. He plans to look at other outcomes, including patient-reported quality of life and health economic measures, and to take a different approach to future research.

Rather than assess MS outcomes from a disease-biology perspective, “I will be looking at MS outcomes from the perspective of its key stakeholders—the individual and society,” and the factors that influence them, Dr. He said.
 

Confirmatory evidence?

Commenting on the findings, Robert Gross, MD, a neurologist at the Rocky Mountain MS Center at the University of Colorado Denver in Aurora, said it is “hard to believe we are still having this debate” about earlier versus later HET.

There are now “numerous studies, including head-to-head trials and large cohort studies, showing superiority of highly efficacious agents to older disease-modifying therapies of more limited efficacy, as well as better outcomes with early versus delayed use of high-efficacy therapy,” said Dr. Gross, who was not involved with the current research.

“This study further adds to the evidence that we should be preferentially starting folks with relapsing-remitting MS right away on high-efficacy therapy, rather than waiting for relapses and disease progression to occur,” he added.

Drs. He and Gross have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Suicide prevention is a high priority for the National Institute of Mental Health (NIMH) and will be one specific area of focus in the federal agency’s 5-year strategic plan that’s set to be released soon, according to Director Joshua A. Gordon, MD, PhD.

The agency is updating its strategic plan to guide research efforts and priorities over the next 5 years, Dr. Gordon said at the annual meeting of the American Psychiatric Association, which was held as a virtual live event.

That strategic plan, which will cover a broader range of priorities, is scheduled to be published “within the next few weeks,” Dr. Gordon said.

Closing the research gap in suicide prevention is a high priority for NIMH, Dr. Gordon said, especially in light of the age-adjusted U.S. suicide rates that have been increasing consistently in men and women for the past 2 decades, as data from the Centers for Disease Control and Prevention show.

“And although we must acknowledge we don’t quite know why, there is lots of speculation and a little bit of data, but not really conclusive stuff,” he said. “We also recognize that, in addition to trying to understand why, we need to try interventions that will reverse this increase.”

Identifying those at risk for suicide is a key focus of research, according to Dr. Gordon, who highlighted results of the ED-SAFE study, describing it as a “mainstay” of approaches to reducing risk through intervention.

In that recent study, an emergency department (ED)-based suicide prevention intervention cut total suicide attempts by 30%, compared with treatment as usual (JAMA Psychiatry. 2017 Jun;74[6]:563-70). That intervention included universal suicide risk screening plus secondary screening by the physician in the ED, discharge resources, and post-ED telephone calls intended to reduce suicide risk.

The ED-SAFE study is an example of taking the lessons learned in psychiatry and bringing them to a “broader swath” of individuals who might be at risk, said Dr. Gordon, a research psychiatrist who was a faculty member at Columbia University, New York, prior to being appointed director of NIMH.

“Of course, we’d like to do this not just in emergency rooms, but in primary care offices as well,” said Dr. Gordon, who noted that ongoing studies are aimed at demonstrating similar results in primary care patient populations, including adults and children.

Beyond this ask-and-you-will-find approach, there are “more modern” methods that involve applying predictive modeling and analytics to large data sets, identifying individuals who might not otherwise be suspected as being at risk and getting them into treatment, according to the director.

In one recent report, investigators said a risk prediction method using a machine learning approach on 3.7 million patients across five U.S. health systems was able to detect 38% of suicide attempts a mean of 2.1 years in advance (JAMA Netw Open. 2020 Mar 25;3[3]:3201262).

Machine learning might be able to detect the risk of suicidal behavior in unselected patients, based on these findings and might facilitate development of clinical decision support tools for risk reduction, the investigators said.

“We’re now studying how to implement these algorithms in real-world practice,” Dr. Gordon said.

Beyond identification, new interventions are needed for suicide reduction, he added, calling ketamine infusion “one of the most promising” recent developments that may help reduce suicidal ideation.

“You can take someone with high levels of suicidal ideation and treat them with ketamine, and within an hour that ideation is gone,” he said. “So the question is, can we use this in real-world practice to reduce suicide risk?”

The NIMH focus on suicide prevention will intensify the agency’s focus on recent initiatives in detecting and preventing suicide behavior and ideation in the juvenile justice system, applied research toward the goal of zero-suicide health care systems, and looking at the safety and feasibility of rapid-acting interventions for severe suicide risk, among others, according to Dr. Gordon, who became director of the agency in 2016.

“We have a number of initiatives aimed at taking what we’ve learned over the past few years, and helping that have a significant public health impact,” Dr. Gordon said.

Dr. Gordon reported no disclosures.

SOURCE: Gordon JA. APA 2020, Abstract.

Suicide prevention is a high priority for the National Institute of Mental Health (NIMH) and will be one specific area of focus in the federal agency’s 5-year strategic plan that’s set to be released soon, according to Director Joshua A. Gordon, MD, PhD.

The agency is updating its strategic plan to guide research efforts and priorities over the next 5 years, Dr. Gordon said at the annual meeting of the American Psychiatric Association, which was held as a virtual live event.

That strategic plan, which will cover a broader range of priorities, is scheduled to be published “within the next few weeks,” Dr. Gordon said.

Closing the research gap in suicide prevention is a high priority for NIMH, Dr. Gordon said, especially in light of the age-adjusted U.S. suicide rates that have been increasing consistently in men and women for the past 2 decades, as data from the Centers for Disease Control and Prevention show.

“And although we must acknowledge we don’t quite know why, there is lots of speculation and a little bit of data, but not really conclusive stuff,” he said. “We also recognize that, in addition to trying to understand why, we need to try interventions that will reverse this increase.”

Identifying those at risk for suicide is a key focus of research, according to Dr. Gordon, who highlighted results of the ED-SAFE study, describing it as a “mainstay” of approaches to reducing risk through intervention.

In that recent study, an emergency department (ED)-based suicide prevention intervention cut total suicide attempts by 30%, compared with treatment as usual (JAMA Psychiatry. 2017 Jun;74[6]:563-70). That intervention included universal suicide risk screening plus secondary screening by the physician in the ED, discharge resources, and post-ED telephone calls intended to reduce suicide risk.

The ED-SAFE study is an example of taking the lessons learned in psychiatry and bringing them to a “broader swath” of individuals who might be at risk, said Dr. Gordon, a research psychiatrist who was a faculty member at Columbia University, New York, prior to being appointed director of NIMH.

“Of course, we’d like to do this not just in emergency rooms, but in primary care offices as well,” said Dr. Gordon, who noted that ongoing studies are aimed at demonstrating similar results in primary care patient populations, including adults and children.

Beyond this ask-and-you-will-find approach, there are “more modern” methods that involve applying predictive modeling and analytics to large data sets, identifying individuals who might not otherwise be suspected as being at risk and getting them into treatment, according to the director.

In one recent report, investigators said a risk prediction method using a machine learning approach on 3.7 million patients across five U.S. health systems was able to detect 38% of suicide attempts a mean of 2.1 years in advance (JAMA Netw Open. 2020 Mar 25;3[3]:3201262).

Machine learning might be able to detect the risk of suicidal behavior in unselected patients, based on these findings and might facilitate development of clinical decision support tools for risk reduction, the investigators said.

“We’re now studying how to implement these algorithms in real-world practice,” Dr. Gordon said.

Beyond identification, new interventions are needed for suicide reduction, he added, calling ketamine infusion “one of the most promising” recent developments that may help reduce suicidal ideation.

“You can take someone with high levels of suicidal ideation and treat them with ketamine, and within an hour that ideation is gone,” he said. “So the question is, can we use this in real-world practice to reduce suicide risk?”

The NIMH focus on suicide prevention will intensify the agency’s focus on recent initiatives in detecting and preventing suicide behavior and ideation in the juvenile justice system, applied research toward the goal of zero-suicide health care systems, and looking at the safety and feasibility of rapid-acting interventions for severe suicide risk, among others, according to Dr. Gordon, who became director of the agency in 2016.

“We have a number of initiatives aimed at taking what we’ve learned over the past few years, and helping that have a significant public health impact,” Dr. Gordon said.

