Gene and Cell Therapy

George Stamatoyannopoulos, MD, who conducted important research into hemoglobinopathies, passed away this month at the age of 84.

Dr Stamatoyannopoulos’s research encompassed human genetics and hematology, including the structure and function of hemoglobinopathies, the genetics of thalassemia, and the molecular and cellular control of globin gene switching.

For much of his career, Dr Stamatoyannopoulos focused on the development of gene therapy for hemoglobinopathies and other disorders.

Dr Stamatoyannopoulos was born in Athens, Greece, on March 11, 1934. He entered medical school in Athens at age 17 and graduated at the top of his class 7 years later.

After his medical training, Dr Stamatoyannopoulos pursued thesis research on inherited blood disorders, particularly anemias.

Dr Stamatoyannopoulos performed the first large-scale molecular geographical survey of a genetic trait, which revealed the relationship between malaria and both thalassemia and sickle cell traits.

Dr Stamatoyannopoulos also discovered that fetal hemoglobin could ameliorate the effects of thalassemia. His theory that thalassemia and sickle cell anemia could be treated by re-activating fetal hemoglobin has underpinned decades of efforts to cure these disorders.

As a young investigator, Dr Stamatoyannopoulos expanded genetic studies of blood diseases in Greece, where his work drew the attention of medical genetics pioneer Arno Motulsky, MD.

Dr Motulsky recruited Dr Stamatoyannopoulos to the University of Washington (Seattle) in 1964. Dr Stamatoyannopoulos became a full professor there in 1973, founded the Markey Molecular Medicine Center, and was chief of medical genetics from 1989 to 2005.

Dr Stamatoyannopoulos organized the founding of the American Society of Gene and Cell Therapy. His contributions were recognized by establishment of the Stamatoyannopoulos lecture, the society’s highest award.

Dr Stamatoyannopoulos also served as president of the American Society of Hematology (1992) and president of the American Society of Gene and Cell Therapy (1996). He held leadership positions in other medical and scientific societies as well.

Dr Stamatoyannopoulos authored more than 420 scientific papers and 14 books, including The Molecular Basis of Blood Diseases.

Dr Stamatoyannopoulos died June 16, 2018. He is survived by his wife and collaborator Thalia Papayannopoulou, MD, (a professor of medicine and internationally recognized hematologist), 2 sons, and 3 grandchildren.

Gene and Cell Therapy

George Stamatoyannopoulos, MD, who conducted important research into hemoglobinopathies, passed away this month at the age of 84.

Dr Stamatoyannopoulos’s research encompassed human genetics and hematology, including the structure and function of hemoglobinopathies, the genetics of thalassemia, and the molecular and cellular control of globin gene switching.

For much of his career, Dr Stamatoyannopoulos focused on the development of gene therapy for hemoglobinopathies and other disorders.

Dr Stamatoyannopoulos was born in Athens, Greece, on March 11, 1934. He entered medical school in Athens at age 17 and graduated at the top of his class 7 years later.

After his medical training, Dr Stamatoyannopoulos pursued thesis research on inherited blood disorders, particularly anemias.

Dr Stamatoyannopoulos performed the first large-scale molecular geographical survey of a genetic trait, which revealed the relationship between malaria and both thalassemia and sickle cell traits.

Dr Stamatoyannopoulos also discovered that fetal hemoglobin could ameliorate the effects of thalassemia. His theory that thalassemia and sickle cell anemia could be treated by re-activating fetal hemoglobin has underpinned decades of efforts to cure these disorders.

As a young investigator, Dr Stamatoyannopoulos expanded genetic studies of blood diseases in Greece, where his work drew the attention of medical genetics pioneer Arno Motulsky, MD.

Dr Motulsky recruited Dr Stamatoyannopoulos to the University of Washington (Seattle) in 1964. Dr Stamatoyannopoulos became a full professor there in 1973, founded the Markey Molecular Medicine Center, and was chief of medical genetics from 1989 to 2005.

Dr Stamatoyannopoulos organized the founding of the American Society of Gene and Cell Therapy. His contributions were recognized by establishment of the Stamatoyannopoulos lecture, the society’s highest award.

Dr Stamatoyannopoulos also served as president of the American Society of Hematology (1992) and president of the American Society of Gene and Cell Therapy (1996). He held leadership positions in other medical and scientific societies as well.

Dr Stamatoyannopoulos authored more than 420 scientific papers and 14 books, including The Molecular Basis of Blood Diseases.

Dr Stamatoyannopoulos died June 16, 2018. He is survived by his wife and collaborator Thalia Papayannopoulou, MD, (a professor of medicine and internationally recognized hematologist), 2 sons, and 3 grandchildren.

Gene and Cell Therapy

George Stamatoyannopoulos, MD, who conducted important research into hemoglobinopathies, passed away this month at the age of 84.

Dr Stamatoyannopoulos’s research encompassed human genetics and hematology, including the structure and function of hemoglobinopathies, the genetics of thalassemia, and the molecular and cellular control of globin gene switching.

For much of his career, Dr Stamatoyannopoulos focused on the development of gene therapy for hemoglobinopathies and other disorders.

Dr Stamatoyannopoulos was born in Athens, Greece, on March 11, 1934. He entered medical school in Athens at age 17 and graduated at the top of his class 7 years later.

After his medical training, Dr Stamatoyannopoulos pursued thesis research on inherited blood disorders, particularly anemias.

Dr Stamatoyannopoulos performed the first large-scale molecular geographical survey of a genetic trait, which revealed the relationship between malaria and both thalassemia and sickle cell traits.

Dr Stamatoyannopoulos also discovered that fetal hemoglobin could ameliorate the effects of thalassemia. His theory that thalassemia and sickle cell anemia could be treated by re-activating fetal hemoglobin has underpinned decades of efforts to cure these disorders.

As a young investigator, Dr Stamatoyannopoulos expanded genetic studies of blood diseases in Greece, where his work drew the attention of medical genetics pioneer Arno Motulsky, MD.

Dr Motulsky recruited Dr Stamatoyannopoulos to the University of Washington (Seattle) in 1964. Dr Stamatoyannopoulos became a full professor there in 1973, founded the Markey Molecular Medicine Center, and was chief of medical genetics from 1989 to 2005.

Dr Stamatoyannopoulos organized the founding of the American Society of Gene and Cell Therapy. His contributions were recognized by establishment of the Stamatoyannopoulos lecture, the society’s highest award.

Dr Stamatoyannopoulos also served as president of the American Society of Hematology (1992) and president of the American Society of Gene and Cell Therapy (1996). He held leadership positions in other medical and scientific societies as well.

Dr Stamatoyannopoulos authored more than 420 scientific papers and 14 books, including The Molecular Basis of Blood Diseases.

Dr Stamatoyannopoulos died June 16, 2018. He is survived by his wife and collaborator Thalia Papayannopoulou, MD, (a professor of medicine and internationally recognized hematologist), 2 sons, and 3 grandchildren.

AMSTERDAM – In patients with autoimmune diseases, cancer treatment with checkpoint inhibitor immunotherapy increases the risk of flares, but these flares are associated with improved cancer outcomes, according to a multicenter, retrospective study presented at the European Congress of Rheumatology.

“Survival was longer in patients who experienced a flare of their preexisting autoimmune disease or any other immune-related adverse event, but this gain was lost if an immunosuppressive therapy was used,” reported Alice Tison, a resident in rheumatology at the Centre Hospitalier Universitaire, Brest, France.

These were some of the mixed messages from this evaluation, which involved 112 patients with preexisting autoimmune disease (PAD) whose data were collected from 11 tertiary care centers in France. Of the cases of PAD represented, the majority involved joint diseases, including psoriatic arthritis (28%), rheumatoid arthritis (18%), and spondyloarthritis (4.5%). However, other types of PAD, including inflammatory bowel disease (13%), were included in the series.

Only 33% of the patients had active disease at the time that checkpoint inhibitor therapy was initiated, and only 21% were taking an immunosuppressive therapy for their disease. Of those on therapy, the majority were taking steroids, but about a third of those on therapy were taking a disease-modifying antirheumatic drug, such as methotrexate.

With the initiation of checkpoint inhibitors, which were offered primarily for the treatment of melanoma (59%) and non–small cell lung cancer (36%), 42% of patients with PAD developed a disease flare. Of these, 30% were considered severe. Other immune-related events not considered related to the underlying disease, such as colitis, were also observed but at rates not clearly different than those observed in patients without PAD.

The activity of checkpoint inhibitors did not appear to be different than that observed in non-PAD patients. For example, the overall response rate was 48% in those with melanoma and 54% in those with non–small cell lung cancer. After a median of 8 months of follow-up, the median progression-free survival was 12.4 months and 9.7 months for the two diseases, respectively. Median overall survival had not been reached in either disease.

However, those with a flare or another immune-related adverse event had significantly better progression-free survival (P = .016) and overall survival (P = .004) when compared with those who did not flare or have an immune-related adverse event. According to Ms. Tison, this has been reported before, but a more surprising finding was that the gain in progression-free survival and overall survival was lost in those treated with an immunosuppressive drug.

Even though non-PAD patients commonly receive steroids for immune-related adverse events such as colitis, the loss of benefit in PAD patients who received immunosuppressive therapies may be caused by, at least in part, cross-reactivity between tumor antigens and autoantigens, Ms. Tison speculated.

Ms. Tison was cautious in drawing conclusions about specific strategies to optimize benefits from checkpoint inhibitors in PAD based on this limited series of patients. However, she did suggest that discontinuation of immunosuppressive therapies prior to initiating checkpoint inhibitors may be prudent in PAD patients, particularly those with inactive disease.

Overall, she emphasized that checkpoint inhibitors “have revolutionized the management of several cancers” and should not be denied to PAD patients who are otherwise appropriate candidates. Although flares are common, more than half of PAD patients in this series did not flare and flares were mild to moderate in most of those who did.

“The response to checkpoint inhibitors in PAD patients is good,” Ms. Tison advised. For those who do flare, “we need prospective studies to understand which strategies provide a good balance of benefit to risk” for cancer immunotherapy and for the options to manage immune-related adverse events.

The study was not industry funded. Ms. Tison reported no potential conflicts of interest.

SOURCE: Tison A et al. Ann Rheum Dis. 2018;77(Suppl 2):147. EULAR Congress 2018, Abstract OP0196.

AMSTERDAM – In patients with autoimmune diseases, cancer treatment with checkpoint inhibitor immunotherapy increases the risk of flares, but these flares are associated with improved cancer outcomes, according to a multicenter, retrospective study presented at the European Congress of Rheumatology.

“Survival was longer in patients who experienced a flare of their preexisting autoimmune disease or any other immune-related adverse event, but this gain was lost if an immunosuppressive therapy was used,” reported Alice Tison, a resident in rheumatology at the Centre Hospitalier Universitaire, Brest, France.

These were some of the mixed messages from this evaluation, which involved 112 patients with preexisting autoimmune disease (PAD) whose data were collected from 11 tertiary care centers in France. Of the cases of PAD represented, the majority involved joint diseases, including psoriatic arthritis (28%), rheumatoid arthritis (18%), and spondyloarthritis (4.5%). However, other types of PAD, including inflammatory bowel disease (13%), were included in the series.

Only 33% of the patients had active disease at the time that checkpoint inhibitor therapy was initiated, and only 21% were taking an immunosuppressive therapy for their disease. Of those on therapy, the majority were taking steroids, but about a third of those on therapy were taking a disease-modifying antirheumatic drug, such as methotrexate.

With the initiation of checkpoint inhibitors, which were offered primarily for the treatment of melanoma (59%) and non–small cell lung cancer (36%), 42% of patients with PAD developed a disease flare. Of these, 30% were considered severe. Other immune-related events not considered related to the underlying disease, such as colitis, were also observed but at rates not clearly different than those observed in patients without PAD.

The activity of checkpoint inhibitors did not appear to be different than that observed in non-PAD patients. For example, the overall response rate was 48% in those with melanoma and 54% in those with non–small cell lung cancer. After a median of 8 months of follow-up, the median progression-free survival was 12.4 months and 9.7 months for the two diseases, respectively. Median overall survival had not been reached in either disease.

However, those with a flare or another immune-related adverse event had significantly better progression-free survival (P = .016) and overall survival (P = .004) when compared with those who did not flare or have an immune-related adverse event. According to Ms. Tison, this has been reported before, but a more surprising finding was that the gain in progression-free survival and overall survival was lost in those treated with an immunosuppressive drug.

Even though non-PAD patients commonly receive steroids for immune-related adverse events such as colitis, the loss of benefit in PAD patients who received immunosuppressive therapies may be caused by, at least in part, cross-reactivity between tumor antigens and autoantigens, Ms. Tison speculated.

Ms. Tison was cautious in drawing conclusions about specific strategies to optimize benefits from checkpoint inhibitors in PAD based on this limited series of patients. However, she did suggest that discontinuation of immunosuppressive therapies prior to initiating checkpoint inhibitors may be prudent in PAD patients, particularly those with inactive disease.

Overall, she emphasized that checkpoint inhibitors “have revolutionized the management of several cancers” and should not be denied to PAD patients who are otherwise appropriate candidates. Although flares are common, more than half of PAD patients in this series did not flare and flares were mild to moderate in most of those who did.

“The response to checkpoint inhibitors in PAD patients is good,” Ms. Tison advised. For those who do flare, “we need prospective studies to understand which strategies provide a good balance of benefit to risk” for cancer immunotherapy and for the options to manage immune-related adverse events.

The study was not industry funded. Ms. Tison reported no potential conflicts of interest.

SOURCE: Tison A et al. Ann Rheum Dis. 2018;77(Suppl 2):147. EULAR Congress 2018, Abstract OP0196.

AMSTERDAM – In patients with autoimmune diseases, cancer treatment with checkpoint inhibitor immunotherapy increases the risk of flares, but these flares are associated with improved cancer outcomes, according to a multicenter, retrospective study presented at the European Congress of Rheumatology.

“Survival was longer in patients who experienced a flare of their preexisting autoimmune disease or any other immune-related adverse event, but this gain was lost if an immunosuppressive therapy was used,” reported Alice Tison, a resident in rheumatology at the Centre Hospitalier Universitaire, Brest, France.

These were some of the mixed messages from this evaluation, which involved 112 patients with preexisting autoimmune disease (PAD) whose data were collected from 11 tertiary care centers in France. Of the cases of PAD represented, the majority involved joint diseases, including psoriatic arthritis (28%), rheumatoid arthritis (18%), and spondyloarthritis (4.5%). However, other types of PAD, including inflammatory bowel disease (13%), were included in the series.

Only 33% of the patients had active disease at the time that checkpoint inhibitor therapy was initiated, and only 21% were taking an immunosuppressive therapy for their disease. Of those on therapy, the majority were taking steroids, but about a third of those on therapy were taking a disease-modifying antirheumatic drug, such as methotrexate.

With the initiation of checkpoint inhibitors, which were offered primarily for the treatment of melanoma (59%) and non–small cell lung cancer (36%), 42% of patients with PAD developed a disease flare. Of these, 30% were considered severe. Other immune-related events not considered related to the underlying disease, such as colitis, were also observed but at rates not clearly different than those observed in patients without PAD.

The activity of checkpoint inhibitors did not appear to be different than that observed in non-PAD patients. For example, the overall response rate was 48% in those with melanoma and 54% in those with non–small cell lung cancer. After a median of 8 months of follow-up, the median progression-free survival was 12.4 months and 9.7 months for the two diseases, respectively. Median overall survival had not been reached in either disease.

However, those with a flare or another immune-related adverse event had significantly better progression-free survival (P = .016) and overall survival (P = .004) when compared with those who did not flare or have an immune-related adverse event. According to Ms. Tison, this has been reported before, but a more surprising finding was that the gain in progression-free survival and overall survival was lost in those treated with an immunosuppressive drug.

Even though non-PAD patients commonly receive steroids for immune-related adverse events such as colitis, the loss of benefit in PAD patients who received immunosuppressive therapies may be caused by, at least in part, cross-reactivity between tumor antigens and autoantigens, Ms. Tison speculated.

Ms. Tison was cautious in drawing conclusions about specific strategies to optimize benefits from checkpoint inhibitors in PAD based on this limited series of patients. However, she did suggest that discontinuation of immunosuppressive therapies prior to initiating checkpoint inhibitors may be prudent in PAD patients, particularly those with inactive disease.

Overall, she emphasized that checkpoint inhibitors “have revolutionized the management of several cancers” and should not be denied to PAD patients who are otherwise appropriate candidates. Although flares are common, more than half of PAD patients in this series did not flare and flares were mild to moderate in most of those who did.

“The response to checkpoint inhibitors in PAD patients is good,” Ms. Tison advised. For those who do flare, “we need prospective studies to understand which strategies provide a good balance of benefit to risk” for cancer immunotherapy and for the options to manage immune-related adverse events.

The study was not industry funded. Ms. Tison reported no potential conflicts of interest.

SOURCE: Tison A et al. Ann Rheum Dis. 2018;77(Suppl 2):147. EULAR Congress 2018, Abstract OP0196.

AMSTERDAM – Opioids cannot be justified for the routine treatment for musculoskeletal pain because risks outweigh benefits, according to a detailed review of published studies presented at the European Congress of Rheumatology.

“There is very little evidence of benefit for the long-term management of nonmalignant pain, but very good evidence for harm,” reported Blair Smith, MD, head of the population health sciences division, University of Dundee (Scotland).

Ted Bosworth/MDedge News

In the treatment of musculoskeletal pain, the goals are increased function and quality of life, rather than complete relief of pain, according to Dr. Smith. On this basis, opioids are not an appropriate routine therapy. He reported that pain relief is not well documented, while side effects such as sedation, dizziness, and constipation, are likely to be counterproductive to improved outcomes.

There is no absolute contraindication for opioids in the control of chronic musculoskeletal pain, but Dr. Smith’s summary of the data led him to conclude that they should be used judiciously and “only for carefully selected patients.”

Of the many studies he reviewed to draw this conclusion, one of the most recent was identified as the most persuasive. Published earlier this year, the SPACE study is “the first good-quality study of long-term opioid use” in patients with musculoskeletal complaints. It was negative.

“The pain intensity at the end of 12 months of treatment was slightly but significantly worse among those randomized to opioids,” reported Dr. Smith. “There was no difference in patient function, but there was an increased risk of adverse events.”

In the SPACE study, 240 patients with moderate to severe chronic back pain or hip or knee osteoarthritis were randomized to opioid or nonopioid pain management. In the nonopioid group, the first therapeutic step was acetaminophen, but medications could be changed, added, or adjusted within both groups to improve patient response.

At the end of 12 months, a lack of benefit on both pain control and functional improvement from opioids relative to nonopioid treatment was accompanied by a higher rate of adverse effects. This led the authors to conclude that opioids are not supported for musculoskeletal pain.

Not all the evidence argues against opioids for noncancer pain management, according to Dr. Smith, but he emphasized that those who support use of opioids do so for pain control only. They do not confirm an advantage for function and quality of life, which he suggested are the key endpoints. For example, a 2010 Cochrane review concluded from a systematic literature review that there is “weak evidence” for pain relief but inconclusive evidence of an improvement in functioning and quality of life.

Other investigators have drawn the same conclusion, according to Dr. Smith. He cited a statement from the International Association for Study of Pain that advises, “Caution should be used for prescribing opioids for chronic pain.” Although this statement was not specific to musculoskeletal pain, the IASP does specify that pain medications should be employed “to promote increased function and improved quality of life rather than complete relief of pain,” according to Dr. Smith.

Opioid prescriptions for chronic pain have been increasing in Europe as they have in the United States, but Dr. Smith indicated that opioids, if used at all, should be prescribed for very short periods and for very specific goals, particularly improvement in function.

“Probably most important for my [primary care] colleagues, patients prescribed opioids should be evaluated early and frequently to gauge benefit,” Dr. Smith said. Although he believes pain control is an important and worthwhile goal, it must be approached within the context of improved well-being rather than as an isolated endpoint.
 

SOURCE: Smith B et al. EULAR 2018, Abstract No. SP0073.

AMSTERDAM – Opioids cannot be justified for the routine treatment for musculoskeletal pain because risks outweigh benefits, according to a detailed review of published studies presented at the European Congress of Rheumatology.

“There is very little evidence of benefit for the long-term management of nonmalignant pain, but very good evidence for harm,” reported Blair Smith, MD, head of the population health sciences division, University of Dundee (Scotland).

Ted Bosworth/MDedge News

In the treatment of musculoskeletal pain, the goals are increased function and quality of life, rather than complete relief of pain, according to Dr. Smith. On this basis, opioids are not an appropriate routine therapy. He reported that pain relief is not well documented, while side effects such as sedation, dizziness, and constipation, are likely to be counterproductive to improved outcomes.

There is no absolute contraindication for opioids in the control of chronic musculoskeletal pain, but Dr. Smith’s summary of the data led him to conclude that they should be used judiciously and “only for carefully selected patients.”

Of the many studies he reviewed to draw this conclusion, one of the most recent was identified as the most persuasive. Published earlier this year, the SPACE study is “the first good-quality study of long-term opioid use” in patients with musculoskeletal complaints. It was negative.

“The pain intensity at the end of 12 months of treatment was slightly but significantly worse among those randomized to opioids,” reported Dr. Smith. “There was no difference in patient function, but there was an increased risk of adverse events.”

In the SPACE study, 240 patients with moderate to severe chronic back pain or hip or knee osteoarthritis were randomized to opioid or nonopioid pain management. In the nonopioid group, the first therapeutic step was acetaminophen, but medications could be changed, added, or adjusted within both groups to improve patient response.

At the end of 12 months, a lack of benefit on both pain control and functional improvement from opioids relative to nonopioid treatment was accompanied by a higher rate of adverse effects. This led the authors to conclude that opioids are not supported for musculoskeletal pain.

Not all the evidence argues against opioids for noncancer pain management, according to Dr. Smith, but he emphasized that those who support use of opioids do so for pain control only. They do not confirm an advantage for function and quality of life, which he suggested are the key endpoints. For example, a 2010 Cochrane review concluded from a systematic literature review that there is “weak evidence” for pain relief but inconclusive evidence of an improvement in functioning and quality of life.

Other investigators have drawn the same conclusion, according to Dr. Smith. He cited a statement from the International Association for Study of Pain that advises, “Caution should be used for prescribing opioids for chronic pain.” Although this statement was not specific to musculoskeletal pain, the IASP does specify that pain medications should be employed “to promote increased function and improved quality of life rather than complete relief of pain,” according to Dr. Smith.

Opioid prescriptions for chronic pain have been increasing in Europe as they have in the United States, but Dr. Smith indicated that opioids, if used at all, should be prescribed for very short periods and for very specific goals, particularly improvement in function.

“Probably most important for my [primary care] colleagues, patients prescribed opioids should be evaluated early and frequently to gauge benefit,” Dr. Smith said. Although he believes pain control is an important and worthwhile goal, it must be approached within the context of improved well-being rather than as an isolated endpoint.
 

SOURCE: Smith B et al. EULAR 2018, Abstract No. SP0073.

AMSTERDAM – Opioids cannot be justified for the routine treatment for musculoskeletal pain because risks outweigh benefits, according to a detailed review of published studies presented at the European Congress of Rheumatology.

“There is very little evidence of benefit for the long-term management of nonmalignant pain, but very good evidence for harm,” reported Blair Smith, MD, head of the population health sciences division, University of Dundee (Scotland).

Ted Bosworth/MDedge News

In the treatment of musculoskeletal pain, the goals are increased function and quality of life, rather than complete relief of pain, according to Dr. Smith. On this basis, opioids are not an appropriate routine therapy. He reported that pain relief is not well documented, while side effects such as sedation, dizziness, and constipation, are likely to be counterproductive to improved outcomes.

There is no absolute contraindication for opioids in the control of chronic musculoskeletal pain, but Dr. Smith’s summary of the data led him to conclude that they should be used judiciously and “only for carefully selected patients.”

Of the many studies he reviewed to draw this conclusion, one of the most recent was identified as the most persuasive. Published earlier this year, the SPACE study is “the first good-quality study of long-term opioid use” in patients with musculoskeletal complaints. It was negative.