Dr. Gordon reported no disclosures.

SOURCE: Gordon JA. APA 2020, Abstract.

Suicide prevention is a high priority for the National Institute of Mental Health (NIMH) and will be one specific area of focus in the federal agency’s 5-year strategic plan that’s set to be released soon, according to Director Joshua A. Gordon, MD, PhD.

The agency is updating its strategic plan to guide research efforts and priorities over the next 5 years, Dr. Gordon said at the annual meeting of the American Psychiatric Association, which was held as a virtual live event.

That strategic plan, which will cover a broader range of priorities, is scheduled to be published “within the next few weeks,” Dr. Gordon said.

Closing the research gap in suicide prevention is a high priority for NIMH, Dr. Gordon said, especially in light of the age-adjusted U.S. suicide rates that have been increasing consistently in men and women for the past 2 decades, as data from the Centers for Disease Control and Prevention show.

“And although we must acknowledge we don’t quite know why, there is lots of speculation and a little bit of data, but not really conclusive stuff,” he said. “We also recognize that, in addition to trying to understand why, we need to try interventions that will reverse this increase.”

Identifying those at risk for suicide is a key focus of research, according to Dr. Gordon, who highlighted results of the ED-SAFE study, describing it as a “mainstay” of approaches to reducing risk through intervention.

In that recent study, an emergency department (ED)-based suicide prevention intervention cut total suicide attempts by 30%, compared with treatment as usual (JAMA Psychiatry. 2017 Jun;74[6]:563-70). That intervention included universal suicide risk screening plus secondary screening by the physician in the ED, discharge resources, and post-ED telephone calls intended to reduce suicide risk.

The ED-SAFE study is an example of taking the lessons learned in psychiatry and bringing them to a “broader swath” of individuals who might be at risk, said Dr. Gordon, a research psychiatrist who was a faculty member at Columbia University, New York, prior to being appointed director of NIMH.

“Of course, we’d like to do this not just in emergency rooms, but in primary care offices as well,” said Dr. Gordon, who noted that ongoing studies are aimed at demonstrating similar results in primary care patient populations, including adults and children.

Beyond this ask-and-you-will-find approach, there are “more modern” methods that involve applying predictive modeling and analytics to large data sets, identifying individuals who might not otherwise be suspected as being at risk and getting them into treatment, according to the director.

In one recent report, investigators said a risk prediction method using a machine learning approach on 3.7 million patients across five U.S. health systems was able to detect 38% of suicide attempts a mean of 2.1 years in advance (JAMA Netw Open. 2020 Mar 25;3[3]:3201262).

Machine learning might be able to detect the risk of suicidal behavior in unselected patients, based on these findings and might facilitate development of clinical decision support tools for risk reduction, the investigators said.

“We’re now studying how to implement these algorithms in real-world practice,” Dr. Gordon said.

Beyond identification, new interventions are needed for suicide reduction, he added, calling ketamine infusion “one of the most promising” recent developments that may help reduce suicidal ideation.

“You can take someone with high levels of suicidal ideation and treat them with ketamine, and within an hour that ideation is gone,” he said. “So the question is, can we use this in real-world practice to reduce suicide risk?”

The NIMH focus on suicide prevention will intensify the agency’s focus on recent initiatives in detecting and preventing suicide behavior and ideation in the juvenile justice system, applied research toward the goal of zero-suicide health care systems, and looking at the safety and feasibility of rapid-acting interventions for severe suicide risk, among others, according to Dr. Gordon, who became director of the agency in 2016.

“We have a number of initiatives aimed at taking what we’ve learned over the past few years, and helping that have a significant public health impact,” Dr. Gordon said.

Dr. Gordon reported no disclosures.

SOURCE: Gordon JA. APA 2020, Abstract.

The use of alcohol, tobacco products, and drugs by pregnant women is a substantial problem that may be more prevalent than previously thought, according to researcher Kimberly Yonkers, MD.

Higher levels of substance use during pregnancy means more negative impacts on maternal and fetal, neonatal, and child health. However, one bit of good news is that pregnant women still are less likely than nonpregnant women to engage in such behavior, said Dr. Yonkers, director of psychological medicine and the Center for Wellbeing of Women and Mothers at Yale University, New Haven, Conn.

“We need to capitalize on that and explore it, and try and figure out ways that women can maintain their well-being from pregnancy to the postnatal period,” Dr. Yonkers said in a featured presentation at the annual meeting of the American Psychiatric Association, which was held as a virtual live event.

Tobacco predominates among substances of concern used by pregnant women, with 11.6% reporting past-month use in 2018, according to the National Survey on Drug Use and Health, Dr. Yonkers said. Alcohol was next, with 9.9% of pregnant women reporting use in the past month, followed by drugs at 5.4%, of which marijuana was the most common.

Those numbers may jump much higher when focusing on substance use that’s biologically verified, she added, referring to a recent three-center cross-sectional study she and her colleagues published in Addiction (2019 Jun 19. doi: 10.1111/add.14651). In that study, alcohol use was as high as 18.9% among pregnant women who either had positive urine or self-reported use. Similarly, rates of nicotine or nicotine byproduct detected were 27% at one center in the study, and tetrahydrocannabinol reached 29.4% at that same center.

“These numbers are impressive,” Dr. Yonkers told attendees at the meeting. “So what we may be seeing in terms of the National Survey on Drug Use and Health, as valuable as it is, is in all likelihood it underestimates the use of substances in pregnancy.”

Substance use goes down in pregnancy as some women become more mindful of perinatal health, though unfortunately, that abstinence is offset by a dramatic rise in substance use in the 6-12 months’ post partum, research suggests.

Interestingly, big differences are found in both abstinence and relapse rates, with some data sets showing that, while alcohol is stopped fairly early, cigarettes are stopped much later, if at all.

On the postpartum side of the equation, relapse rates look similar for cigarettes, alcohol, and marijuana, but for some reason, cocaine relapse rates are much lower “That’s kind of nice, and we’d like to be able to understand what it is about this whole process that enabled that relative period of wellness,” Dr. Yonkers said.

Opioid use disorder is rising among pregnant women, just like it is in the general population, and 50% – or possibly even as high as 80% – of babies born to these women will experience neonatal opioid withdrawal, Dr. Yonkers said.

Maternal mortality in the United States increased by 34% from 2008 to 2016; while that’s a sobering statistic, Dr. Yonkers said, opioid-related maternal mortality doubled over that same time period.

“We really have to be mindful that we’re not just talking about taking care of kids and offspring, but we have to take care of moms – it’s really critical,” she said.

With the increasing legalization of cannabis, it’s expected that a lot more cannabis-exposed pregnancies will be seen in clinical practice, and some studies are starting to show an increase in prevalence in the preconception, prenatal, and postpartum period.

While some people feel that cannabis is benign, more data are needed, according to Dr. Yonkers, who said that cannabis and its metabolites cross the blood/placenta and blood/milk barriers, and that cannabinoid receptors are “very important” to fertility, implantation, and fetal development. One study recently published linked cannabis use in pregnancy to significant increases in preterm birth rates (JAMA. 2019 Jun 18;322[2]:145-52).

“We don’t really have a context for this, so we don’t really know what’s going to have an impact, and what’s not,” Dr. Yonkers said.

While both standard and novel treatments could help in the quest to achieve and maintain well-being in this unique patient population, Dr. Yonkers said that health equity and universal approaches to care might be needed to more comprehensively address the problem, which means taking a close look at how much money women have, the resources available to them, and where they live.

In many communities, eliminating inequalities in care will be critical to successfully addressing substance use issues in pregnant women, agreed Maureen Sayres Van Niel, MD, a specialist in women’s psychiatry in Boston and president of the Women’s Caucus of the APA.

“What we see is such a disparity in the delivery of care to women who are poor and living in communities where the socioeconomic and financial problems are very severe,” Dr. Van Niel said in an interview. “Unless we address these disparities, women will not be getting the kind of health care that they really need to have in the perinatal period.”