“The pain intensity at the end of 12 months of treatment was slightly but significantly worse among those randomized to opioids,” reported Dr. Smith. “There was no difference in patient function, but there was an increased risk of adverse events.”

In the SPACE study, 240 patients with moderate to severe chronic back pain or hip or knee osteoarthritis were randomized to opioid or nonopioid pain management. In the nonopioid group, the first therapeutic step was acetaminophen, but medications could be changed, added, or adjusted within both groups to improve patient response.

At the end of 12 months, a lack of benefit on both pain control and functional improvement from opioids relative to nonopioid treatment was accompanied by a higher rate of adverse effects. This led the authors to conclude that opioids are not supported for musculoskeletal pain.

Not all the evidence argues against opioids for noncancer pain management, according to Dr. Smith, but he emphasized that those who support use of opioids do so for pain control only. They do not confirm an advantage for function and quality of life, which he suggested are the key endpoints. For example, a 2010 Cochrane review concluded from a systematic literature review that there is “weak evidence” for pain relief but inconclusive evidence of an improvement in functioning and quality of life.

Other investigators have drawn the same conclusion, according to Dr. Smith. He cited a statement from the International Association for Study of Pain that advises, “Caution should be used for prescribing opioids for chronic pain.” Although this statement was not specific to musculoskeletal pain, the IASP does specify that pain medications should be employed “to promote increased function and improved quality of life rather than complete relief of pain,” according to Dr. Smith.

Opioid prescriptions for chronic pain have been increasing in Europe as they have in the United States, but Dr. Smith indicated that opioids, if used at all, should be prescribed for very short periods and for very specific goals, particularly improvement in function.

“Probably most important for my [primary care] colleagues, patients prescribed opioids should be evaluated early and frequently to gauge benefit,” Dr. Smith said. Although he believes pain control is an important and worthwhile goal, it must be approached within the context of improved well-being rather than as an isolated endpoint.
 

SOURCE: Smith B et al. EULAR 2018, Abstract No. SP0073.

AMSTERDAM – In patients with psoriatic arthritis (PsA), new evidence suggests selection of biologic disease-modifying antirheumatic drugs (bDMARDs) might be individualized by T-helper cell phenotype to improve disease control, according to the results of a study presented at the European Congress of Rheumatology.

“Our findings suggest a potential for precision medicine in patients with psoriatic arthritis,” reported Ippei Miyagawa, MD, of the University of Occupational and Environmental Health in Kitakyushu, Japan.

SOURCE: Miyagawa I et al. Ann Rheum Dis. 2018;77(Suppl 2):206-7. EULAR Congress 2018, Abstract OP0321.

AMSTERDAM – In patients with psoriatic arthritis (PsA), new evidence suggests selection of biologic disease-modifying antirheumatic drugs (bDMARDs) might be individualized by T-helper cell phenotype to improve disease control, according to the results of a study presented at the European Congress of Rheumatology.

“Our findings suggest a potential for precision medicine in patients with psoriatic arthritis,” reported Ippei Miyagawa, MD, of the University of Occupational and Environmental Health in Kitakyushu, Japan.

SOURCE: Miyagawa I et al. Ann Rheum Dis. 2018;77(Suppl 2):206-7. EULAR Congress 2018, Abstract OP0321.

AMSTERDAM – In patients with psoriatic arthritis (PsA), new evidence suggests selection of biologic disease-modifying antirheumatic drugs (bDMARDs) might be individualized by T-helper cell phenotype to improve disease control, according to the results of a study presented at the European Congress of Rheumatology.

“Our findings suggest a potential for precision medicine in patients with psoriatic arthritis,” reported Ippei Miyagawa, MD, of the University of Occupational and Environmental Health in Kitakyushu, Japan.

SOURCE: Miyagawa I et al. Ann Rheum Dis. 2018;77(Suppl 2):206-7. EULAR Congress 2018, Abstract OP0321.

June 28, 1969, is the day that many consider to be the origin of the modern LGBTQ (Lesbian, Gay, Bisexual, Transgender, Queer/Questioning) movement.¹ At that time, it was not uncommon for police officers to conduct raids on bars frequented by LGBTQ patrons, but this night was different. This night the patrons of the Stonewall Inn fought back. The subsequent violent clashes fueled the national organization of groups concentrated on the goal of advocating for LGBTQ rights. On June 28th, 1970, protests to commemorate the events at Stonewall occurred; many refer to these as the first Pride events. Since then the month of June has been seen as the unofficial Pride month for the LGBTQ community. These events began as demonstrations for equal rights and protections for LGBTQ individuals, but over time, events have grown also to become a celebration of queer lives and sexuality.²

Josve05a/Getty Images

Ways to get involved

Find out about local Pride events in your community and consider attending or volunteering. One of the contributing factors to LGBTQ health disparities is limited access to competent care. Many LGBTQ youth and adults have reported experiences of discrimination in the health care setting.^3,4 When we, as health care providers, are visible at Pride events, we can have important effects on our local communities by showing them that we recognize and affirm LGBTQ identities.

Consider asking your organization or institution to provide support at local Pride events, post messages of support during Pride month, or host educational sessions about the care of LGBTQ youth.

Dr. Chelvakumar is an attending physician in the division of adolescent medicine at Nationwide Children’s Hospital and an assistant professor of clinical pediatrics at Ohio State University, both in Columbus. She said she had no relevant financial disclosures. Email her at [email protected].

Resources

Human Rights Campaign/Pride: You can learn more about the history of Pride and events in your state and community at www.hrc.org/pride.

How to contact your elected officials: You can find contact information for your local, state, and federal government representatives at www.usa.gov/elected-officials.

National LGBT Health Education Center: You can find educational resources to help optimize care of LGBT patients at www.lgbthealtheducation.org/.

U.S. Transgender Survey: You can read the report from a survey of almost 28,000 transgender respondents in the U.S. Specific information is available about experiences with health care; state level reports also available at www.ustranssurvey.org/reports/.
 

References

1. GLAAD Pride Month Resource Kit for Jounalists: www.glaad.org/publications/pridekit

2. Human Rights Campaign: History of LGBT Pride. www.hrc.org/blog/the-history-of-lgbt-pride-from-1970-to-now

3. The Report of the 2015 U.S. Transgender Survey (Washington, DC: National Center for Transgender Equality, 2016).

4. Healthy People 2020: Lesbian, Gay, Bisexual and Transgender Health.

June 28, 1969, is the day that many consider to be the origin of the modern LGBTQ (Lesbian, Gay, Bisexual, Transgender, Queer/Questioning) movement.¹ At that time, it was not uncommon for police officers to conduct raids on bars frequented by LGBTQ patrons, but this night was different. This night the patrons of the Stonewall Inn fought back. The subsequent violent clashes fueled the national organization of groups concentrated on the goal of advocating for LGBTQ rights. On June 28th, 1970, protests to commemorate the events at Stonewall occurred; many refer to these as the first Pride events. Since then the month of June has been seen as the unofficial Pride month for the LGBTQ community. These events began as demonstrations for equal rights and protections for LGBTQ individuals, but over time, events have grown also to become a celebration of queer lives and sexuality.²

Josve05a/Getty Images

Ways to get involved

Find out about local Pride events in your community and consider attending or volunteering. One of the contributing factors to LGBTQ health disparities is limited access to competent care. Many LGBTQ youth and adults have reported experiences of discrimination in the health care setting.^3,4 When we, as health care providers, are visible at Pride events, we can have important effects on our local communities by showing them that we recognize and affirm LGBTQ identities.

Consider asking your organization or institution to provide support at local Pride events, post messages of support during Pride month, or host educational sessions about the care of LGBTQ youth.

Dr. Chelvakumar is an attending physician in the division of adolescent medicine at Nationwide Children’s Hospital and an assistant professor of clinical pediatrics at Ohio State University, both in Columbus. She said she had no relevant financial disclosures. Email her at [email protected].

Resources

Human Rights Campaign/Pride: You can learn more about the history of Pride and events in your state and community at www.hrc.org/pride.

How to contact your elected officials: You can find contact information for your local, state, and federal government representatives at www.usa.gov/elected-officials.

National LGBT Health Education Center: You can find educational resources to help optimize care of LGBT patients at www.lgbthealtheducation.org/.

U.S. Transgender Survey: You can read the report from a survey of almost 28,000 transgender respondents in the U.S. Specific information is available about experiences with health care; state level reports also available at www.ustranssurvey.org/reports/.
 

References

1. GLAAD Pride Month Resource Kit for Jounalists: www.glaad.org/publications/pridekit

2. Human Rights Campaign: History of LGBT Pride. www.hrc.org/blog/the-history-of-lgbt-pride-from-1970-to-now

3. The Report of the 2015 U.S. Transgender Survey (Washington, DC: National Center for Transgender Equality, 2016).

4. Healthy People 2020: Lesbian, Gay, Bisexual and Transgender Health.

June 28, 1969, is the day that many consider to be the origin of the modern LGBTQ (Lesbian, Gay, Bisexual, Transgender, Queer/Questioning) movement.¹ At that time, it was not uncommon for police officers to conduct raids on bars frequented by LGBTQ patrons, but this night was different. This night the patrons of the Stonewall Inn fought back. The subsequent violent clashes fueled the national organization of groups concentrated on the goal of advocating for LGBTQ rights. On June 28th, 1970, protests to commemorate the events at Stonewall occurred; many refer to these as the first Pride events. Since then the month of June has been seen as the unofficial Pride month for the LGBTQ community. These events began as demonstrations for equal rights and protections for LGBTQ individuals, but over time, events have grown also to become a celebration of queer lives and sexuality.²

Josve05a/Getty Images

Ways to get involved

Find out about local Pride events in your community and consider attending or volunteering. One of the contributing factors to LGBTQ health disparities is limited access to competent care. Many LGBTQ youth and adults have reported experiences of discrimination in the health care setting.^3,4 When we, as health care providers, are visible at Pride events, we can have important effects on our local communities by showing them that we recognize and affirm LGBTQ identities.

Consider asking your organization or institution to provide support at local Pride events, post messages of support during Pride month, or host educational sessions about the care of LGBTQ youth.

Dr. Chelvakumar is an attending physician in the division of adolescent medicine at Nationwide Children’s Hospital and an assistant professor of clinical pediatrics at Ohio State University, both in Columbus. She said she had no relevant financial disclosures. Email her at [email protected].

Resources

Human Rights Campaign/Pride: You can learn more about the history of Pride and events in your state and community at www.hrc.org/pride.

How to contact your elected officials: You can find contact information for your local, state, and federal government representatives at www.usa.gov/elected-officials.

National LGBT Health Education Center: You can find educational resources to help optimize care of LGBT patients at www.lgbthealtheducation.org/.

U.S. Transgender Survey: You can read the report from a survey of almost 28,000 transgender respondents in the U.S. Specific information is available about experiences with health care; state level reports also available at www.ustranssurvey.org/reports/.
 

References

1. GLAAD Pride Month Resource Kit for Jounalists: www.glaad.org/publications/pridekit

2. Human Rights Campaign: History of LGBT Pride. www.hrc.org/blog/the-history-of-lgbt-pride-from-1970-to-now

3. The Report of the 2015 U.S. Transgender Survey (Washington, DC: National Center for Transgender Equality, 2016).

4. Healthy People 2020: Lesbian, Gay, Bisexual and Transgender Health.

Median progression-free survival (PFS) based on traditional RECIST criteria did not correlate with overall survival (OS) in a meta-analysis of 12 randomized controlled trials of nivolumab or pembrolizumab monotherapy.

There was no correlation in terms of medians or gains in medians, although hazard ratios for OS and PFS did correlate significantly, said Bishal Gyawali, MD, PhD, of Nagoya (Japan) University Hospital with his associates. “The protective effects of treatment were greater for OS than for PFS,” they concluded in JAMA Network Open. “Progression-free survival cannot adequately capture the benefit of PD-1 inhibitors; thus, OS should remain the gold standard end point for trials of PD-1 inhibitors.”

Progression-free survival often has been used as a surrogate for OS because the latter takes time to ascertain and can be contaminated by crossover or postprogression treatment. However, it can be problematic to assume that the two outcomes correlate. Progression “is defined as an increase in tumor size beyond an arbitrary cutoff and is prone to bias, particularly when the investigators are not blinded,” the researchers noted. Furthermore, PD-1 inhibitors show an “atypical response pattern,” including long durations of response, responses after initial progression (known as pseudoprogression), and even response after treatment cessation.

The analysis, the first to formally compare PFS and OS across PD-1 inhibitors, included 10 randomized, controlled trials comparing nivolumab or pembrolizumab with nonimmunotherapy in adults with solid tumors. Two additional trials evaluated pembrolizumab or nivolumab following treatment with ipilimumab. In all, the studies included 5,417 patients. There was no significant heterogeneity among studies, the researchers said.

Median PFS and median OS correlated poorly, with an R² value of 0.46 (P = .09). Change in PFS also did not correlate with change in OS (R² = 0.23; P = .28). In contrast, hazard ratios for PFS and OS correlated significantly (R2 = 0.41; P = .048). The protective effects of treatment were higher for OS than for PFS (pooled HR, 1.2; 95% confidence interval, 1.1-1.3; P = .002).

This might be because traditional RECIST (response evaluation criteria in solid tumors) criteria predate the era of immunotherapy and do not accurately capture disease progression when patients are on immuno-oncologics. For example, pseudoprogression (in which T-cell infiltrates cause the tumor to grow before it shrinks) could be misconstrued as progression. Also, PD-1 inhibitors can continue working even after treatment cessation, which could affect OS more than PFS, the researchers noted.

Regardless, “PD-1 inhibitors may have larger effects on OS than on PFS, which would be unprecedented in oncology therapeutics,” they concluded. “These results support the rationale of using OS as the primary end point of future phase 3 trials of PD-1 inhibitors and discourage the use of PFS as a sole primary end point as the latter may provide misleading information about the efficacy of these drugs.”

Funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, and the Engelberg Foundation. The investigators reported having no relevant conflicts of interest. One coinvestigator reported research support from the Laura and John Arnold Foundation. The other investigators had no conflicts.

SOURCE: Gyawali B et al. JAMA Network Open. 2018 June 22. doi: 10.1001/jamanetworkopen.2018.0416.

Median progression-free survival (PFS) based on traditional RECIST criteria did not correlate with overall survival (OS) in a meta-analysis of 12 randomized controlled trials of nivolumab or pembrolizumab monotherapy.

There was no correlation in terms of medians or gains in medians, although hazard ratios for OS and PFS did correlate significantly, said Bishal Gyawali, MD, PhD, of Nagoya (Japan) University Hospital with his associates. “The protective effects of treatment were greater for OS than for PFS,” they concluded in JAMA Network Open. “Progression-free survival cannot adequately capture the benefit of PD-1 inhibitors; thus, OS should remain the gold standard end point for trials of PD-1 inhibitors.”

Progression-free survival often has been used as a surrogate for OS because the latter takes time to ascertain and can be contaminated by crossover or postprogression treatment. However, it can be problematic to assume that the two outcomes correlate. Progression “is defined as an increase in tumor size beyond an arbitrary cutoff and is prone to bias, particularly when the investigators are not blinded,” the researchers noted. Furthermore, PD-1 inhibitors show an “atypical response pattern,” including long durations of response, responses after initial progression (known as pseudoprogression), and even response after treatment cessation.

The analysis, the first to formally compare PFS and OS across PD-1 inhibitors, included 10 randomized, controlled trials comparing nivolumab or pembrolizumab with nonimmunotherapy in adults with solid tumors. Two additional trials evaluated pembrolizumab or nivolumab following treatment with ipilimumab. In all, the studies included 5,417 patients. There was no significant heterogeneity among studies, the researchers said.

Median PFS and median OS correlated poorly, with an R² value of 0.46 (P = .09). Change in PFS also did not correlate with change in OS (R² = 0.23; P = .28). In contrast, hazard ratios for PFS and OS correlated significantly (R2 = 0.41; P = .048). The protective effects of treatment were higher for OS than for PFS (pooled HR, 1.2; 95% confidence interval, 1.1-1.3; P = .002).

This might be because traditional RECIST (response evaluation criteria in solid tumors) criteria predate the era of immunotherapy and do not accurately capture disease progression when patients are on immuno-oncologics. For example, pseudoprogression (in which T-cell infiltrates cause the tumor to grow before it shrinks) could be misconstrued as progression. Also, PD-1 inhibitors can continue working even after treatment cessation, which could affect OS more than PFS, the researchers noted.

Regardless, “PD-1 inhibitors may have larger effects on OS than on PFS, which would be unprecedented in oncology therapeutics,” they concluded. “These results support the rationale of using OS as the primary end point of future phase 3 trials of PD-1 inhibitors and discourage the use of PFS as a sole primary end point as the latter may provide misleading information about the efficacy of these drugs.”

Funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, and the Engelberg Foundation. The investigators reported having no relevant conflicts of interest. One coinvestigator reported research support from the Laura and John Arnold Foundation. The other investigators had no conflicts.

SOURCE: Gyawali B et al. JAMA Network Open. 2018 June 22. doi: 10.1001/jamanetworkopen.2018.0416.

Median progression-free survival (PFS) based on traditional RECIST criteria did not correlate with overall survival (OS) in a meta-analysis of 12 randomized controlled trials of nivolumab or pembrolizumab monotherapy.

There was no correlation in terms of medians or gains in medians, although hazard ratios for OS and PFS did correlate significantly, said Bishal Gyawali, MD, PhD, of Nagoya (Japan) University Hospital with his associates. “The protective effects of treatment were greater for OS than for PFS,” they concluded in JAMA Network Open. “Progression-free survival cannot adequately capture the benefit of PD-1 inhibitors; thus, OS should remain the gold standard end point for trials of PD-1 inhibitors.”

Progression-free survival often has been used as a surrogate for OS because the latter takes time to ascertain and can be contaminated by crossover or postprogression treatment. However, it can be problematic to assume that the two outcomes correlate. Progression “is defined as an increase in tumor size beyond an arbitrary cutoff and is prone to bias, particularly when the investigators are not blinded,” the researchers noted. Furthermore, PD-1 inhibitors show an “atypical response pattern,” including long durations of response, responses after initial progression (known as pseudoprogression), and even response after treatment cessation.

The analysis, the first to formally compare PFS and OS across PD-1 inhibitors, included 10 randomized, controlled trials comparing nivolumab or pembrolizumab with nonimmunotherapy in adults with solid tumors. Two additional trials evaluated pembrolizumab or nivolumab following treatment with ipilimumab. In all, the studies included 5,417 patients. There was no significant heterogeneity among studies, the researchers said.

Median PFS and median OS correlated poorly, with an R² value of 0.46 (P = .09). Change in PFS also did not correlate with change in OS (R² = 0.23; P = .28). In contrast, hazard ratios for PFS and OS correlated significantly (R2 = 0.41; P = .048). The protective effects of treatment were higher for OS than for PFS (pooled HR, 1.2; 95% confidence interval, 1.1-1.3; P = .002).

This might be because traditional RECIST (response evaluation criteria in solid tumors) criteria predate the era of immunotherapy and do not accurately capture disease progression when patients are on immuno-oncologics. For example, pseudoprogression (in which T-cell infiltrates cause the tumor to grow before it shrinks) could be misconstrued as progression. Also, PD-1 inhibitors can continue working even after treatment cessation, which could affect OS more than PFS, the researchers noted.

Regardless, “PD-1 inhibitors may have larger effects on OS than on PFS, which would be unprecedented in oncology therapeutics,” they concluded. “These results support the rationale of using OS as the primary end point of future phase 3 trials of PD-1 inhibitors and discourage the use of PFS as a sole primary end point as the latter may provide misleading information about the efficacy of these drugs.”

Funders included the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, and the Engelberg Foundation. The investigators reported having no relevant conflicts of interest. One coinvestigator reported research support from the Laura and John Arnold Foundation. The other investigators had no conflicts.

SOURCE: Gyawali B et al. JAMA Network Open. 2018 June 22. doi: 10.1001/jamanetworkopen.2018.0416.

ORLANDO – Higher risk translates to higher benefits. That’s the message of a new analysis of the ODYSSEY Outcomes trial in the PCSK9-inhibitor alirocumab that finds people with diabetes gained about twice the reduction in risk of major adverse cardiac events as their non-diabetic counterparts.

“Patients with diabetes and a recent heart attack are at double the risk of a cardiovascular event in the next 3 years as are nondiabetics, despite guideline-based care,” said study presenting author Kausik Ray, MD, ChB, of the School of Public Health of Imperial College London, in an interview. “These patients in our study had LDL of around 89 mg/dL despite high-intensity statins. Current guidelines recommend a goal of LDL of 55 mg/dL in this group. We brought LDL down to around 38 mg/ dL, and showed that by doing this, diabetics derived a greater reduction in the risk of major cardiovascular events. A greater absolute benefit was observed, and a smaller number needed to treat.”

Dr. Ray presented the study findings, a prespecified analysis of results of ODYSSEY Outcomes, at the annual scientific sessions of the American Diabetes Association.

The trial randomly assigned 18,924 patients with recent acute coronary syndrome and LDL cholesterol of at least 70 mg/dL, despite maximum statin therapy, to 75 mg of alirocumab every 2 weeks or placebo. Doses of alirocumab were increased blindly, to 150 mg, to reach LDL cholesterol levels of 25-50 mg/dL.

During a median 2.8 years of follow-up, the overall cumulative rate of major cardiac adverse events (coronary heart disease death, nonfatal MI, ischemic stroke, or hospitalization for unstable angina) occurred in 9.5% of the overall population randomized to alirocumab and 11.1% of those on placebo, for an absolute risk reduction of 1.6% and a statistically significant and clinically meaningful 15% reduction in relative risk. The results were presented at the annual scientific sessions of the American College of Cardiology in March.

In the current analysis, in patients with diabetes, the cumulative rate of incidents was 14.1% (380 of 2,693) with alirocumab and 16.4% (452 of 2,751) with placebo, for an ARR of 2.3%.

The ARRs for the prediabetes and normoglycemia groups were both 1.2%.

Dr. Ray noted that there’s no sign that the drug works differently in patients with diabetes. “The drug works in the same way and as effectively in everyone: LDL came down by 64% at 16 weeks in everyone. But absolute risk depends upon absolute risk to start with. So, in higher-risk patients, the absolute benefit is greater.”

According to Dr. Ray, the number needed to treat is 43 over 30 months for people with diabetes and 73 over 30 months for people without diabetes.

Prediman K. Shah, MD, director of the Oppenheimer Atherosclerosis Research Center at Cedars-Sinai Medical Center and professor of medicine at the University of California, Los Angeles, questioned the cost effectiveness of the medication in an interview.

“Even among the diabetics, the absolute risk reduction is about 2%, which is underwhelming considering the high cost,” he said. “If the cost were to drop to levels closer to cost of statins, such a small risk reduction may be worth the expense.”

Insurers have been skeptical of covering alirocumab because of its $14,000/year cost. However, Sanofi and Regeneron, which jointly market alirocumab, announced in March 2018 that they “will offer U.S. payers that agree to reduce burdensome access barriers for high-risk patients a further reduced net price for Praluent Injection (alirocumab) in alignment with a new value assessment for high-risk patients from the [United States].”

In response, Dr. Ray said “the benefits quoted are time-to-first-event, and these are modest. But if you look at recurrent events, which represent the natural course of disease, then the benefits and absolute benefits are greater. These are add-on therapies and will never be used in every single patient at current cost.”

Glen J. Pearson, PharmD, of the University of Alberta, Edmonton, said in an interview that, “while these absolute numbers do seem relatively small, it must be remembered that these patients are already receiving very effective therapies to reduce their risk of future cardiovascular outcomes.”

ODYSSEY Outcomes was funded by Sanofi and Regeneron. The presenter reports various disclosures including consulting and research support relationships with Sanofi and Regeneron. The other study authors report various disclosures. Dr. Pearson reports no relevant disclosures. Dr. Shah reports receiving grant support from Sanofi Regeneron.

SOURCE: Ray K et al. ADA 2018, Abstract 6-LB.