Dr. Yonkers reported a disclosure related to UpToDate.
 

The use of alcohol, tobacco products, and drugs by pregnant women is a substantial problem that may be more prevalent than previously thought, according to researcher Kimberly Yonkers, MD.

Higher levels of substance use during pregnancy means more negative impacts on maternal and fetal, neonatal, and child health. However, one bit of good news is that pregnant women still are less likely than nonpregnant women to engage in such behavior, said Dr. Yonkers, director of psychological medicine and the Center for Wellbeing of Women and Mothers at Yale University, New Haven, Conn.

“We need to capitalize on that and explore it, and try and figure out ways that women can maintain their well-being from pregnancy to the postnatal period,” Dr. Yonkers said in a featured presentation at the annual meeting of the American Psychiatric Association, which was held as a virtual live event.

Tobacco predominates among substances of concern used by pregnant women, with 11.6% reporting past-month use in 2018, according to the National Survey on Drug Use and Health, Dr. Yonkers said. Alcohol was next, with 9.9% of pregnant women reporting use in the past month, followed by drugs at 5.4%, of which marijuana was the most common.

Those numbers may jump much higher when focusing on substance use that’s biologically verified, she added, referring to a recent three-center cross-sectional study she and her colleagues published in Addiction (2019 Jun 19. doi: 10.1111/add.14651). In that study, alcohol use was as high as 18.9% among pregnant women who either had positive urine or self-reported use. Similarly, rates of nicotine or nicotine byproduct detected were 27% at one center in the study, and tetrahydrocannabinol reached 29.4% at that same center.

“These numbers are impressive,” Dr. Yonkers told attendees at the meeting. “So what we may be seeing in terms of the National Survey on Drug Use and Health, as valuable as it is, is in all likelihood it underestimates the use of substances in pregnancy.”

Substance use goes down in pregnancy as some women become more mindful of perinatal health, though unfortunately, that abstinence is offset by a dramatic rise in substance use in the 6-12 months’ post partum, research suggests.

Interestingly, big differences are found in both abstinence and relapse rates, with some data sets showing that, while alcohol is stopped fairly early, cigarettes are stopped much later, if at all.

On the postpartum side of the equation, relapse rates look similar for cigarettes, alcohol, and marijuana, but for some reason, cocaine relapse rates are much lower “That’s kind of nice, and we’d like to be able to understand what it is about this whole process that enabled that relative period of wellness,” Dr. Yonkers said.

Opioid use disorder is rising among pregnant women, just like it is in the general population, and 50% – or possibly even as high as 80% – of babies born to these women will experience neonatal opioid withdrawal, Dr. Yonkers said.

Maternal mortality in the United States increased by 34% from 2008 to 2016; while that’s a sobering statistic, Dr. Yonkers said, opioid-related maternal mortality doubled over that same time period.

“We really have to be mindful that we’re not just talking about taking care of kids and offspring, but we have to take care of moms – it’s really critical,” she said.

With the increasing legalization of cannabis, it’s expected that a lot more cannabis-exposed pregnancies will be seen in clinical practice, and some studies are starting to show an increase in prevalence in the preconception, prenatal, and postpartum period.

While some people feel that cannabis is benign, more data are needed, according to Dr. Yonkers, who said that cannabis and its metabolites cross the blood/placenta and blood/milk barriers, and that cannabinoid receptors are “very important” to fertility, implantation, and fetal development. One study recently published linked cannabis use in pregnancy to significant increases in preterm birth rates (JAMA. 2019 Jun 18;322[2]:145-52).

“We don’t really have a context for this, so we don’t really know what’s going to have an impact, and what’s not,” Dr. Yonkers said.

While both standard and novel treatments could help in the quest to achieve and maintain well-being in this unique patient population, Dr. Yonkers said that health equity and universal approaches to care might be needed to more comprehensively address the problem, which means taking a close look at how much money women have, the resources available to them, and where they live.

In many communities, eliminating inequalities in care will be critical to successfully addressing substance use issues in pregnant women, agreed Maureen Sayres Van Niel, MD, a specialist in women’s psychiatry in Boston and president of the Women’s Caucus of the APA.

“What we see is such a disparity in the delivery of care to women who are poor and living in communities where the socioeconomic and financial problems are very severe,” Dr. Van Niel said in an interview. “Unless we address these disparities, women will not be getting the kind of health care that they really need to have in the perinatal period.”

Dr. Yonkers reported a disclosure related to UpToDate.
 

The use of alcohol, tobacco products, and drugs by pregnant women is a substantial problem that may be more prevalent than previously thought, according to researcher Kimberly Yonkers, MD.

Higher levels of substance use during pregnancy means more negative impacts on maternal and fetal, neonatal, and child health. However, one bit of good news is that pregnant women still are less likely than nonpregnant women to engage in such behavior, said Dr. Yonkers, director of psychological medicine and the Center for Wellbeing of Women and Mothers at Yale University, New Haven, Conn.

“We need to capitalize on that and explore it, and try and figure out ways that women can maintain their well-being from pregnancy to the postnatal period,” Dr. Yonkers said in a featured presentation at the annual meeting of the American Psychiatric Association, which was held as a virtual live event.

Tobacco predominates among substances of concern used by pregnant women, with 11.6% reporting past-month use in 2018, according to the National Survey on Drug Use and Health, Dr. Yonkers said. Alcohol was next, with 9.9% of pregnant women reporting use in the past month, followed by drugs at 5.4%, of which marijuana was the most common.

Those numbers may jump much higher when focusing on substance use that’s biologically verified, she added, referring to a recent three-center cross-sectional study she and her colleagues published in Addiction (2019 Jun 19. doi: 10.1111/add.14651). In that study, alcohol use was as high as 18.9% among pregnant women who either had positive urine or self-reported use. Similarly, rates of nicotine or nicotine byproduct detected were 27% at one center in the study, and tetrahydrocannabinol reached 29.4% at that same center.

“These numbers are impressive,” Dr. Yonkers told attendees at the meeting. “So what we may be seeing in terms of the National Survey on Drug Use and Health, as valuable as it is, is in all likelihood it underestimates the use of substances in pregnancy.”

Substance use goes down in pregnancy as some women become more mindful of perinatal health, though unfortunately, that abstinence is offset by a dramatic rise in substance use in the 6-12 months’ post partum, research suggests.

Interestingly, big differences are found in both abstinence and relapse rates, with some data sets showing that, while alcohol is stopped fairly early, cigarettes are stopped much later, if at all.

On the postpartum side of the equation, relapse rates look similar for cigarettes, alcohol, and marijuana, but for some reason, cocaine relapse rates are much lower “That’s kind of nice, and we’d like to be able to understand what it is about this whole process that enabled that relative period of wellness,” Dr. Yonkers said.

Opioid use disorder is rising among pregnant women, just like it is in the general population, and 50% – or possibly even as high as 80% – of babies born to these women will experience neonatal opioid withdrawal, Dr. Yonkers said.

Maternal mortality in the United States increased by 34% from 2008 to 2016; while that’s a sobering statistic, Dr. Yonkers said, opioid-related maternal mortality doubled over that same time period.

“We really have to be mindful that we’re not just talking about taking care of kids and offspring, but we have to take care of moms – it’s really critical,” she said.

With the increasing legalization of cannabis, it’s expected that a lot more cannabis-exposed pregnancies will be seen in clinical practice, and some studies are starting to show an increase in prevalence in the preconception, prenatal, and postpartum period.

While some people feel that cannabis is benign, more data are needed, according to Dr. Yonkers, who said that cannabis and its metabolites cross the blood/placenta and blood/milk barriers, and that cannabinoid receptors are “very important” to fertility, implantation, and fetal development. One study recently published linked cannabis use in pregnancy to significant increases in preterm birth rates (JAMA. 2019 Jun 18;322[2]:145-52).

“We don’t really have a context for this, so we don’t really know what’s going to have an impact, and what’s not,” Dr. Yonkers said.