ORLANDO – Higher risk translates to higher benefits. That’s the message of a new analysis of the ODYSSEY Outcomes trial in the PCSK9-inhibitor alirocumab that finds people with diabetes gained about twice the reduction in risk of major adverse cardiac events as their non-diabetic counterparts.

“Patients with diabetes and a recent heart attack are at double the risk of a cardiovascular event in the next 3 years as are nondiabetics, despite guideline-based care,” said study presenting author Kausik Ray, MD, ChB, of the School of Public Health of Imperial College London, in an interview. “These patients in our study had LDL of around 89 mg/dL despite high-intensity statins. Current guidelines recommend a goal of LDL of 55 mg/dL in this group. We brought LDL down to around 38 mg/ dL, and showed that by doing this, diabetics derived a greater reduction in the risk of major cardiovascular events. A greater absolute benefit was observed, and a smaller number needed to treat.”

Dr. Ray presented the study findings, a prespecified analysis of results of ODYSSEY Outcomes, at the annual scientific sessions of the American Diabetes Association.

The trial randomly assigned 18,924 patients with recent acute coronary syndrome and LDL cholesterol of at least 70 mg/dL, despite maximum statin therapy, to 75 mg of alirocumab every 2 weeks or placebo. Doses of alirocumab were increased blindly, to 150 mg, to reach LDL cholesterol levels of 25-50 mg/dL.

During a median 2.8 years of follow-up, the overall cumulative rate of major cardiac adverse events (coronary heart disease death, nonfatal MI, ischemic stroke, or hospitalization for unstable angina) occurred in 9.5% of the overall population randomized to alirocumab and 11.1% of those on placebo, for an absolute risk reduction of 1.6% and a statistically significant and clinically meaningful 15% reduction in relative risk. The results were presented at the annual scientific sessions of the American College of Cardiology in March.

In the current analysis, in patients with diabetes, the cumulative rate of incidents was 14.1% (380 of 2,693) with alirocumab and 16.4% (452 of 2,751) with placebo, for an ARR of 2.3%.

The ARRs for the prediabetes and normoglycemia groups were both 1.2%.

Dr. Ray noted that there’s no sign that the drug works differently in patients with diabetes. “The drug works in the same way and as effectively in everyone: LDL came down by 64% at 16 weeks in everyone. But absolute risk depends upon absolute risk to start with. So, in higher-risk patients, the absolute benefit is greater.”

According to Dr. Ray, the number needed to treat is 43 over 30 months for people with diabetes and 73 over 30 months for people without diabetes.

Prediman K. Shah, MD, director of the Oppenheimer Atherosclerosis Research Center at Cedars-Sinai Medical Center and professor of medicine at the University of California, Los Angeles, questioned the cost effectiveness of the medication in an interview.

“Even among the diabetics, the absolute risk reduction is about 2%, which is underwhelming considering the high cost,” he said. “If the cost were to drop to levels closer to cost of statins, such a small risk reduction may be worth the expense.”

Insurers have been skeptical of covering alirocumab because of its $14,000/year cost. However, Sanofi and Regeneron, which jointly market alirocumab, announced in March 2018 that they “will offer U.S. payers that agree to reduce burdensome access barriers for high-risk patients a further reduced net price for Praluent Injection (alirocumab) in alignment with a new value assessment for high-risk patients from the [United States].”

In response, Dr. Ray said “the benefits quoted are time-to-first-event, and these are modest. But if you look at recurrent events, which represent the natural course of disease, then the benefits and absolute benefits are greater. These are add-on therapies and will never be used in every single patient at current cost.”

Glen J. Pearson, PharmD, of the University of Alberta, Edmonton, said in an interview that, “while these absolute numbers do seem relatively small, it must be remembered that these patients are already receiving very effective therapies to reduce their risk of future cardiovascular outcomes.”

ODYSSEY Outcomes was funded by Sanofi and Regeneron. The presenter reports various disclosures including consulting and research support relationships with Sanofi and Regeneron. The other study authors report various disclosures. Dr. Pearson reports no relevant disclosures. Dr. Shah reports receiving grant support from Sanofi Regeneron.

SOURCE: Ray K et al. ADA 2018, Abstract 6-LB.

ORLANDO – Higher risk translates to higher benefits. That’s the message of a new analysis of the ODYSSEY Outcomes trial in the PCSK9-inhibitor alirocumab that finds people with diabetes gained about twice the reduction in risk of major adverse cardiac events as their non-diabetic counterparts.

“Patients with diabetes and a recent heart attack are at double the risk of a cardiovascular event in the next 3 years as are nondiabetics, despite guideline-based care,” said study presenting author Kausik Ray, MD, ChB, of the School of Public Health of Imperial College London, in an interview. “These patients in our study had LDL of around 89 mg/dL despite high-intensity statins. Current guidelines recommend a goal of LDL of 55 mg/dL in this group. We brought LDL down to around 38 mg/ dL, and showed that by doing this, diabetics derived a greater reduction in the risk of major cardiovascular events. A greater absolute benefit was observed, and a smaller number needed to treat.”

Dr. Ray presented the study findings, a prespecified analysis of results of ODYSSEY Outcomes, at the annual scientific sessions of the American Diabetes Association.

The trial randomly assigned 18,924 patients with recent acute coronary syndrome and LDL cholesterol of at least 70 mg/dL, despite maximum statin therapy, to 75 mg of alirocumab every 2 weeks or placebo. Doses of alirocumab were increased blindly, to 150 mg, to reach LDL cholesterol levels of 25-50 mg/dL.

During a median 2.8 years of follow-up, the overall cumulative rate of major cardiac adverse events (coronary heart disease death, nonfatal MI, ischemic stroke, or hospitalization for unstable angina) occurred in 9.5% of the overall population randomized to alirocumab and 11.1% of those on placebo, for an absolute risk reduction of 1.6% and a statistically significant and clinically meaningful 15% reduction in relative risk. The results were presented at the annual scientific sessions of the American College of Cardiology in March.

In the current analysis, in patients with diabetes, the cumulative rate of incidents was 14.1% (380 of 2,693) with alirocumab and 16.4% (452 of 2,751) with placebo, for an ARR of 2.3%.

The ARRs for the prediabetes and normoglycemia groups were both 1.2%.

Dr. Ray noted that there’s no sign that the drug works differently in patients with diabetes. “The drug works in the same way and as effectively in everyone: LDL came down by 64% at 16 weeks in everyone. But absolute risk depends upon absolute risk to start with. So, in higher-risk patients, the absolute benefit is greater.”

According to Dr. Ray, the number needed to treat is 43 over 30 months for people with diabetes and 73 over 30 months for people without diabetes.

Prediman K. Shah, MD, director of the Oppenheimer Atherosclerosis Research Center at Cedars-Sinai Medical Center and professor of medicine at the University of California, Los Angeles, questioned the cost effectiveness of the medication in an interview.

“Even among the diabetics, the absolute risk reduction is about 2%, which is underwhelming considering the high cost,” he said. “If the cost were to drop to levels closer to cost of statins, such a small risk reduction may be worth the expense.”

Insurers have been skeptical of covering alirocumab because of its $14,000/year cost. However, Sanofi and Regeneron, which jointly market alirocumab, announced in March 2018 that they “will offer U.S. payers that agree to reduce burdensome access barriers for high-risk patients a further reduced net price for Praluent Injection (alirocumab) in alignment with a new value assessment for high-risk patients from the [United States].”

In response, Dr. Ray said “the benefits quoted are time-to-first-event, and these are modest. But if you look at recurrent events, which represent the natural course of disease, then the benefits and absolute benefits are greater. These are add-on therapies and will never be used in every single patient at current cost.”

Glen J. Pearson, PharmD, of the University of Alberta, Edmonton, said in an interview that, “while these absolute numbers do seem relatively small, it must be remembered that these patients are already receiving very effective therapies to reduce their risk of future cardiovascular outcomes.”

ODYSSEY Outcomes was funded by Sanofi and Regeneron. The presenter reports various disclosures including consulting and research support relationships with Sanofi and Regeneron. The other study authors report various disclosures. Dr. Pearson reports no relevant disclosures. Dr. Shah reports receiving grant support from Sanofi Regeneron.

SOURCE: Ray K et al. ADA 2018, Abstract 6-LB.

Inadvertent bowel injuries that happen during ventral hernia surgery are rare, occurring in only about 2% of these cases, a database review has determined. But patients who experience this kind of injury have a significantly longer length of stay and are at increased risk for fistulas, sepsis, reoperations and readmissions, and even death, David M. Krpata, MD, of the Cleveland Clinic and his colleagues wrote in Surgery.

“When these events occur, the surgeon must decide whether to repair primarily or resect the bowel, proceed with definitive hernia repair with mesh, or abort the procedure and repair primarily the hernia defect,” they wrote. The lack of published studies on this injury prompted the research team to look into prevalence and outcomes in order to offer some data to guide surgical decision making.

The research team examined surgical outcomes among 5,916 patients who underwent a ventral hernia repair during 2013-2017 and were included in the Americas Hernia Society Quality Collaborative, a national hernia surgery database. The database included information from the records of 180 surgeons.

The multivariate analysis controlled for sex, race, elective case, wound status, hernia width, immunosuppressants, subcutaneous flaps, myofascial release, drains, smoking, body mass index, age, diabetes, laparoscopic surgery, mesh type, and concomitant procedure.

Among the cohort, there were 110 full-thickness bowel injuries (1.9%). Three patients also had a bladder injury. Most of the enterotomies were small-bowel injuries (85%); the rest were colon injuries. The majority of patients (64%) underwent a primary repair; 36% required bowel resection. Injuries were most common among patients with larger hernia defects, recurrent repairs, mesh or active infection, a history of abdominal wound infection, and older age.

Patients with the accidental enterotomies were less likely to get a mesh repair (85% vs. 94%). When they did, their surgeons were less likely to use a permanent synthetic barrier–coated mesh and more likely to use biologic mesh, absorbable mesh, and/or uncoated synthetic mesh. But the investigators wrote: “Further data are necessary to address specifically what is the most appropriate mesh to utilize (if any) after an inadvertent enterotomy has occurred and which compartment within the abdominal wall is safest.”

In the fully adjusted analysis, injured patients were no more likely to experience surgical site infections, but they were significantly more likely to develop an enterocutaneous fistula (4% vs. 1%), sepsis (2% vs. 1%), and to die (3% vs 1%) after a bowel injury. They also had a significantly longer length of stay (7 vs. 4 days), and more reoperations (6% vs. 3%). Major wound complication was the most common reason for reoperation (43%) and readmission (58%).

The limitations of this study mostly reflect variables not captured by the database. For example, the tenacity of adhesions and the duration of adhesiolysis are not accounted for. The investigators noted that “patients with an enterotomy likely had more tenacious adhesions, given that an operative time greater than 2 hours had a greater association with an enterotomy (91% vs. 71%).” These patients were more likely to be older and have COPD. In addition, unrecognized enterotomies were not accounted for in the data, but inclusion of those injuries would likely have meant worse outcomes.

“Although definitive hernia repair with mesh can be safely performed, surgeons should consider multiple factors, including type of mesh and location of mesh in the abdominal wall, before proceeding with definitive repair in any case of an enterotomy,” Dr. Krpata and his coauthors concluded.

The investigators reported no financial disclosures.

[email protected]

SOURCE: Krpata et al. Surg. 2018. doi: 10.1016/j.surg.2018.04.003

Inadvertent bowel injuries that happen during ventral hernia surgery are rare, occurring in only about 2% of these cases, a database review has determined. But patients who experience this kind of injury have a significantly longer length of stay and are at increased risk for fistulas, sepsis, reoperations and readmissions, and even death, David M. Krpata, MD, of the Cleveland Clinic and his colleagues wrote in Surgery.

“When these events occur, the surgeon must decide whether to repair primarily or resect the bowel, proceed with definitive hernia repair with mesh, or abort the procedure and repair primarily the hernia defect,” they wrote. The lack of published studies on this injury prompted the research team to look into prevalence and outcomes in order to offer some data to guide surgical decision making.

The research team examined surgical outcomes among 5,916 patients who underwent a ventral hernia repair during 2013-2017 and were included in the Americas Hernia Society Quality Collaborative, a national hernia surgery database. The database included information from the records of 180 surgeons.