While both standard and novel treatments could help in the quest to achieve and maintain well-being in this unique patient population, Dr. Yonkers said that health equity and universal approaches to care might be needed to more comprehensively address the problem, which means taking a close look at how much money women have, the resources available to them, and where they live.

In many communities, eliminating inequalities in care will be critical to successfully addressing substance use issues in pregnant women, agreed Maureen Sayres Van Niel, MD, a specialist in women’s psychiatry in Boston and president of the Women’s Caucus of the APA.

“What we see is such a disparity in the delivery of care to women who are poor and living in communities where the socioeconomic and financial problems are very severe,” Dr. Van Niel said in an interview. “Unless we address these disparities, women will not be getting the kind of health care that they really need to have in the perinatal period.”

Dr. Yonkers reported a disclosure related to UpToDate.
 

As alcohol-related death and disease rates rise, framing alcohol use disorder as a treatable disease with neurobiologic underpinnings might help reduce the stigma that many patients endure, according to George F. Koob, PhD, director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

“Alcohol misuse and alcohol use disorder (AUD) have not gone away during the opioid crisis, and [they have] not gone away during the current (COVID-19) pandemic,” Dr. Koob said in a presentation at the annual meeting of the American Psychiatric Association, which was held as a virtual live event.

There are at least 14 million individuals in the United States with AUD now, compared with 2 million with opioid use disorder, Dr. Koob said.

Clinicians should strive to reduce stigma related to AUD, he said, and reinforce the understanding that these millions of individuals have a treatable chronic condition – just like hypertension or diabetes are treatable chronic conditions.

However, framing AUD as a treatable chronic condition is just one of many issues that need to be addressed, he said, adding that rates of screening and referral for AUD need to be increased among patients with other mental health conditions.

Psychiatrists can play a key role in reducing that screening and treatment gap, though concerningly, data suggest fewer than half of psychiatric patients with substance use disorders (SUDs) are being diagnosed or treated, said Andrew J. Saxon, MD, director of the Center of Excellence in Substance Abuse Treatment and Education (CESATE) VA Puget Sound Health Care System in Seattle.

Only about 9% of psychiatrist office visits from 2012 to 2015 involved a substance use disorder diagnosis or prescribed medication, whereas at least 20% of adults with mental health conditions also have an SUD, according to authors of a recent study in Psychiatric Services (2018 Jan 16. doi: 10.1176/appi.ps.201700457).

Better efforts are needed to improve training or somehow better incentivize psychiatrists to screen for alcohol use disorder and make sure patients get treatment for addiction, Dr. Saxon said in an interview.

“What we have is a lack of subspecialists in addiction psychiatry,” said Dr. Saxon, former director of the addiction psychiatry residency program at the University of Washington. “That becomes self-perpetuating, because we don’t have the knowledge experts to train the residents, and therefore, the residency programs don’t provide a rich enough experience.”
 

Changes in alcohol-related deaths

A new report (Alcoholism Clin Exper Res. 2020 Jan;44[1]:178-87) highlights the gravity of the AUD problem, showing that alcohol-related deaths have doubled over the past few decades, Dr. Koob said in his presentation.

Among individuals 16 years of age or older, the number of alcohol-related deaths in the United States rose from 35,914 in 1999 to 72,558 (or about 2.6% of all U.S. deaths) in 2017, according to that report, which was based on U.S. mortality data from the National Center for Health Statistics. The largest increase was seen in non-Hispanic white females, according to the investigators.

Alcohol is playing a more prominent role in “deaths of despair,” said Dr. Koob, noting that it contributes to about one-quarter of suicides and up to 20% of drug overdoses. “Probably even more salient is that half of liver disease in the United States is now caused by alcohol,” he added.

Misuse of alcohol is correlated with poor mental health, an observation that Dr. Koob said was particularly relevant to the current COVID-19 pandemic, he said, since alcohol is commonly used to cope with stress and symptoms of mental health conditions.

“In the end, it makes the prognosis worse,” he said.
 

Addressing AUD stigma

A better understanding of the neurobiology of addiction may reduce the stigma associated with AUD, helping reframe the issue as a “health condition, rather than as a moral failing,” Dr. Koob said.

Stigma remains a major barrier to AUD treatment, he added, explaining that factors contributing to stigma include shame patients may feel for what they perceive as a personal failure, and lack of knowledge about treatment options.

Separating AUD treatment from primary care exacerbates that problem, perpetuating the sense that AUD is somehow a “different” kind of issue, he said.

Health care clinicians in primary care can help alleviate the stigma by engaging in screening and offering referral to treatment, he said, adding that the NIAAA offers a navigator website designed to help individuals negotiate the process of choosing a treatment approach for AUD.

Language matters, according to Dr. Koob, who suggested using nonstigmatizing “person-first” terminology to refer to affected individuals not as alcoholics, but as “persons with AUD.”

Challenges ahead for AUD

There’s still a lot of work to be done to understand differences in alcohol pathology between men and women, especially as gaps narrow between the sexes for AUD incidence, early-onset drinking, frequency and intensity of drinking, and self-reported consequences, Dr. Koob said.

Age differences are also important to study. On one hand, older individuals appear to be more sensitive to the effects of alcohol, he said, because of metabolism changes, neurocognitive decline, and “inflamm-aging,” or the chronic and low level inflammatory state associated with aging.

Adolescents are also an increased-risk population of research interest, since brain wiring connections are “particularly sensitive” to alcohol in the teen years, potentially setting up changes in vulnerability to AUD that last into adulthood.

Other challenges include the unmet need for better and more individualized AUD treatments, the issue of alcohol tolerance, which Dr. Koob said has been “ignored for many years” by researchers, the contribution of pain to AUD, and the way that dysregulated sleep contributes to AUD, and vice versa.

Research likewise remains “challenging” regarding conditions that are frequently found in conjunction with AUD, such as major depressive episodes, anxiety disorders, and posttraumatic stress disorder: “These are all areas that we’re intensely interested in as comorbidities with AUD,” Dr. Koob said.

Dr. Koob reported no disclosures.

SOURCE: Koob GF. APA 2020, Abstract.

As alcohol-related death and disease rates rise, framing alcohol use disorder as a treatable disease with neurobiologic underpinnings might help reduce the stigma that many patients endure, according to George F. Koob, PhD, director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

“Alcohol misuse and alcohol use disorder (AUD) have not gone away during the opioid crisis, and [they have] not gone away during the current (COVID-19) pandemic,” Dr. Koob said in a presentation at the annual meeting of the American Psychiatric Association, which was held as a virtual live event.

There are at least 14 million individuals in the United States with AUD now, compared with 2 million with opioid use disorder, Dr. Koob said.

Clinicians should strive to reduce stigma related to AUD, he said, and reinforce the understanding that these millions of individuals have a treatable chronic condition – just like hypertension or diabetes are treatable chronic conditions.

However, framing AUD as a treatable chronic condition is just one of many issues that need to be addressed, he said, adding that rates of screening and referral for AUD need to be increased among patients with other mental health conditions.

Psychiatrists can play a key role in reducing that screening and treatment gap, though concerningly, data suggest fewer than half of psychiatric patients with substance use disorders (SUDs) are being diagnosed or treated, said Andrew J. Saxon, MD, director of the Center of Excellence in Substance Abuse Treatment and Education (CESATE) VA Puget Sound Health Care System in Seattle.

Only about 9% of psychiatrist office visits from 2012 to 2015 involved a substance use disorder diagnosis or prescribed medication, whereas at least 20% of adults with mental health conditions also have an SUD, according to authors of a recent study in Psychiatric Services (2018 Jan 16. doi: 10.1176/appi.ps.201700457).

Better efforts are needed to improve training or somehow better incentivize psychiatrists to screen for alcohol use disorder and make sure patients get treatment for addiction, Dr. Saxon said in an interview.

“What we have is a lack of subspecialists in addiction psychiatry,” said Dr. Saxon, former director of the addiction psychiatry residency program at the University of Washington. “That becomes self-perpetuating, because we don’t have the knowledge experts to train the residents, and therefore, the residency programs don’t provide a rich enough experience.”
 

Changes in alcohol-related deaths

A new report (Alcoholism Clin Exper Res. 2020 Jan;44[1]:178-87) highlights the gravity of the AUD problem, showing that alcohol-related deaths have doubled over the past few decades, Dr. Koob said in his presentation.

Among individuals 16 years of age or older, the number of alcohol-related deaths in the United States rose from 35,914 in 1999 to 72,558 (or about 2.6% of all U.S. deaths) in 2017, according to that report, which was based on U.S. mortality data from the National Center for Health Statistics. The largest increase was seen in non-Hispanic white females, according to the investigators.

Alcohol is playing a more prominent role in “deaths of despair,” said Dr. Koob, noting that it contributes to about one-quarter of suicides and up to 20% of drug overdoses. “Probably even more salient is that half of liver disease in the United States is now caused by alcohol,” he added.

Misuse of alcohol is correlated with poor mental health, an observation that Dr. Koob said was particularly relevant to the current COVID-19 pandemic, he said, since alcohol is commonly used to cope with stress and symptoms of mental health conditions.

“In the end, it makes the prognosis worse,” he said.
 

Addressing AUD stigma

A better understanding of the neurobiology of addiction may reduce the stigma associated with AUD, helping reframe the issue as a “health condition, rather than as a moral failing,” Dr. Koob said.

Stigma remains a major barrier to AUD treatment, he added, explaining that factors contributing to stigma include shame patients may feel for what they perceive as a personal failure, and lack of knowledge about treatment options.

Separating AUD treatment from primary care exacerbates that problem, perpetuating the sense that AUD is somehow a “different” kind of issue, he said.

Health care clinicians in primary care can help alleviate the stigma by engaging in screening and offering referral to treatment, he said, adding that the NIAAA offers a navigator website designed to help individuals negotiate the process of choosing a treatment approach for AUD.

Language matters, according to Dr. Koob, who suggested using nonstigmatizing “person-first” terminology to refer to affected individuals not as alcoholics, but as “persons with AUD.”

Challenges ahead for AUD

There’s still a lot of work to be done to understand differences in alcohol pathology between men and women, especially as gaps narrow between the sexes for AUD incidence, early-onset drinking, frequency and intensity of drinking, and self-reported consequences, Dr. Koob said.

Age differences are also important to study. On one hand, older individuals appear to be more sensitive to the effects of alcohol, he said, because of metabolism changes, neurocognitive decline, and “inflamm-aging,” or the chronic and low level inflammatory state associated with aging.

Adolescents are also an increased-risk population of research interest, since brain wiring connections are “particularly sensitive” to alcohol in the teen years, potentially setting up changes in vulnerability to AUD that last into adulthood.

Other challenges include the unmet need for better and more individualized AUD treatments, the issue of alcohol tolerance, which Dr. Koob said has been “ignored for many years” by researchers, the contribution of pain to AUD, and the way that dysregulated sleep contributes to AUD, and vice versa.

Research likewise remains “challenging” regarding conditions that are frequently found in conjunction with AUD, such as major depressive episodes, anxiety disorders, and posttraumatic stress disorder: “These are all areas that we’re intensely interested in as comorbidities with AUD,” Dr. Koob said.

Dr. Koob reported no disclosures.

SOURCE: Koob GF. APA 2020, Abstract.

As alcohol-related death and disease rates rise, framing alcohol use disorder as a treatable disease with neurobiologic underpinnings might help reduce the stigma that many patients endure, according to George F. Koob, PhD, director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

“Alcohol misuse and alcohol use disorder (AUD) have not gone away during the opioid crisis, and [they have] not gone away during the current (COVID-19) pandemic,” Dr. Koob said in a presentation at the annual meeting of the American Psychiatric Association, which was held as a virtual live event.

There are at least 14 million individuals in the United States with AUD now, compared with 2 million with opioid use disorder, Dr. Koob said.

Clinicians should strive to reduce stigma related to AUD, he said, and reinforce the understanding that these millions of individuals have a treatable chronic condition – just like hypertension or diabetes are treatable chronic conditions.

However, framing AUD as a treatable chronic condition is just one of many issues that need to be addressed, he said, adding that rates of screening and referral for AUD need to be increased among patients with other mental health conditions.

Psychiatrists can play a key role in reducing that screening and treatment gap, though concerningly, data suggest fewer than half of psychiatric patients with substance use disorders (SUDs) are being diagnosed or treated, said Andrew J. Saxon, MD, director of the Center of Excellence in Substance Abuse Treatment and Education (CESATE) VA Puget Sound Health Care System in Seattle.

Only about 9% of psychiatrist office visits from 2012 to 2015 involved a substance use disorder diagnosis or prescribed medication, whereas at least 20% of adults with mental health conditions also have an SUD, according to authors of a recent study in Psychiatric Services (2018 Jan 16. doi: 10.1176/appi.ps.201700457).

Better efforts are needed to improve training or somehow better incentivize psychiatrists to screen for alcohol use disorder and make sure patients get treatment for addiction, Dr. Saxon said in an interview.

“What we have is a lack of subspecialists in addiction psychiatry,” said Dr. Saxon, former director of the addiction psychiatry residency program at the University of Washington. “That becomes self-perpetuating, because we don’t have the knowledge experts to train the residents, and therefore, the residency programs don’t provide a rich enough experience.”
 

Changes in alcohol-related deaths

A new report (Alcoholism Clin Exper Res. 2020 Jan;44[1]:178-87) highlights the gravity of the AUD problem, showing that alcohol-related deaths have doubled over the past few decades, Dr. Koob said in his presentation.

Among individuals 16 years of age or older, the number of alcohol-related deaths in the United States rose from 35,914 in 1999 to 72,558 (or about 2.6% of all U.S. deaths) in 2017, according to that report, which was based on U.S. mortality data from the National Center for Health Statistics. The largest increase was seen in non-Hispanic white females, according to the investigators.

Alcohol is playing a more prominent role in “deaths of despair,” said Dr. Koob, noting that it contributes to about one-quarter of suicides and up to 20% of drug overdoses. “Probably even more salient is that half of liver disease in the United States is now caused by alcohol,” he added.

Misuse of alcohol is correlated with poor mental health, an observation that Dr. Koob said was particularly relevant to the current COVID-19 pandemic, he said, since alcohol is commonly used to cope with stress and symptoms of mental health conditions.

“In the end, it makes the prognosis worse,” he said.
 

Addressing AUD stigma

A better understanding of the neurobiology of addiction may reduce the stigma associated with AUD, helping reframe the issue as a “health condition, rather than as a moral failing,” Dr. Koob said.

Stigma remains a major barrier to AUD treatment, he added, explaining that factors contributing to stigma include shame patients may feel for what they perceive as a personal failure, and lack of knowledge about treatment options.

Separating AUD treatment from primary care exacerbates that problem, perpetuating the sense that AUD is somehow a “different” kind of issue, he said.

Health care clinicians in primary care can help alleviate the stigma by engaging in screening and offering referral to treatment, he said, adding that the NIAAA offers a navigator website designed to help individuals negotiate the process of choosing a treatment approach for AUD.

Language matters, according to Dr. Koob, who suggested using nonstigmatizing “person-first” terminology to refer to affected individuals not as alcoholics, but as “persons with AUD.”

Challenges ahead for AUD

There’s still a lot of work to be done to understand differences in alcohol pathology between men and women, especially as gaps narrow between the sexes for AUD incidence, early-onset drinking, frequency and intensity of drinking, and self-reported consequences, Dr. Koob said.

Age differences are also important to study. On one hand, older individuals appear to be more sensitive to the effects of alcohol, he said, because of metabolism changes, neurocognitive decline, and “inflamm-aging,” or the chronic and low level inflammatory state associated with aging.

Adolescents are also an increased-risk population of research interest, since brain wiring connections are “particularly sensitive” to alcohol in the teen years, potentially setting up changes in vulnerability to AUD that last into adulthood.

Other challenges include the unmet need for better and more individualized AUD treatments, the issue of alcohol tolerance, which Dr. Koob said has been “ignored for many years” by researchers, the contribution of pain to AUD, and the way that dysregulated sleep contributes to AUD, and vice versa.