The multivariate analysis controlled for sex, race, elective case, wound status, hernia width, immunosuppressants, subcutaneous flaps, myofascial release, drains, smoking, body mass index, age, diabetes, laparoscopic surgery, mesh type, and concomitant procedure.

Among the cohort, there were 110 full-thickness bowel injuries (1.9%). Three patients also had a bladder injury. Most of the enterotomies were small-bowel injuries (85%); the rest were colon injuries. The majority of patients (64%) underwent a primary repair; 36% required bowel resection. Injuries were most common among patients with larger hernia defects, recurrent repairs, mesh or active infection, a history of abdominal wound infection, and older age.

Patients with the accidental enterotomies were less likely to get a mesh repair (85% vs. 94%). When they did, their surgeons were less likely to use a permanent synthetic barrier–coated mesh and more likely to use biologic mesh, absorbable mesh, and/or uncoated synthetic mesh. But the investigators wrote: “Further data are necessary to address specifically what is the most appropriate mesh to utilize (if any) after an inadvertent enterotomy has occurred and which compartment within the abdominal wall is safest.”

In the fully adjusted analysis, injured patients were no more likely to experience surgical site infections, but they were significantly more likely to develop an enterocutaneous fistula (4% vs. 1%), sepsis (2% vs. 1%), and to die (3% vs 1%) after a bowel injury. They also had a significantly longer length of stay (7 vs. 4 days), and more reoperations (6% vs. 3%). Major wound complication was the most common reason for reoperation (43%) and readmission (58%).

The limitations of this study mostly reflect variables not captured by the database. For example, the tenacity of adhesions and the duration of adhesiolysis are not accounted for. The investigators noted that “patients with an enterotomy likely had more tenacious adhesions, given that an operative time greater than 2 hours had a greater association with an enterotomy (91% vs. 71%).” These patients were more likely to be older and have COPD. In addition, unrecognized enterotomies were not accounted for in the data, but inclusion of those injuries would likely have meant worse outcomes.

“Although definitive hernia repair with mesh can be safely performed, surgeons should consider multiple factors, including type of mesh and location of mesh in the abdominal wall, before proceeding with definitive repair in any case of an enterotomy,” Dr. Krpata and his coauthors concluded.

The investigators reported no financial disclosures.

[email protected]

SOURCE: Krpata et al. Surg. 2018. doi: 10.1016/j.surg.2018.04.003

Inadvertent bowel injuries that happen during ventral hernia surgery are rare, occurring in only about 2% of these cases, a database review has determined. But patients who experience this kind of injury have a significantly longer length of stay and are at increased risk for fistulas, sepsis, reoperations and readmissions, and even death, David M. Krpata, MD, of the Cleveland Clinic and his colleagues wrote in Surgery.

“When these events occur, the surgeon must decide whether to repair primarily or resect the bowel, proceed with definitive hernia repair with mesh, or abort the procedure and repair primarily the hernia defect,” they wrote. The lack of published studies on this injury prompted the research team to look into prevalence and outcomes in order to offer some data to guide surgical decision making.

The research team examined surgical outcomes among 5,916 patients who underwent a ventral hernia repair during 2013-2017 and were included in the Americas Hernia Society Quality Collaborative, a national hernia surgery database. The database included information from the records of 180 surgeons.

The multivariate analysis controlled for sex, race, elective case, wound status, hernia width, immunosuppressants, subcutaneous flaps, myofascial release, drains, smoking, body mass index, age, diabetes, laparoscopic surgery, mesh type, and concomitant procedure.

Among the cohort, there were 110 full-thickness bowel injuries (1.9%). Three patients also had a bladder injury. Most of the enterotomies were small-bowel injuries (85%); the rest were colon injuries. The majority of patients (64%) underwent a primary repair; 36% required bowel resection. Injuries were most common among patients with larger hernia defects, recurrent repairs, mesh or active infection, a history of abdominal wound infection, and older age.

Patients with the accidental enterotomies were less likely to get a mesh repair (85% vs. 94%). When they did, their surgeons were less likely to use a permanent synthetic barrier–coated mesh and more likely to use biologic mesh, absorbable mesh, and/or uncoated synthetic mesh. But the investigators wrote: “Further data are necessary to address specifically what is the most appropriate mesh to utilize (if any) after an inadvertent enterotomy has occurred and which compartment within the abdominal wall is safest.”

In the fully adjusted analysis, injured patients were no more likely to experience surgical site infections, but they were significantly more likely to develop an enterocutaneous fistula (4% vs. 1%), sepsis (2% vs. 1%), and to die (3% vs 1%) after a bowel injury. They also had a significantly longer length of stay (7 vs. 4 days), and more reoperations (6% vs. 3%). Major wound complication was the most common reason for reoperation (43%) and readmission (58%).

The limitations of this study mostly reflect variables not captured by the database. For example, the tenacity of adhesions and the duration of adhesiolysis are not accounted for. The investigators noted that “patients with an enterotomy likely had more tenacious adhesions, given that an operative time greater than 2 hours had a greater association with an enterotomy (91% vs. 71%).” These patients were more likely to be older and have COPD. In addition, unrecognized enterotomies were not accounted for in the data, but inclusion of those injuries would likely have meant worse outcomes.

“Although definitive hernia repair with mesh can be safely performed, surgeons should consider multiple factors, including type of mesh and location of mesh in the abdominal wall, before proceeding with definitive repair in any case of an enterotomy,” Dr. Krpata and his coauthors concluded.

The investigators reported no financial disclosures.

[email protected]

SOURCE: Krpata et al. Surg. 2018. doi: 10.1016/j.surg.2018.04.003

To the Editor:

A 20-year-old man with no notable medical history presented to our dermatology clinic for evaluation of mildly painful, hemorrhagic bullae on the bilateral halluces of 1 month’s duration. On initial presentation the patient reported the lesions developed after wearing a new pair of tight-fitting shoes, suggesting a diagnosis of trauma-induced bullae. The patient was instructed to wear loose-fitting shoes and to follow up in 6 weeks to assess for improvement. At follow-up the bullae had resolved with residual violaceous patches on the bilateral distal halluces. He additionally developed a faint retiform erythematous patch on the left distal toe (Figure 1). The patient also had reticulate erythematous patches on the dorsal aspects of the hands extending to the forearms and legs resembling livedo reticularis. The patient was unsure if the skin lesions were triggered or worsened by cold exposure and reported that he smoked half a pack of cigarettes daily. At this time, the differential diagnosis still included trauma; however, there was concern for either embolic, thrombotic, or connective-tissue disease. A 4-mm punch biopsy of the left distal hallux demonstrated basal vacuolar interface dermatitis with superficial and deep perivascular inflammation and deep periadnexal mucin deposition (Figure 2) consistent with lupus dermatitis.

Serologic workup revealed increased antinuclear antibody titers of 1:320 (reference range, <1:40) and anti-Ro/Sjögren syndrome antigen antibodies of 86 (reference range, <20). There was no elevation in anti–double-stranded DNA, anti-Smith, antiribonucleoprotein, or anticardiolipin antibodies. Complement levels also were within reference range. Furthermore, the patient denied a history of Raynaud phenomenon, photosensitivity, oral ulcers, joint pain, shortness of breath, pleuritic chest pain, arthritis, blood clots, or any other systemic symptoms. Additional evaluation by the rheumatology department did not support criteria for systemic lupus erythematosus (SLE). In the context of the clinical presentation, histologic findings, and serologic markers, a diagnosis of chilblain lupus erythematosus (CHLE) was made. He was counseled on sun protection and smoking cessation and declined systemic therapy citing concern for side effects. Follow-up with the dermatology and rheumatology departments was advised.

Cutaneous lupus erythematosus (CLE) comprises various forms of lupus, including acute cutaneous lupus, subacute cutaneous lupus, and chronic cutaneous lupus. Chilblain lupus erythematosus is a rare subset of chronic CLE that first was described in 1888¹ and is characterized by tender violaceous papules and plaques that typically present in an acral distribution (ie, fingers, toes, nose, cheeks, ears). The skin lesions often are triggered or exacerbated by cold temperatures and dampness. As the lesions evolve, they can ulcerate, fissure, become hyperkeratotic, or result in atrophic plaques with scarring.^2,3 A subset of patients also may have concurrent Raynaud phenomenon.¹ Up to 20% of patients will eventually develop SLE, especially those patients with concurrent discoid lupus erythematosus, warranting close long-term follow-up.³ Serologic studies can reveal antinuclear antibodies, anti-Ro/Sjögren syndrome antigen antibodies, rheumatic factor, and anti–double-stranded DNA antibodies.^1,4 Hypergammaglobulinemia also is a common finding in patients with CHLE, affecting more than two-thirds of patients.¹ Typical features of CHLE seen on histopathology include interface dermatitis, perivascular lymphocytic infiltrate, apoptotic keratinocytes, lichenoid tissue reaction, and increased dermal mucin.^1,4

Chilblain lupus erythematosus most commonly presents sporadically; however, there is a familial form that has been previously described.⁵ Sporadic CHLE usually occurs in middle-aged females, in contrast to familial CHLE, which presents in early childhood.¹ The pathogenesis of the sporadic form is poorly understood, but it is thought to be stimulated by vasoconstriction or microvascular injury provoked by cold exposure. Furthermore, hypergammaglobulinemia and the presence of autoantibodies may contribute to the pathogenesis by increasing blood viscosity.¹ The familial form is caused by heterozygous mutations in either TREX1, a gene encoding the 3′ to 5′ repair exonuclease 1, or SAMHD1, the gene encoding for SAM domain and HD domain 1. TREX1 is an intracellular deoxyribonuclease that has specificity for single-stranded DNA. It is hypothesized that a deficiency in TREX1 leads to the accumulation of nucleic acids, which activate innate immune sensors and lead to a type I interferon response that favors the development of autoimmunity.⁵

Several drugs including thiazides, terbinafine, calcium channel blockers, angiotensin-converting enzyme inhibitors, and chemotherapeutic agents have been reported to trigger CHLE.⁴ Tumor necrosis factor α inhibitors have been shown to precipitate CHLE.⁶ Of note, drug-induced CHLE usually is limited to the skin and has not been shown to progress to SLE.⁶ Lebeau et al⁴ described a patient with breast cancer and preexisting CHLE that flared while the patient received docetaxel therapy, suggesting that certain drugs may not only induce but also may aggravate CHLE.

Many of the therapies that are effective in SLE such as antimalarial agents (ie, chloroquine, hydroxychloroquine) often are less efficacious in treating the lesions of CHLE.¹ However, these patients often can be managed successfully by physical protection from the cold environment.¹ Calcium channel blockers such as nifedipine also have been implicated, as they counteract vasoconstriction, which is thought to contribute to the pathogenesis of CHLE.¹ Topical and systemic steroids also have been used to treat CHLE. Dapsone and pentoxifylline are other treatment modalities that have been effective in select cases of CHLE.⁵ Boehm and Bieber⁷ reported near resolution of CHLE with mycophenolate mofetil in an elderly woman with skin lesions that had been refractory to systemic steroids, antimalarial agents, azathioprine, dapsone, and pentoxifylline, suggesting that mycophenolate mofetil may be a therapeutic option for recalcitrant cases of CHLE. Local immunosuppressive agents such as tacrolimus also can be considered in treatment-refractory disease.

Chilblain lupus erythematosus is a rare chronic form of CLE that typically occurs sporadically but also has a familial form that has been described in several families. It most commonly is observed in middle-aged women, but we describe a case in a young man. Although CHLE typically does not respond well to traditional lupus therapies used in the management of SLE, good effects have been observed with cold avoidance, calcium channel blockers, and topical or oral steroids. For treatment-refractory cases, mycophenolate mofetil and other immunosuppressive agents have been shown to be effective.

To the Editor:

A 20-year-old man with no notable medical history presented to our dermatology clinic for evaluation of mildly painful, hemorrhagic bullae on the bilateral halluces of 1 month’s duration. On initial presentation the patient reported the lesions developed after wearing a new pair of tight-fitting shoes, suggesting a diagnosis of trauma-induced bullae. The patient was instructed to wear loose-fitting shoes and to follow up in 6 weeks to assess for improvement. At follow-up the bullae had resolved with residual violaceous patches on the bilateral distal halluces. He additionally developed a faint retiform erythematous patch on the left distal toe (Figure 1). The patient also had reticulate erythematous patches on the dorsal aspects of the hands extending to the forearms and legs resembling livedo reticularis. The patient was unsure if the skin lesions were triggered or worsened by cold exposure and reported that he smoked half a pack of cigarettes daily. At this time, the differential diagnosis still included trauma; however, there was concern for either embolic, thrombotic, or connective-tissue disease. A 4-mm punch biopsy of the left distal hallux demonstrated basal vacuolar interface dermatitis with superficial and deep perivascular inflammation and deep periadnexal mucin deposition (Figure 2) consistent with lupus dermatitis.

Serologic workup revealed increased antinuclear antibody titers of 1:320 (reference range, <1:40) and anti-Ro/Sjögren syndrome antigen antibodies of 86 (reference range, <20). There was no elevation in anti–double-stranded DNA, anti-Smith, antiribonucleoprotein, or anticardiolipin antibodies. Complement levels also were within reference range. Furthermore, the patient denied a history of Raynaud phenomenon, photosensitivity, oral ulcers, joint pain, shortness of breath, pleuritic chest pain, arthritis, blood clots, or any other systemic symptoms. Additional evaluation by the rheumatology department did not support criteria for systemic lupus erythematosus (SLE). In the context of the clinical presentation, histologic findings, and serologic markers, a diagnosis of chilblain lupus erythematosus (CHLE) was made. He was counseled on sun protection and smoking cessation and declined systemic therapy citing concern for side effects. Follow-up with the dermatology and rheumatology departments was advised.

Cutaneous lupus erythematosus (CLE) comprises various forms of lupus, including acute cutaneous lupus, subacute cutaneous lupus, and chronic cutaneous lupus. Chilblain lupus erythematosus is a rare subset of chronic CLE that first was described in 1888¹ and is characterized by tender violaceous papules and plaques that typically present in an acral distribution (ie, fingers, toes, nose, cheeks, ears). The skin lesions often are triggered or exacerbated by cold temperatures and dampness. As the lesions evolve, they can ulcerate, fissure, become hyperkeratotic, or result in atrophic plaques with scarring.^2,3 A subset of patients also may have concurrent Raynaud phenomenon.¹ Up to 20% of patients will eventually develop SLE, especially those patients with concurrent discoid lupus erythematosus, warranting close long-term follow-up.³ Serologic studies can reveal antinuclear antibodies, anti-Ro/Sjögren syndrome antigen antibodies, rheumatic factor, and anti–double-stranded DNA antibodies.^1,4 Hypergammaglobulinemia also is a common finding in patients with CHLE, affecting more than two-thirds of patients.¹ Typical features of CHLE seen on histopathology include interface dermatitis, perivascular lymphocytic infiltrate, apoptotic keratinocytes, lichenoid tissue reaction, and increased dermal mucin.^1,4

Chilblain lupus erythematosus most commonly presents sporadically; however, there is a familial form that has been previously described.⁵ Sporadic CHLE usually occurs in middle-aged females, in contrast to familial CHLE, which presents in early childhood.¹ The pathogenesis of the sporadic form is poorly understood, but it is thought to be stimulated by vasoconstriction or microvascular injury provoked by cold exposure. Furthermore, hypergammaglobulinemia and the presence of autoantibodies may contribute to the pathogenesis by increasing blood viscosity.¹ The familial form is caused by heterozygous mutations in either TREX1, a gene encoding the 3′ to 5′ repair exonuclease 1, or SAMHD1, the gene encoding for SAM domain and HD domain 1. TREX1 is an intracellular deoxyribonuclease that has specificity for single-stranded DNA. It is hypothesized that a deficiency in TREX1 leads to the accumulation of nucleic acids, which activate innate immune sensors and lead to a type I interferon response that favors the development of autoimmunity.⁵

Several drugs including thiazides, terbinafine, calcium channel blockers, angiotensin-converting enzyme inhibitors, and chemotherapeutic agents have been reported to trigger CHLE.⁴ Tumor necrosis factor α inhibitors have been shown to precipitate CHLE.⁶ Of note, drug-induced CHLE usually is limited to the skin and has not been shown to progress to SLE.⁶ Lebeau et al⁴ described a patient with breast cancer and preexisting CHLE that flared while the patient received docetaxel therapy, suggesting that certain drugs may not only induce but also may aggravate CHLE.

Many of the therapies that are effective in SLE such as antimalarial agents (ie, chloroquine, hydroxychloroquine) often are less efficacious in treating the lesions of CHLE.¹ However, these patients often can be managed successfully by physical protection from the cold environment.¹ Calcium channel blockers such as nifedipine also have been implicated, as they counteract vasoconstriction, which is thought to contribute to the pathogenesis of CHLE.¹ Topical and systemic steroids also have been used to treat CHLE. Dapsone and pentoxifylline are other treatment modalities that have been effective in select cases of CHLE.⁵ Boehm and Bieber⁷ reported near resolution of CHLE with mycophenolate mofetil in an elderly woman with skin lesions that had been refractory to systemic steroids, antimalarial agents, azathioprine, dapsone, and pentoxifylline, suggesting that mycophenolate mofetil may be a therapeutic option for recalcitrant cases of CHLE. Local immunosuppressive agents such as tacrolimus also can be considered in treatment-refractory disease.

Chilblain lupus erythematosus is a rare chronic form of CLE that typically occurs sporadically but also has a familial form that has been described in several families. It most commonly is observed in middle-aged women, but we describe a case in a young man. Although CHLE typically does not respond well to traditional lupus therapies used in the management of SLE, good effects have been observed with cold avoidance, calcium channel blockers, and topical or oral steroids. For treatment-refractory cases, mycophenolate mofetil and other immunosuppressive agents have been shown to be effective.

To the Editor:

A 20-year-old man with no notable medical history presented to our dermatology clinic for evaluation of mildly painful, hemorrhagic bullae on the bilateral halluces of 1 month’s duration. On initial presentation the patient reported the lesions developed after wearing a new pair of tight-fitting shoes, suggesting a diagnosis of trauma-induced bullae. The patient was instructed to wear loose-fitting shoes and to follow up in 6 weeks to assess for improvement. At follow-up the bullae had resolved with residual violaceous patches on the bilateral distal halluces. He additionally developed a faint retiform erythematous patch on the left distal toe (Figure 1). The patient also had reticulate erythematous patches on the dorsal aspects of the hands extending to the forearms and legs resembling livedo reticularis. The patient was unsure if the skin lesions were triggered or worsened by cold exposure and reported that he smoked half a pack of cigarettes daily. At this time, the differential diagnosis still included trauma; however, there was concern for either embolic, thrombotic, or connective-tissue disease. A 4-mm punch biopsy of the left distal hallux demonstrated basal vacuolar interface dermatitis with superficial and deep perivascular inflammation and deep periadnexal mucin deposition (Figure 2) consistent with lupus dermatitis.

Serologic workup revealed increased antinuclear antibody titers of 1:320 (reference range, <1:40) and anti-Ro/Sjögren syndrome antigen antibodies of 86 (reference range, <20). There was no elevation in anti–double-stranded DNA, anti-Smith, antiribonucleoprotein, or anticardiolipin antibodies. Complement levels also were within reference range. Furthermore, the patient denied a history of Raynaud phenomenon, photosensitivity, oral ulcers, joint pain, shortness of breath, pleuritic chest pain, arthritis, blood clots, or any other systemic symptoms. Additional evaluation by the rheumatology department did not support criteria for systemic lupus erythematosus (SLE). In the context of the clinical presentation, histologic findings, and serologic markers, a diagnosis of chilblain lupus erythematosus (CHLE) was made. He was counseled on sun protection and smoking cessation and declined systemic therapy citing concern for side effects. Follow-up with the dermatology and rheumatology departments was advised.

Cutaneous lupus erythematosus (CLE) comprises various forms of lupus, including acute cutaneous lupus, subacute cutaneous lupus, and chronic cutaneous lupus. Chilblain lupus erythematosus is a rare subset of chronic CLE that first was described in 1888¹ and is characterized by tender violaceous papules and plaques that typically present in an acral distribution (ie, fingers, toes, nose, cheeks, ears). The skin lesions often are triggered or exacerbated by cold temperatures and dampness. As the lesions evolve, they can ulcerate, fissure, become hyperkeratotic, or result in atrophic plaques with scarring.^2,3 A subset of patients also may have concurrent Raynaud phenomenon.¹ Up to 20% of patients will eventually develop SLE, especially those patients with concurrent discoid lupus erythematosus, warranting close long-term follow-up.³ Serologic studies can reveal antinuclear antibodies, anti-Ro/Sjögren syndrome antigen antibodies, rheumatic factor, and anti–double-stranded DNA antibodies.^1,4 Hypergammaglobulinemia also is a common finding in patients with CHLE, affecting more than two-thirds of patients.¹ Typical features of CHLE seen on histopathology include interface dermatitis, perivascular lymphocytic infiltrate, apoptotic keratinocytes, lichenoid tissue reaction, and increased dermal mucin.^1,4

Chilblain lupus erythematosus most commonly presents sporadically; however, there is a familial form that has been previously described.⁵ Sporadic CHLE usually occurs in middle-aged females, in contrast to familial CHLE, which presents in early childhood.¹ The pathogenesis of the sporadic form is poorly understood, but it is thought to be stimulated by vasoconstriction or microvascular injury provoked by cold exposure. Furthermore, hypergammaglobulinemia and the presence of autoantibodies may contribute to the pathogenesis by increasing blood viscosity.¹ The familial form is caused by heterozygous mutations in either TREX1, a gene encoding the 3′ to 5′ repair exonuclease 1, or SAMHD1, the gene encoding for SAM domain and HD domain 1. TREX1 is an intracellular deoxyribonuclease that has specificity for single-stranded DNA. It is hypothesized that a deficiency in TREX1 leads to the accumulation of nucleic acids, which activate innate immune sensors and lead to a type I interferon response that favors the development of autoimmunity.⁵

Several drugs including thiazides, terbinafine, calcium channel blockers, angiotensin-converting enzyme inhibitors, and chemotherapeutic agents have been reported to trigger CHLE.⁴ Tumor necrosis factor α inhibitors have been shown to precipitate CHLE.⁶ Of note, drug-induced CHLE usually is limited to the skin and has not been shown to progress to SLE.⁶ Lebeau et al⁴ described a patient with breast cancer and preexisting CHLE that flared while the patient received docetaxel therapy, suggesting that certain drugs may not only induce but also may aggravate CHLE.

Many of the therapies that are effective in SLE such as antimalarial agents (ie, chloroquine, hydroxychloroquine) often are less efficacious in treating the lesions of CHLE.¹ However, these patients often can be managed successfully by physical protection from the cold environment.¹ Calcium channel blockers such as nifedipine also have been implicated, as they counteract vasoconstriction, which is thought to contribute to the pathogenesis of CHLE.¹ Topical and systemic steroids also have been used to treat CHLE. Dapsone and pentoxifylline are other treatment modalities that have been effective in select cases of CHLE.⁵ Boehm and Bieber⁷ reported near resolution of CHLE with mycophenolate mofetil in an elderly woman with skin lesions that had been refractory to systemic steroids, antimalarial agents, azathioprine, dapsone, and pentoxifylline, suggesting that mycophenolate mofetil may be a therapeutic option for recalcitrant cases of CHLE. Local immunosuppressive agents such as tacrolimus also can be considered in treatment-refractory disease.

Chilblain lupus erythematosus is a rare chronic form of CLE that typically occurs sporadically but also has a familial form that has been described in several families. It most commonly is observed in middle-aged women, but we describe a case in a young man. Although CHLE typically does not respond well to traditional lupus therapies used in the management of SLE, good effects have been observed with cold avoidance, calcium channel blockers, and topical or oral steroids. For treatment-refractory cases, mycophenolate mofetil and other immunosuppressive agents have been shown to be effective.

To the Editor:

A 46-year-old man presented with multiple tense bullae and denuded patches on the palms (Figure 1A) and soles (Figure 1B). The blisters first appeared 2 months prior to presentation, shortly after he was diagnosed with stage IVB mantle cell lymphoma, and waxed and waned in intensity since then. He denied antecedent trauma or friction and reported that all sites were painful. He had no family or personal history of blistering disorders.