Research likewise remains “challenging” regarding conditions that are frequently found in conjunction with AUD, such as major depressive episodes, anxiety disorders, and posttraumatic stress disorder: “These are all areas that we’re intensely interested in as comorbidities with AUD,” Dr. Koob said.

Dr. Koob reported no disclosures.

SOURCE: Koob GF. APA 2020, Abstract.

Altering the gut microbiome may reduce the tumor-promoting effects of cigarette smoking, based on a preclinical study.

Mice treated with microbiome-depleting antibiotics or genetically modified to lack an adaptive immune response did not show increased rates of cancer growth when exposed to cigarette smoke, reported lead author Prateek Sharma, MBBS, of the University of Miami, and colleagues.

Although previous research has shown that the gut microbiome plays a role in the progression of cancer and that smoking alters the gut microbiome, the collective effects of these changes have not been studied, the investigators wrote in an abstract released as part of the annual Digestive Disease Week, which was canceled because of COVID-19.

“There is information that smoking changes the gut microbiome ... but the impact of this change is not known,” Dr. Sharma said in a virtual press conference.

To learn more, the investigators first performed an experiment using wild-type mice. All mice were injected with a cancer cell line from the pancreas, colon, or bladder. Mice were then sorted into four groups, in which they were given microbiome-depleting antibiotics and exposed to smoke, given antibiotics alone, exposed to smoke alone, or left untreated and unexposed to serve as controls. Tumor size was then measured over the course of 2 months.

The experiment revealed that mice exposed to smoke but not treated with antibiotics had increased rates of tumor growth regardless of cancer type. But in mice treated with antibiotics, the tumor-promoting effects of smoke exposure were completely lost; the mice had rates of tumor growth even lower than controls.

This experiment was repeated with mice genetically engineered to lack an adaptive immune response. Regardless of smoke or antibiotic exposure, all mice had comparable rates of tumor growth.

Dr. Sharma offered a summary of the findings and their possible implications for human medicine.

“Cigarette smoking changes the gut microbiome, and this changed gut microbiome interacts with the immune system to affect cancer progression,” he said. “If we can target this changed microbiome with modulation strategies like antibiotics, probiotics, or administration of good bacteria, we can alter this process. And if the same results are found in human studies, it could go a long way to affect cancer outcomes in smokers.”

In addition to human studies, Dr. Sharma said that future research should aim to uncover the underlying mechanisms involved in this process, including the types of bacteria that play a role.

When asked if the study might lessen concerns about the negative impacts of smoking among cancer patients, Dr. Sharma suggested that, even if the findings do translate to humans, smoking would still carry significant health risks.

“Even if gut microbiome modulation strategies do work in these patients, it may help a little, but it’s not going to bring it down to the level of nonsmokers, so it’s no way an excuse to not fear or continue [smoking],” he said.

The study was funded by the Florida Department of Health. The investigators reported no conflicts of interest.

Altering the gut microbiome may reduce the tumor-promoting effects of cigarette smoking, based on a preclinical study.

Mice treated with microbiome-depleting antibiotics or genetically modified to lack an adaptive immune response did not show increased rates of cancer growth when exposed to cigarette smoke, reported lead author Prateek Sharma, MBBS, of the University of Miami, and colleagues.

Although previous research has shown that the gut microbiome plays a role in the progression of cancer and that smoking alters the gut microbiome, the collective effects of these changes have not been studied, the investigators wrote in an abstract released as part of the annual Digestive Disease Week, which was canceled because of COVID-19.

“There is information that smoking changes the gut microbiome ... but the impact of this change is not known,” Dr. Sharma said in a virtual press conference.

To learn more, the investigators first performed an experiment using wild-type mice. All mice were injected with a cancer cell line from the pancreas, colon, or bladder. Mice were then sorted into four groups, in which they were given microbiome-depleting antibiotics and exposed to smoke, given antibiotics alone, exposed to smoke alone, or left untreated and unexposed to serve as controls. Tumor size was then measured over the course of 2 months.

The experiment revealed that mice exposed to smoke but not treated with antibiotics had increased rates of tumor growth regardless of cancer type. But in mice treated with antibiotics, the tumor-promoting effects of smoke exposure were completely lost; the mice had rates of tumor growth even lower than controls.

This experiment was repeated with mice genetically engineered to lack an adaptive immune response. Regardless of smoke or antibiotic exposure, all mice had comparable rates of tumor growth.

Dr. Sharma offered a summary of the findings and their possible implications for human medicine.

“Cigarette smoking changes the gut microbiome, and this changed gut microbiome interacts with the immune system to affect cancer progression,” he said. “If we can target this changed microbiome with modulation strategies like antibiotics, probiotics, or administration of good bacteria, we can alter this process. And if the same results are found in human studies, it could go a long way to affect cancer outcomes in smokers.”

In addition to human studies, Dr. Sharma said that future research should aim to uncover the underlying mechanisms involved in this process, including the types of bacteria that play a role.

When asked if the study might lessen concerns about the negative impacts of smoking among cancer patients, Dr. Sharma suggested that, even if the findings do translate to humans, smoking would still carry significant health risks.

“Even if gut microbiome modulation strategies do work in these patients, it may help a little, but it’s not going to bring it down to the level of nonsmokers, so it’s no way an excuse to not fear or continue [smoking],” he said.

The study was funded by the Florida Department of Health. The investigators reported no conflicts of interest.

Altering the gut microbiome may reduce the tumor-promoting effects of cigarette smoking, based on a preclinical study.

Mice treated with microbiome-depleting antibiotics or genetically modified to lack an adaptive immune response did not show increased rates of cancer growth when exposed to cigarette smoke, reported lead author Prateek Sharma, MBBS, of the University of Miami, and colleagues.

Although previous research has shown that the gut microbiome plays a role in the progression of cancer and that smoking alters the gut microbiome, the collective effects of these changes have not been studied, the investigators wrote in an abstract released as part of the annual Digestive Disease Week, which was canceled because of COVID-19.

“There is information that smoking changes the gut microbiome ... but the impact of this change is not known,” Dr. Sharma said in a virtual press conference.

To learn more, the investigators first performed an experiment using wild-type mice. All mice were injected with a cancer cell line from the pancreas, colon, or bladder. Mice were then sorted into four groups, in which they were given microbiome-depleting antibiotics and exposed to smoke, given antibiotics alone, exposed to smoke alone, or left untreated and unexposed to serve as controls. Tumor size was then measured over the course of 2 months.

The experiment revealed that mice exposed to smoke but not treated with antibiotics had increased rates of tumor growth regardless of cancer type. But in mice treated with antibiotics, the tumor-promoting effects of smoke exposure were completely lost; the mice had rates of tumor growth even lower than controls.

This experiment was repeated with mice genetically engineered to lack an adaptive immune response. Regardless of smoke or antibiotic exposure, all mice had comparable rates of tumor growth.

Dr. Sharma offered a summary of the findings and their possible implications for human medicine.

“Cigarette smoking changes the gut microbiome, and this changed gut microbiome interacts with the immune system to affect cancer progression,” he said. “If we can target this changed microbiome with modulation strategies like antibiotics, probiotics, or administration of good bacteria, we can alter this process. And if the same results are found in human studies, it could go a long way to affect cancer outcomes in smokers.”

In addition to human studies, Dr. Sharma said that future research should aim to uncover the underlying mechanisms involved in this process, including the types of bacteria that play a role.

When asked if the study might lessen concerns about the negative impacts of smoking among cancer patients, Dr. Sharma suggested that, even if the findings do translate to humans, smoking would still carry significant health risks.

“Even if gut microbiome modulation strategies do work in these patients, it may help a little, but it’s not going to bring it down to the level of nonsmokers, so it’s no way an excuse to not fear or continue [smoking],” he said.

The study was funded by the Florida Department of Health. The investigators reported no conflicts of interest.