The mantle cell lymphoma initially was treated with 4 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy more than 2.5 years prior to the current presentation, which resulted in partial remission, followed by R-ICE (rituximab, ifosfamide, carboplatin, etoposide) therapy as well as autologous stem cell transplantation; complete remission was achieved. His recovery was complicated by a necrotic small bowel leading to resection. Eighteen months following the second course of chemotherapy, a mass was noted on the neck; biopsy performed by an outside dermatologist revealed mantle cell lymphoma.

Punch biopsy revealed a subepidermal bulla. Six weeks later, biopsy of a newly developed hand lesion performed at our office revealed a subepidermal cleft with minimal dermal infiltrate (Figure 2). Direct immunofluorescence was negative for immunoglobulin and complement deposition. Porphyrin elevation was not detected with a 24-hour urine assay. New lesions were drained and injected with triamcinolone, which appeared to hasten healing.

Mantle cell lymphoma is a distinct lymphoproliferative disorder of B cells that represents less than 7% of non-Hodgkin lymphoma cases.¹ The tumor cells originate in the mantle zone of the lymph nodes. Most patients present with advanced disease involving lymph nodes and other organs. The disease is characterized by male predominance and an aggressive course with a median overall survival of less than 5 years.¹

Epidermolysis bullosa acquisita is a rare blistering disease that usually develops in adulthood. It is a subepidermal disorder characterized by the appearance of fragile tense bullae. Epidermolysis bullosa acquisita can be divided into 2 subtypes: inflammatory and mechanobullous (classic EBA).² Inflammatory EBA presents similarly to bullous pemphigoid and other subepithelial autoimmune blistering diseases. Vesiculobullous lesions predominate on the trunk and extremities and often are accompanied by intense pruritus. The less common mechanobullous noninflammatory subtype, illustrated in our case, presents in trauma-prone areas with skin fragility and tense noninflamed vesicles and bullae that rupture leaving erosions. Associated findings may include milia and scarring. Lesions appear in areas exposed to friction and trauma such as the hands, feet, elbows, knees, and lower back. The differential diagnosis includes dystrophic epidermolysis bullosa, porphyria cutanea tarda, and pseudoporphyria. Dystrophic epidermolysis bullosa is ruled out by family history and disease onset at birth. The lesions of porphyria cutanea tarda and pseudoporphyria occur on sun-exposed areas; porphyrin levels are elevated in the former. Direct immunofluorescence of a perilesional EBA site usually reveals IgG deposition.³ Negative direct immunofluorescence in our case could have resulted from technical error, sample location, or response to systemic immunosuppressive treatment.⁴

Epidermolysis bullosa acquisita is caused by autoantibodies against type VII collagen.^2,3 After the autoantibodies bind, a complement cascade reaction is activated, leading to deposition of C3a and C5a, which recruit leukocytes and mast cells. The anchoring fibrils in the basement membrane zones of the skin and mucosa are disrupted.^5,6 Injection of anti–type VII collagen antibodies into mice induces a blistering disease resembling EBA.⁷ In a study of 14 patients with EBA, disease severity was correlated to levels of anticollagen autoantibodies measured by enzyme-linked immunosorbent assay.⁸

Epidermolysis bullosa acquisita has been linked to Crohn disease and approximately 30% of EBA cases occur in patients with this disease.^9,10 Two case reports document an association with multiple myeloma.^11,12 Treatment often proves challenging and unsatisfactory; valid controlled clinical trials are impossible given the paucity of cases. Successful therapeutic outcomes have been reported with oral prednisone,¹³ colchicine,¹⁴ cyclosporine,¹⁵ dapsone,¹⁶ and rituximab.¹⁷ Our patient received 2 separate courses of rituximab as part of chemotherapy for mantle cell lymphoma without measurable improvement. He was lost to follow-up after recurrence of the lymphoma and we learned from his wife that he had died.

To the Editor:

A 46-year-old man presented with multiple tense bullae and denuded patches on the palms (Figure 1A) and soles (Figure 1B). The blisters first appeared 2 months prior to presentation, shortly after he was diagnosed with stage IVB mantle cell lymphoma, and waxed and waned in intensity since then. He denied antecedent trauma or friction and reported that all sites were painful. He had no family or personal history of blistering disorders.

The mantle cell lymphoma initially was treated with 4 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy more than 2.5 years prior to the current presentation, which resulted in partial remission, followed by R-ICE (rituximab, ifosfamide, carboplatin, etoposide) therapy as well as autologous stem cell transplantation; complete remission was achieved. His recovery was complicated by a necrotic small bowel leading to resection. Eighteen months following the second course of chemotherapy, a mass was noted on the neck; biopsy performed by an outside dermatologist revealed mantle cell lymphoma.

Punch biopsy revealed a subepidermal bulla. Six weeks later, biopsy of a newly developed hand lesion performed at our office revealed a subepidermal cleft with minimal dermal infiltrate (Figure 2). Direct immunofluorescence was negative for immunoglobulin and complement deposition. Porphyrin elevation was not detected with a 24-hour urine assay. New lesions were drained and injected with triamcinolone, which appeared to hasten healing.

Mantle cell lymphoma is a distinct lymphoproliferative disorder of B cells that represents less than 7% of non-Hodgkin lymphoma cases.¹ The tumor cells originate in the mantle zone of the lymph nodes. Most patients present with advanced disease involving lymph nodes and other organs. The disease is characterized by male predominance and an aggressive course with a median overall survival of less than 5 years.¹

Epidermolysis bullosa acquisita is a rare blistering disease that usually develops in adulthood. It is a subepidermal disorder characterized by the appearance of fragile tense bullae. Epidermolysis bullosa acquisita can be divided into 2 subtypes: inflammatory and mechanobullous (classic EBA).² Inflammatory EBA presents similarly to bullous pemphigoid and other subepithelial autoimmune blistering diseases. Vesiculobullous lesions predominate on the trunk and extremities and often are accompanied by intense pruritus. The less common mechanobullous noninflammatory subtype, illustrated in our case, presents in trauma-prone areas with skin fragility and tense noninflamed vesicles and bullae that rupture leaving erosions. Associated findings may include milia and scarring. Lesions appear in areas exposed to friction and trauma such as the hands, feet, elbows, knees, and lower back. The differential diagnosis includes dystrophic epidermolysis bullosa, porphyria cutanea tarda, and pseudoporphyria. Dystrophic epidermolysis bullosa is ruled out by family history and disease onset at birth. The lesions of porphyria cutanea tarda and pseudoporphyria occur on sun-exposed areas; porphyrin levels are elevated in the former. Direct immunofluorescence of a perilesional EBA site usually reveals IgG deposition.³ Negative direct immunofluorescence in our case could have resulted from technical error, sample location, or response to systemic immunosuppressive treatment.⁴

Epidermolysis bullosa acquisita is caused by autoantibodies against type VII collagen.^2,3 After the autoantibodies bind, a complement cascade reaction is activated, leading to deposition of C3a and C5a, which recruit leukocytes and mast cells. The anchoring fibrils in the basement membrane zones of the skin and mucosa are disrupted.^5,6 Injection of anti–type VII collagen antibodies into mice induces a blistering disease resembling EBA.⁷ In a study of 14 patients with EBA, disease severity was correlated to levels of anticollagen autoantibodies measured by enzyme-linked immunosorbent assay.⁸

Epidermolysis bullosa acquisita has been linked to Crohn disease and approximately 30% of EBA cases occur in patients with this disease.^9,10 Two case reports document an association with multiple myeloma.^11,12 Treatment often proves challenging and unsatisfactory; valid controlled clinical trials are impossible given the paucity of cases. Successful therapeutic outcomes have been reported with oral prednisone,¹³ colchicine,¹⁴ cyclosporine,¹⁵ dapsone,¹⁶ and rituximab.¹⁷ Our patient received 2 separate courses of rituximab as part of chemotherapy for mantle cell lymphoma without measurable improvement. He was lost to follow-up after recurrence of the lymphoma and we learned from his wife that he had died.

To the Editor:

A 46-year-old man presented with multiple tense bullae and denuded patches on the palms (Figure 1A) and soles (Figure 1B). The blisters first appeared 2 months prior to presentation, shortly after he was diagnosed with stage IVB mantle cell lymphoma, and waxed and waned in intensity since then. He denied antecedent trauma or friction and reported that all sites were painful. He had no family or personal history of blistering disorders.

The mantle cell lymphoma initially was treated with 4 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy more than 2.5 years prior to the current presentation, which resulted in partial remission, followed by R-ICE (rituximab, ifosfamide, carboplatin, etoposide) therapy as well as autologous stem cell transplantation; complete remission was achieved. His recovery was complicated by a necrotic small bowel leading to resection. Eighteen months following the second course of chemotherapy, a mass was noted on the neck; biopsy performed by an outside dermatologist revealed mantle cell lymphoma.

Punch biopsy revealed a subepidermal bulla. Six weeks later, biopsy of a newly developed hand lesion performed at our office revealed a subepidermal cleft with minimal dermal infiltrate (Figure 2). Direct immunofluorescence was negative for immunoglobulin and complement deposition. Porphyrin elevation was not detected with a 24-hour urine assay. New lesions were drained and injected with triamcinolone, which appeared to hasten healing.

Mantle cell lymphoma is a distinct lymphoproliferative disorder of B cells that represents less than 7% of non-Hodgkin lymphoma cases.¹ The tumor cells originate in the mantle zone of the lymph nodes. Most patients present with advanced disease involving lymph nodes and other organs. The disease is characterized by male predominance and an aggressive course with a median overall survival of less than 5 years.¹

Epidermolysis bullosa acquisita is a rare blistering disease that usually develops in adulthood. It is a subepidermal disorder characterized by the appearance of fragile tense bullae. Epidermolysis bullosa acquisita can be divided into 2 subtypes: inflammatory and mechanobullous (classic EBA).² Inflammatory EBA presents similarly to bullous pemphigoid and other subepithelial autoimmune blistering diseases. Vesiculobullous lesions predominate on the trunk and extremities and often are accompanied by intense pruritus. The less common mechanobullous noninflammatory subtype, illustrated in our case, presents in trauma-prone areas with skin fragility and tense noninflamed vesicles and bullae that rupture leaving erosions. Associated findings may include milia and scarring. Lesions appear in areas exposed to friction and trauma such as the hands, feet, elbows, knees, and lower back. The differential diagnosis includes dystrophic epidermolysis bullosa, porphyria cutanea tarda, and pseudoporphyria. Dystrophic epidermolysis bullosa is ruled out by family history and disease onset at birth. The lesions of porphyria cutanea tarda and pseudoporphyria occur on sun-exposed areas; porphyrin levels are elevated in the former. Direct immunofluorescence of a perilesional EBA site usually reveals IgG deposition.³ Negative direct immunofluorescence in our case could have resulted from technical error, sample location, or response to systemic immunosuppressive treatment.⁴

Epidermolysis bullosa acquisita is caused by autoantibodies against type VII collagen.^2,3 After the autoantibodies bind, a complement cascade reaction is activated, leading to deposition of C3a and C5a, which recruit leukocytes and mast cells. The anchoring fibrils in the basement membrane zones of the skin and mucosa are disrupted.^5,6 Injection of anti–type VII collagen antibodies into mice induces a blistering disease resembling EBA.⁷ In a study of 14 patients with EBA, disease severity was correlated to levels of anticollagen autoantibodies measured by enzyme-linked immunosorbent assay.⁸

Epidermolysis bullosa acquisita has been linked to Crohn disease and approximately 30% of EBA cases occur in patients with this disease.^9,10 Two case reports document an association with multiple myeloma.^11,12 Treatment often proves challenging and unsatisfactory; valid controlled clinical trials are impossible given the paucity of cases. Successful therapeutic outcomes have been reported with oral prednisone,¹³ colchicine,¹⁴ cyclosporine,¹⁵ dapsone,¹⁶ and rituximab.¹⁷ Our patient received 2 separate courses of rituximab as part of chemotherapy for mantle cell lymphoma without measurable improvement. He was lost to follow-up after recurrence of the lymphoma and we learned from his wife that he had died.