Diastolic dysfunction, a common and often undiagnosed condition in older individuals, could be contributing to the increasing burden of cognitive decline, a new study suggests. “We found people with worsening diastolic dysfunction have more white matter hyperintensities on brain imaging and greater difficulty with executive functioning, suggesting that diastolic dysfunction is a common modifiable risk factor for cognitive impairment,” said lead author Alicia S. Parker, MD. Dr. Parker is assistant professor of cognitive and behavioral neurology at the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health, San Antonio.

“This is an entirely new finding. While there have been some small studies suggesting a link between diastolic dysfunction and a reduction in working memory, this is by far the largest dataset on this topic and the first study that has included brain imaging and neuropsychological measures,” she said.

“Diastolic dysfunction is very common in the older population, and we need to do more to find it and treat it to help prevent or reduce cognitive decline,” Dr. Parker added.

This research is being presented online as part of the 2020 American Academy of Neurology Science Highlights.

Dr. Parker explained that systolic dysfunction is known to have a major effect on cardiovascular outcomes and has been found to be associated with cognitive decline. Proposed mechanisms for cognitive decline in patients with systolic dysfunction include low cardiac output, embolic infarctions, and hypoxic changes, among others.

“There is increasing interest in analyzing the influence of diastolic dysfunction on cardiovascular outcomes, and the effects of diastolic dysfunction on cognition are not currently well delineated, which this study seeks to address,” she added.

“While these results are new, they are not surprising. In general, we are finding more and more that heart health is connected to brain health,” she commented.

Dr. Parker and her colleagues started the current research after noticing in clinic that among patients with significant diastolic dysfunction, there were often changes on brain MRI imaging, and the patients often had trouble with executive function. “The effect of diastolic dysfunction on cognition has not been well characterized, so we wanted to look at this,” she said.

The investigators analyzed data from the Framingham Heart Study Offspring Cohort at examination 8, collected between 2005 and 2008. The study sample included 1,438 individuals older than 55 years who had undergone neuropsychological assessment and echocardiographic diastolic measurement. Systolic measurements were normal for the participants, and they did not currently have dementia, stroke, or other neurologic illness.

Results showed that increasing E/E’ ratio (the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity) indicated increasing diastolic dysfunction and was associated with an increase in the incidence of mild cognitive impairment (hazard ratio, 1.29; 95% confidence interval, 1.01-1.66; P < .043).

An increased E/E’ ratio was associated with increased executive function impairment in the “similarities” (beta, –0.29; P < .002) and “phonemic fluency” (–1.28; P < .001) tasks.

Participants with moderate to severe diastolic dysfunction were more impaired with respect to both similarities (–0.62; P < .046) and phonemic fluency (–2.60; P < .023).

Data from 1,217 participants showed that among those with mild diastolic dysfunction, there was a trend toward an increase in white matter hyperintensities (0.11; P < .105). For participants with moderate to severe diastolic dysfunction, white matter hyperintensities were increased (0.30; P < 0.001).

The results were unchanged after the researchers adjusted for many other predictors of cognitive decline affecting diastolic function.

The researchers conclude: “As cerebral small vessel disease clinically presents with executive dysfunction, these results align well.” They add that replication in additional cohorts and analyses of cognition in treatment trials of diastolic dysfunction are warranted.

Earlier interventions

Commenting on the study, Marco R. Di Tullio, MD, professor of medicine and Columbia University Medical Center, New York City, who is also studying the relationship between subclinical cardiac abnormalities and cognition, said: “This is a promising area of research, as it might allow us to uncover novel risk factors for cognitive decline at an early stage, before the development of clinically manifest cardiac disease, which might allow earlier interventions to decrease or delay the onset of cognitive decline.”

Dr. Di Tullio added that he would like to know more about the interaction between diastolic dysfunction, MRI abnormalities, and cognitive impairment risk. “In this study, MRI abnormalities and cognitive impairment are treated as separate outcomes, with diastolic dysfunction being the exposure for each of them. An additional analysis of the association between diastolic dysfunction and cognitive impairment stratified by presence or absence of brain MRI findings would have been interesting.”

Dr. Parker responded that this is an area of investigation. “We suspect that our cognitive findings would not be explained by any one MRI measure, though a comprehensive examination of MRI findings would be of benefit. The thought that there may be a reversible cardiac abnormality that does not have a structural brain imaging correlate on MRI is an interesting possibility,” she said.

Dr. Di Tullio also pointed out that at present, there is no specific treatment for diastolic dysfunction other than to address some the conditions that predispose to it, such as hypertension and atrial fibrillation.

“We completely agree that specific treatments are an area of investigation and that treatment is therefore targeted at associated modifiable conditions,” Dr. Parker replied.

With regard to more specific estimates of the prevalence of diastolic dysfunction, Dr. Parker cites another Framingham analysis that involved 2,355 persons without any prevalent cardiovascular conditions. That study found that diastolic dysfunction was rare until 50 years of age and then gradually increased with age.

About 5% of people in their 50s had mild diastolic dysfunction, and about 3% had moderate to severe diastolic dysfunction. Among persons in their 60s, about 18% had mild and 5% had severe diastolic dysfunction. Among persons in their 70s, mild diastolic dysfunction occurred in 35%, and moderate to severe disease was present in 18%; and in persons older than 80 years, nearly half had mild and about 20% had moderate to severe diastolic dysfunction.

Dr. Parker has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Diastolic dysfunction, a common and often undiagnosed condition in older individuals, could be contributing to the increasing burden of cognitive decline, a new study suggests. “We found people with worsening diastolic dysfunction have more white matter hyperintensities on brain imaging and greater difficulty with executive functioning, suggesting that diastolic dysfunction is a common modifiable risk factor for cognitive impairment,” said lead author Alicia S. Parker, MD. Dr. Parker is assistant professor of cognitive and behavioral neurology at the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health, San Antonio.

“This is an entirely new finding. While there have been some small studies suggesting a link between diastolic dysfunction and a reduction in working memory, this is by far the largest dataset on this topic and the first study that has included brain imaging and neuropsychological measures,” she said.

“Diastolic dysfunction is very common in the older population, and we need to do more to find it and treat it to help prevent or reduce cognitive decline,” Dr. Parker added.

This research is being presented online as part of the 2020 American Academy of Neurology Science Highlights.

Dr. Parker explained that systolic dysfunction is known to have a major effect on cardiovascular outcomes and has been found to be associated with cognitive decline. Proposed mechanisms for cognitive decline in patients with systolic dysfunction include low cardiac output, embolic infarctions, and hypoxic changes, among others.

“There is increasing interest in analyzing the influence of diastolic dysfunction on cardiovascular outcomes, and the effects of diastolic dysfunction on cognition are not currently well delineated, which this study seeks to address,” she added.

“While these results are new, they are not surprising. In general, we are finding more and more that heart health is connected to brain health,” she commented.

Dr. Parker and her colleagues started the current research after noticing in clinic that among patients with significant diastolic dysfunction, there were often changes on brain MRI imaging, and the patients often had trouble with executive function. “The effect of diastolic dysfunction on cognition has not been well characterized, so we wanted to look at this,” she said.

The investigators analyzed data from the Framingham Heart Study Offspring Cohort at examination 8, collected between 2005 and 2008. The study sample included 1,438 individuals older than 55 years who had undergone neuropsychological assessment and echocardiographic diastolic measurement. Systolic measurements were normal for the participants, and they did not currently have dementia, stroke, or other neurologic illness.

Results showed that increasing E/E’ ratio (the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity) indicated increasing diastolic dysfunction and was associated with an increase in the incidence of mild cognitive impairment (hazard ratio, 1.29; 95% confidence interval, 1.01-1.66; P < .043).

An increased E/E’ ratio was associated with increased executive function impairment in the “similarities” (beta, –0.29; P < .002) and “phonemic fluency” (–1.28; P < .001) tasks.

Participants with moderate to severe diastolic dysfunction were more impaired with respect to both similarities (–0.62; P < .046) and phonemic fluency (–2.60; P < .023).

Data from 1,217 participants showed that among those with mild diastolic dysfunction, there was a trend toward an increase in white matter hyperintensities (0.11; P < .105). For participants with moderate to severe diastolic dysfunction, white matter hyperintensities were increased (0.30; P < 0.001).

The results were unchanged after the researchers adjusted for many other predictors of cognitive decline affecting diastolic function.

The researchers conclude: “As cerebral small vessel disease clinically presents with executive dysfunction, these results align well.” They add that replication in additional cohorts and analyses of cognition in treatment trials of diastolic dysfunction are warranted.

Earlier interventions

Commenting on the study, Marco R. Di Tullio, MD, professor of medicine and Columbia University Medical Center, New York City, who is also studying the relationship between subclinical cardiac abnormalities and cognition, said: “This is a promising area of research, as it might allow us to uncover novel risk factors for cognitive decline at an early stage, before the development of clinically manifest cardiac disease, which might allow earlier interventions to decrease or delay the onset of cognitive decline.”

Dr. Di Tullio added that he would like to know more about the interaction between diastolic dysfunction, MRI abnormalities, and cognitive impairment risk. “In this study, MRI abnormalities and cognitive impairment are treated as separate outcomes, with diastolic dysfunction being the exposure for each of them. An additional analysis of the association between diastolic dysfunction and cognitive impairment stratified by presence or absence of brain MRI findings would have been interesting.”

Dr. Parker responded that this is an area of investigation. “We suspect that our cognitive findings would not be explained by any one MRI measure, though a comprehensive examination of MRI findings would be of benefit. The thought that there may be a reversible cardiac abnormality that does not have a structural brain imaging correlate on MRI is an interesting possibility,” she said.

Dr. Di Tullio also pointed out that at present, there is no specific treatment for diastolic dysfunction other than to address some the conditions that predispose to it, such as hypertension and atrial fibrillation.

“We completely agree that specific treatments are an area of investigation and that treatment is therefore targeted at associated modifiable conditions,” Dr. Parker replied.

With regard to more specific estimates of the prevalence of diastolic dysfunction, Dr. Parker cites another Framingham analysis that involved 2,355 persons without any prevalent cardiovascular conditions. That study found that diastolic dysfunction was rare until 50 years of age and then gradually increased with age.

About 5% of people in their 50s had mild diastolic dysfunction, and about 3% had moderate to severe diastolic dysfunction. Among persons in their 60s, about 18% had mild and 5% had severe diastolic dysfunction. Among persons in their 70s, mild diastolic dysfunction occurred in 35%, and moderate to severe disease was present in 18%; and in persons older than 80 years, nearly half had mild and about 20% had moderate to severe diastolic dysfunction.

Dr. Parker has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

Diastolic dysfunction, a common and often undiagnosed condition in older individuals, could be contributing to the increasing burden of cognitive decline, a new study suggests. “We found people with worsening diastolic dysfunction have more white matter hyperintensities on brain imaging and greater difficulty with executive functioning, suggesting that diastolic dysfunction is a common modifiable risk factor for cognitive impairment,” said lead author Alicia S. Parker, MD. Dr. Parker is assistant professor of cognitive and behavioral neurology at the Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health, San Antonio.

“This is an entirely new finding. While there have been some small studies suggesting a link between diastolic dysfunction and a reduction in working memory, this is by far the largest dataset on this topic and the first study that has included brain imaging and neuropsychological measures,” she said.

“Diastolic dysfunction is very common in the older population, and we need to do more to find it and treat it to help prevent or reduce cognitive decline,” Dr. Parker added.

This research is being presented online as part of the 2020 American Academy of Neurology Science Highlights.

Dr. Parker explained that systolic dysfunction is known to have a major effect on cardiovascular outcomes and has been found to be associated with cognitive decline. Proposed mechanisms for cognitive decline in patients with systolic dysfunction include low cardiac output, embolic infarctions, and hypoxic changes, among others.

“There is increasing interest in analyzing the influence of diastolic dysfunction on cardiovascular outcomes, and the effects of diastolic dysfunction on cognition are not currently well delineated, which this study seeks to address,” she added.

“While these results are new, they are not surprising. In general, we are finding more and more that heart health is connected to brain health,” she commented.

Dr. Parker and her colleagues started the current research after noticing in clinic that among patients with significant diastolic dysfunction, there were often changes on brain MRI imaging, and the patients often had trouble with executive function. “The effect of diastolic dysfunction on cognition has not been well characterized, so we wanted to look at this,” she said.

The investigators analyzed data from the Framingham Heart Study Offspring Cohort at examination 8, collected between 2005 and 2008. The study sample included 1,438 individuals older than 55 years who had undergone neuropsychological assessment and echocardiographic diastolic measurement. Systolic measurements were normal for the participants, and they did not currently have dementia, stroke, or other neurologic illness.

Results showed that increasing E/E’ ratio (the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity) indicated increasing diastolic dysfunction and was associated with an increase in the incidence of mild cognitive impairment (hazard ratio, 1.29; 95% confidence interval, 1.01-1.66; P < .043).

An increased E/E’ ratio was associated with increased executive function impairment in the “similarities” (beta, –0.29; P < .002) and “phonemic fluency” (–1.28; P < .001) tasks.

Participants with moderate to severe diastolic dysfunction were more impaired with respect to both similarities (–0.62; P < .046) and phonemic fluency (–2.60; P < .023).

Data from 1,217 participants showed that among those with mild diastolic dysfunction, there was a trend toward an increase in white matter hyperintensities (0.11; P < .105). For participants with moderate to severe diastolic dysfunction, white matter hyperintensities were increased (0.30; P < 0.001).

The results were unchanged after the researchers adjusted for many other predictors of cognitive decline affecting diastolic function.

The researchers conclude: “As cerebral small vessel disease clinically presents with executive dysfunction, these results align well.” They add that replication in additional cohorts and analyses of cognition in treatment trials of diastolic dysfunction are warranted.

Earlier interventions

Commenting on the study, Marco R. Di Tullio, MD, professor of medicine and Columbia University Medical Center, New York City, who is also studying the relationship between subclinical cardiac abnormalities and cognition, said: “This is a promising area of research, as it might allow us to uncover novel risk factors for cognitive decline at an early stage, before the development of clinically manifest cardiac disease, which might allow earlier interventions to decrease or delay the onset of cognitive decline.”

Dr. Di Tullio added that he would like to know more about the interaction between diastolic dysfunction, MRI abnormalities, and cognitive impairment risk. “In this study, MRI abnormalities and cognitive impairment are treated as separate outcomes, with diastolic dysfunction being the exposure for each of them. An additional analysis of the association between diastolic dysfunction and cognitive impairment stratified by presence or absence of brain MRI findings would have been interesting.”

Dr. Parker responded that this is an area of investigation. “We suspect that our cognitive findings would not be explained by any one MRI measure, though a comprehensive examination of MRI findings would be of benefit. The thought that there may be a reversible cardiac abnormality that does not have a structural brain imaging correlate on MRI is an interesting possibility,” she said.

Dr. Di Tullio also pointed out that at present, there is no specific treatment for diastolic dysfunction other than to address some the conditions that predispose to it, such as hypertension and atrial fibrillation.

“We completely agree that specific treatments are an area of investigation and that treatment is therefore targeted at associated modifiable conditions,” Dr. Parker replied.

With regard to more specific estimates of the prevalence of diastolic dysfunction, Dr. Parker cites another Framingham analysis that involved 2,355 persons without any prevalent cardiovascular conditions. That study found that diastolic dysfunction was rare until 50 years of age and then gradually increased with age.

About 5% of people in their 50s had mild diastolic dysfunction, and about 3% had moderate to severe diastolic dysfunction. Among persons in their 60s, about 18% had mild and 5% had severe diastolic dysfunction. Among persons in their 70s, mild diastolic dysfunction occurred in 35%, and moderate to severe disease was present in 18%; and in persons older than 80 years, nearly half had mild and about 20% had moderate to severe diastolic dysfunction.

Dr. Parker has disclosed no relevant financial relationships.

This article first appeared on Medscape.com.